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CONTROVERSIES IN TREATING DIABETES
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CONTROVERSIES
IN TREATING DIABETES
Clinical
and Research Aspects
Edited by
Derek LeRoith, md, phd

Division of Endocrinology, Diabetes, and Bone Disease, Department
of Medicine, Mount Sinai School of Medicine, New York, NY
Aaron I. Vinik, md, phd,

fcp, facp
Diabetes Research Institute, Department of Medicine, Eastern Virginia
Medical School, The Leonard Strelitz Diabetes Institutes, Norfolk, VA
Editors
Derek LeRoith
Division of Endocrinology, Diabetes,
and Bone Disease
Department of Medicine
Mount Sinai School of Medicine
New York, NY
Aaron I. Vinik
Diabetes Research Institute
Department of Medicine
Eastern Virginia Medical School
The Leonard Strelitz Diabetes Institutes
Norfolk, VA
Series Editor
P. Michael Conn
Oregon Health & Science University
Beaverton, OR
ISBN: 978-1-58829-708-2
e-ISBN: 978-1-59745-572-5
Library of Congress Control Number: 2007933146

2008 Humana Press, a part of Springer Science+Business Media, LLC
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Preface
Undoubtedly, there is a worldwide epidemic of obesity, the metabolic
syndrome and type 2 diabetes, and with these changes comes controversy!
What is the cause of the obesity epidemic? Is the increase in type 2 diabetes
caused by obesity alone or are there other factors involved, such as genetics?
Is the metabolic syndrome truly a syndrome or merely a grouping of risk
factors for cardiovascular disease? How do we effectively prevent and treat
the epidemics of obesity, diabetes, and their devastating complications? This
book is a compilation of discussions by world experts on these topics. Each
chapter was chosen to cover many of the issues that investigators, academics,
and healthcare professionals have to deal with in their institutions and private
practice.
Stress and dietary excess are presented by Rena Wing, and the explosion
of childhood obesity is discussed by Desmond Schatz. On the other hand,
treatments for obesity, metabolic syndrome, and hyperlipidemia are discussed
separately by Drs Kaplan, Meigs, and Goldberg, respectively; very practical
approaches are presented. The treatment of type 2 diabetes and the anticipation that this would prevent complications are discussed by Vivian Fonseca.
Julio Rosenstock presents the case for earlier introduction of insulin in the
armamentarium for treating type 2 diabetics. Werner Walthausal presents the
pros and cons for a polypill that potentially should improve patient compliance.
Incretins are the "new kid on the block" with regard to therapeutic agents
and are discussed by Jens Holst. The exciting new concept for hospitalized
diabetics (and hyperglycemic nondiabetics) is the use of intensive insulin
therapy to manage the hyperglycemia more effectively and reduce mortality
and morbidity. This is discussed by Greet van den Berghe, who pioneered the
studies.
The underlying mechanisms involved in diabetic complications are summarized by Michael Brownlee and the prevention and treatment of retinopathy
and neuropathy is discussed in the chapters by Emily Chew and Aaron Vinik.
An important therapeutic area is transplantation. Usually the pancreas is transplanted simultaneously with the kidney once end-stage renal disease requires a
kidney transplant. This has generally been shown to help in the control of the
diabetes and to protect further complications and damage to vital organs. David
Sutherland discusses whether pancreatic transplantation should be performed
v
vi
Preface
in the absence of a need for renal transplantation; this is a controversial issue

indeed! Another relatively controversial aspect of diabetes management is islet
transplantation and David Harlan discusses this important topic in his chapter.
Finally, a critical aspect of patient care is improving quality of life, and for
diabetics with such a chronic disorder, this is no less important than all the
other aspects discussed in this book! This topic is discussed to Richard Rubin,
an expert in this field!
The editors are indebted to the authors who have taken time from their
busy schedules to help compile Controversies in Treating Diabetes: Clinical
and Research Aspects with such important topics. We hope the readers feel
likewise.
Derek LeRoith
Aaron I. Vinik
Contents
Preface .....................................................................................
Contributors ............................................................................
v
ix
1 Pancreas Transplantation: Should They be Reserved for

Simultaneous Renal Transplants? .................................
David E. R. Sutherland and Angelika C. Gruessner
2 Islet Cell Transplantation: How Effective Is It? .............. 11

Eric H. Liu and David M. Harlan
3 Metabolic Syndrome: Is There Treatment that Works? .. 33
James B. Meigs
4 Intensive Treatment and Complications of Diabetes:
Can They Be Effectively Reduced? ............................... 51
Vivian Fonseca and Ali Jawa
5 Treatment of Type 2 Using Insulin: When to Introduce? 69
Julio Rosenstock and David Owens
6 Diabetic Retinopathy: Can it be Prevented? ................... 95
Emily Y. Chew
7 Diabetic Neuropathies: Evaluation, Management
and Controversies in Treatment Options ...................... 109
Aaron I. Vinik
8 Diabetic Neuropathies: Endpoints in Clinical
Research Studies ............................................................ 135
Aaron I. Vinik
9 Intensive Insulin Therapy for the Critically Ill Patient ... 157
Ilse Vanhorebeek and Greet Van den Berghe
10 Childhood Diabetes Explosion ......................................... 179
Michael S. Stalvey and Desmond A. Schatz
vii
viii
Contents
11 Weight Loss in Type 2 Diabetic Patients:

Is it Worth the Effort? ................................................... 201
Rena R. Wing, Heather M. Niemeier,
and Angela Marinilli Pinto
12 Unifying Hypothesis of Diabetic Complications ............. 233
Takeshi Matsumura and Michael Brownlee
13 The Diabetic Foot ............................................................. 251
Andrew J. M. Boulton
14 Coming of Age for the Incretins ...................................... 269
Jens Juul Holst and Carolyn F. Deacon
15 Controversies in Evaluation and Management of Lipid
Disorders in Diabetes ..................................................... 291
Ronald B. Goldberg
16 Polypills for Treatment of Type 2 Diabetes:
Is the Concept of Polypharmacy Correct? ................... 317
Werner Waldhusl
17 Comorbid Depression and Diabetes:
Natural History and Clinical Aspects ........................... 331
Richard R. Rubin
Index ........................................................................................ 353
Contributors
Andrew J. M. Boulton, md, dsc(hons), frpc Professor of Medicine,
Manchester Royal Infirmary, Manchester, United Kingdom
Michael Brownlee, md Professor of Medicine, Albert Einstein College of
Medicine, Jack and Pearl Resnick Campus, Morris Park Avenue,
Bronx, NY
Emily Y. Chew, md Deputy Director, Division of Epidemiology and
Clinical Research, National Eye Institute Health, Bethesda, MD
Carolyn F. Deacon, dr. med sci Associate Professor, University of
Copenhagen, Department of Medical Physiology, The Panum Institute,
Copenhagen, Denmark
Vivian Fonseca, md, frcp Professor of Medicine and Pharmacology,
Chief of the Section of Endocrinology, Tulane University Health Sciences
Center, New Orleans, LA
Ronald B. Goldberg, md Professor of Medicine, Miller School
of Medicine, University of Miami, Miami, FL
Angelika C. Gruessner, phd University of Minnesota, Minneapolis, MN
David M. Harlan, md, niddk Chief, Islet and Autoimmunity Branch,
National Institutes of Health, Bethesda, MD
Jens, Juul Holst, md Professor of Medical Physiology, Department
of Medical Physiology, The Panum Institute, University of Copenhagen,
Copenhagen, Denmark
Ali Jawa, md King Edward Medical College, Mayo Hospital EMW,
Lahore, Pakistan
L. M. Kaplan, md MGH Weight Center, Massachusetts General Hospital,
Boston, MA
Derek LeRoith, md, phd Division of Endocrinology, Diabetes, and Bone
Disease, Department of Medicine, Mount Sinai School of Medicine,
New York, NY
Eric H. Liu, md Diabetes Branch, National Institute of Diabetes and
Digestive and Kidney, Diseases, Bethesda, MD
Takeshi Matsumura, md Diabetes Research Center, Albert Einstein
College of Medicine, Bronx, NY
James B. Meigs, md, mph Department of Medicine, General Medicine
Division, Massachusetts General Hospital, Harvard Medical School,
Boston, MA
ix
Contributors
Heather M. Niemeier, phd Brown Medical School, The Miriam Hospital,

Providence, RI
David Owens, cbe, md Diabetes Research Unit, University of Wales
College of Medicine, Llandough Hospital, Cardiff, Wales
Angela Marinilli Pinto, phd Brown Medical School, The Miriam
Hospital, Providence, RI
Julio Rosenstock, md Dallas Diabetes & Endocrine Center at Medical
City, Dallas, TX
Richard R. Rubin, md Department of Medicine, John Hopkins University,
Monkton, MD
Desmond A. Schatz, md Associate Chairman of Pediatrics, Medical
Director of the Diabetes Center, University of Florida, Gainesville, FL
Michael S. Stalvey, md Division of Pediatric Endocrinology,
Department of Pediatrics, University of Florida, Gainsenller, FL
David E. R. Sutherland, md, phd Professor, General & Transplant
Surgery, Chief, Division of Transplantation Director, Diabetes Institute
for Immunology and Transplantation, University of Minnesota,
Minneapolis, MN
Greet Van den Berghe, md, phd Department of Intensive Care Medicine,
Catholic University of Leuven, Leuven, Belgium
Ilse Vanhorebeek, phd Department of Intensive Care Medicine, Catholic
University of Leuven, Leuven, Belgium
Aaron I. Vinik, md, phd, fcp, facp Director, Diabetes Research Institute,
Scientific Director, Department of Medicine, Professor of Medicine,
Eastern Virginia Medical School, The Leonard Strelitz Diabetes Institutes,
Norfolk, VA
Werner Waldhusl, md Professor of Internal Medicine, Department of
Medicine III, Division of Endocrinology & Metabolism, Medical University
of Vienna, Vienna, Austria
Rena R. Wing, phd Professor, Department of Psychiatry & Human
Behavior, Brown Medical School, The Miriam Hospital, Providence, RI
Pancreas Transplantation
Should They be Reserved for Simultaneous
Renal Transplants?
David E. R. Sutherland, MD, PHD

and Angelika C. Gruessner, PHD
CONTENTS
Pancreas Transplantation: Should They
Be Reserved for Simultaneous Renal
Transplants?
References
Summary
In summary, solitary pancreas transplants (alone in non-uremicsPTA;
or after a kidneyPAK) should be done, as well as simultaneous pancreaskidney (SPK) transplants in uremic diabetics who cannot get a kidney transplant first (to preempt or shorten the time on dialysis). The approach depends
on the recipient candidate characteristics and on living or deceased donor
availability and suitability. It is regressive to restrict pancreas transplants
to just the uremic population, and in this restricted population to just those
who cannot get an early kidney transplant to preempt the dialysis that would
otherwise be necessary while waiting for both organs from a deceased donor.
For the uremic diabetic in centers where there is a long wait time for a
deceased donor SPK transplants (because of kidney allocation policies), the
best option is a living donor kidney followed by a pancreas transplant; a living
donor eliminates waiting for a kidney, and the waiting time for a solitary
pancreas at present is relatively short. The patient survival rates are high
after either PTA, PAK or SPK transplants, at 3 years 93%, 90% and 91%
respectively, with corresponding graft survival (insulin-independence) rates
From: Contemporary Endocrinology: Controversies in Treating Diabetes:
Clinical and Research Aspects
Edited by: D. LeRoith and A. I. Vinik Humana Press, Totowa, NJ
Sutherland and Gruessner
of 60%, 66% and 78%, respectively. Even though pancreas graft survival
rates are higher after SPK transplants, the gain in patient survival rates by
doing a preemptive kidney transplant more than offsets the lower insulinindependence rates after a PAK. The outcomes justify the continuance of
pancreas transplants in all three categories of recipients, with nearly all nephropathic diabetics being PAK or SPK candidates (since immunosuppression
will be obligatory for a kidney transplant), and selected non-uremic diabetics,
particularly those with hypoglycemic unawareness, being candidates for a PTA.
Key Words: Pancreas, transplant, insulin-independence
PANCREAS TRANSPLANTATION: SHOULD THEY BE

RESERVED FOR SIMULTANEOUS RENAL TRANSPLANTS?
The answer is no. Pancreas transplants are currently done in three recipient
categories, and that practice should continue:
1. Pancreas transplants alone (PTA) in diabetic patients without advanced
nephropathy but who have problems that justify the use of immunosuppression to achieve insulin independence, the main one being hypoglycemic
unawareness (1).
2. Pancreas after kidney (PAK) transplants, done in patients with diabetic
nephropathy. The majority receive a living donor (LD) kidney to preempt
or remove the need for dialysis (2). Such patients are already obligated to
immunosuppression, and it is only the surgical risks that need to be considered.
If uremic diabetic patients were not offered the opportunity for a PAK but told
they could only get a pancreas as a simultaneous pancreas and kidney (SPK)
transplant, it would be a disincentive to perform an LD kidney transplant. Those
who opt for a deceased donor (DD) SPK versus an LD kidney transplant alone
(KTA) would have to go on a waiting list and accept the increased mortality
risk of dialysis versus a preemptive kidney transplant (3).
3. SPK transplants, most commonly done with organs from the same DD, in some
cases with both from an LD, and in others with the kidney from an LD and the
pancreas from a DD (4). Again, the recipient is obligated to immunosuppression
in lieu of the kidney, and there is no reason not to add a pancreas other than
the additional surgical risk. The main drawback to going on the list for a
same DD SPK transplant is the potential long waiting time and the need to go
on dialysis versus receiving a preemptive LD kidney transplant. Because the
wait time for a DD solitary pancreas transplant is relatively short (as opposed
to the wait time for a kidney), an LD kidney followed by a DD pancreas
will usually result in insulin-independence being achieved in the nephropathic
diabetic sooner than if one waits for an SPK. However, for uremic diabetics
without an LD for a kidney graft, an SPK transplant makes sense and in the
USA is associated with higher graft survival rate of the Kidney in SPK Kd
than in uremic diabetic recipients of a DD KTA (5). For 19952004 DD SPK
transplants in the USA, the kidney graft survival rates at 1, 3, and 5 years
were 92, 85, and 77%, respectively, versus 89, 77, and 65% for DD KTA
diabetic recipients (5). As PAK recipients have a functioning kidney at the time
of the pancreas transplant, the kidney graft survival rates are higher in PAK
recipients than in SPK recipients, but this is true even when adjustments are
made in the calculations to account for the attrition that would occur in PAK
candidates (6,7).
Except for the immediate surgical risks, the main drawback of a transplant
(allograft) of any kind is the need for immunosuppression and the side effects
(both immunosuppressive and non-immunosuppressive) of the antirejection
drugs.
Indeed, SPK and PAK recipients get two benefits for the price of immunosuppression: an insulin-independent, as well as a dialysis-free, state. The
benefits are the same whether both organs are transplanted simultaneously or
sequentially. The advantages of an SPK over a PAK transplant is placement
of both organs with one operation and, when both organs are from the same
donor, the ability to use kidney graft function to monitor for rejection episodes
that affect both organs, leading to slightly higher graft survival rate of the
Pancreas in SPK Px (85% at 1 year for 20002004 US cases) than for solitary
pancreas transplants (76% for PTA and 78% for PAK) (2), where monitoring
for rejection is more difficult (6). However, the advantages of an SPK may be
offset by the long waiting time for DD organs when the allocation is primarily
by the rules for kidney allocation, and the mortality rate in uremic candidates
waiting for an SPK transplant is much higher than in candidates waiting for
a PAK transplant who improved their survival probabilities already by having
an expeditious LD kidney transplant that preempted the need for or minimized
their time on dialysis (3,5,7).
Thus, one must ask the question as to why the question is asked, because
the current outcomes (of patient and graft survival rates) in all three categories
have to be considered good. Indeed, PTA recipients enjoy the highest patient
survival rate following transplantation compared with any other organ allograft
recipient groups (not only versus the other categories of pancreas transplants
but versus kidney, heart, and liver recipients as well), according to Port et al.
(8)91% at 5 years for PTA recipients done between 1998 and 2004, versus
81% for DD KTA and 90% for LD KTA recipients, 85% for PAK and 86%
for SPK recipients, and 73% for both liver and heart recipients.
However, there are no randomized trials of pancreas transplantation versus
exogenous insulin treatment in any of the categories, and even in the group with
simultaneous kidney and pancreas transplants, no randomized comparisons
have been done to kidney transplants alone. Thus, even though the graft
survival rates are higher for a pancreas with an SPK than the other categories,
the impact on patient survival or kidney graft survival of adding the pancreas
is technically not known. At least for SPK, it is clear that the relative risk
of dying while waiting for a transplant (usually while on dialysis) is higher
than that for those who actually receive an SPK transplant. For PAK and
PTA recipients, an analysis by Venstrom et al. (9) of the United Network for
Organ Sharing (UNOS) database suggested that the mortality hazard ratio was
slightly higher for PAK and PTA recipients than for those on the waiting list.
A subsequent analysis of the same cohort of patients as well as an updated
cohort by Gruessner et al. (10), correcting for the counting of patients twice
in the Venstrom analysis for those listed at more than one center and for the
inappropriate exclusions of patients based on creatinine criteria, showed the
hazard ratio for dying was higher for those on the PTA- and PAK-waiting lists
than for those who had been transplanted.
The most recent analyses by the International Pancreas Transplant Registry
of US cases in all three categories, as reported to the UNOS data base, support
the above points (2,10), and the highlights are summarized in detail. First,
despite the slightly higher pancreas graft survival rates in the SPK than in the
PAK and PTA categories, the number of transplants in the latter categories has
increased annually for the past decade, whereas the number of SPK transplants
has plateaued (Fig. 1). This change reflects the increased use of LD kidney
transplants to treat uremic diabetics who then go on to get a DD pancreas. Over
that same interval, the graft survival rates have also improved in all categories
but most dramatically in the PAK and PTA recipients (Fig. 2). Patient survival
1200
Number of Transplants
PTA
1000
PAK
SPK
800
600
400
200
0
06
20
04
20
02
20
00
20
98
19
96
19
94
19
92
19
90
19
88
19
Fig. 1. Annual number of US pancreas transplants by category, 19882005.
%
100
80
60
PAK
PTA
40
SPK Px
SPK Kd
20
1988 1990 1992 1994 1996 1998 2000 2002 2004
Fig. 2. Pancreas and simultaneous pancreas and kidney (SPK) kidney graft function for
19882005 US deceased donor (DD) primary pancreas transplants by recipient category.
rates were high in all categories during the entire decade, ranging from 90 to
98% at 1 year and from 80 to 90% at 5 years for the annual cohorts.
In an analysis of contemporary cases (20002005), patient survival rates
are shown in Fig. 3 and pancreas graft survival (insulin-independence) rates
in Fig. 4. At 3 years, patient survival rates in SPK, PAK, and PTA recipients
were 91, 90, and 93%, respectively, and the corresponding 3-year pancreas
graft survival rates were 78, 66, and 60%.
In regard to the question of mortality rates while waiting versus after a
pancreas transplant, the data from the analysis of the UNOS data base for the
period 19952003 by Gruessner et al. (10) are shown. The survival on the
waiting list for each category of patients is shown in Fig. 5. At 1 year, 3%
of PTA and PAK candidates died versus 7% of SPK candidates, a relatively
%
100
90
80
Cat.
PAK
PTA
SPK
70
n
1,624
627
5343
1Yr Surv.
95.6%
96.9%
94.9%
60
0
12
18
24
Months Posttransplant
30
36
Fig. 3. Patient survival rates in US deceased donor (DD) primary pancreas transplants by
recipient category, January 1, 2000 to December 31, 2005.

100
80
60
40
Cat.
PAK
PTA
SPK
20
0
0
n
1,624
628
5,344
1Yr Fxn.
78.0%
75.9%
84.7%
12
18
24
Months Posttransplant
30
36
Fig. 4. Pancreas graft functional survival rates in US deceased donor (DD) primary pancreas
transplants by recipient category, January 1, 2000 to December 31, 2005.
100
90
80
70
60
Cat.
n
PAK 2942
PTA
1207
SPK 12478
50
40
0
12
Survival
1Yr
4Yrs
97.2% 81.7%
96.6% 87.3%
93.4% 58.7%
24
36
Months Waiting
48
60
Fig. 5. Patient survival while waiting, all recipient categories, United Network for Organ
Sharing (UNOS) pancreas waiting list, January 1, 1995 to May 31, 2003.
small difference, but at 4 years, the mortality rates while waiting were 13, 18,
and 41%, respectively, showing the enormous impact remaining uremic has
on survival probabilities for diabetic patients. In contrast, recipients of SPK
transplants have a dramatically increased probability of survival compared
with their counterparts still on the waiting list, with a 45% delta at 4 years
(Fig. 6). Although less dramatic, the PTA (Fig. 7) and PAK recipients (Fig. 8)
also have higher survival rates at 1 and 4 years than their counterparts on
the waiting list, with deltas of 5 and 14% at 4 years. Although of marginal
significance, at least we can conclude that solitary pancreas transplants do not
increase mortality rates in the recipient population (10). The relative hazard of
100
80
60
40
20
Cat.
SPK
Wait
n
6995
5536
Survival
1Yr
97.5%
87.2%
12
4Yrs
90.7%
46.0%
24
Months Waiting
36
48
Fig. 6. Simultaneous pancreas and kidney (SPK) patient survival from time of listing,
United Network for Organ Sharing (UNOS) pancreas waiting list, January 1, 1995 to
May 31, 2003.
100
80
60
40
20
Cat.
PTA
Wait
0
0
n
647
485
Survival
1Yr
98.7%
94.1%
12
4Yrs
89.4%
83.0%
24
Months Waiting
36
48
Fig. 7. Pancreas transplants alone (PTA) patient survival from time of listing, United
Network for Organ Sharing (UNOS) pancreas waiting list, January 1, 1995 to May 31, 2003.
dying after a pancreas transplant is less by 2 months in SPK, 3 months in PAK,

and 8 months in PTA recipients than remaining on the waiting list (Fig. 9).
Retrospective analysis of outcomes done in registries is helpful but does
not begin to capture the dilemma facing the patient. For example, if one were
to say we should only do a pancreas transplant simultaneous with a kidney
transplant from a DD, then one would lose the ability to preempt dialysis with
a kidney transplant, as this would then relegate the patient to not being eligible
for a pancreas transplant, and they may bypass an LD kidney for an SPK and
take the risk of dying while waiting. The apparent advantage of an SPK over
PAK is only in one aspect, a 7% higher pancreas graft survival rate at 1 year
(9% vs. PTA) (2). However, patient survival rates are much higher in uremic

100
80
60
40
20
Cat.
PAK
Wait
n
1714
1228
Survival
1Yr
97.3%
94.7%
12
4Yrs
88.4%
74.5%
24
Months Waiting
36
48
Fig. 8. Pancreas after kidney (PAK) patient survival from time of listing, United
Network for Organ Sharing (UNOS) pancreas waiting list, January 1, 1995 to May 31, 2003.
Relative Hazard Ratio
PAK
PTA
SPK
4
3
2
Wait-Listed Patients
1
0
0
50
100 150 200 250 300

Days since Transplantation
350
Fig. 9. Relative hazard ratios of patient survival while waiting, all recipient categories,
United Network for Organ Sharing (UNOS) pancreas waiting list, January 1, 1995 to
May 31, 2003.
patients who receive a preemptive kidney transplant. If allocation favors SPK

so it would render moot the advantage of doing an LD kidney to preempt
dialysis, then, of course, an SPK is one operation and it has an advantage.
Dialysis can always be preempted with LD SPK transplants (6), but again,
there are almost for sure not enough living volunteers to donate both a kidney
and a pancreas to offset the need. As there are so many non-diabetic uremic
patients waiting for kidney transplants, the national allocation program cannot
allow all DDs to be used for SPK transplants; so, to utilize all pancreases and
not be wasteful, solitary (PAK and PTA) as well as SPK transplants must be
offered.
The above arguments for doing solitary (PAK and PTA) than just SPK
transplants are also pertinent to the minimally invasive form of beta-cell
replacement therapy, islet transplantation (11). What is needed for the liberal
application of beta-cell transplants are antirejection protocols in which the nonimmunosuppressive as well as immunosuppressive side effects are minimized
(12). However, for sure, uremic diabetic patients who undergo kidney transplants should have the option of simultaneous or sequential pancreas transplants to take full advantage of donor availability and suitability, and the use
of PTA in selected non-uremic recipients is certainly justified by the current
outcomes.
REFERENCES
1. Sutherland DER. Pancreas and islet transplant population. In: Gruessner RWG, Sutherland
DER, eds. Transplantation of the Pancreas. New York: Springer-Verlag, 2004:91102.
2. Gruessner AC, Sutherland DE. Pancreas transplant outcomes for United States (US)
and non-US cases as reported to the United Network for Organ Sharing (UNOS) and
the International Pancreas Transplant Registry (IPTR) as of June 2004. Clin Transplant
2005;19:433455.
3. Schnitzler, MA, et al. The life-years saved by a deceased organ donor. Am J Transpl
2005:22892296.
4. Farney, AC, et al. Simultaneous cadaver pancreas living donor kidney transplantation
(SPLK). Ann Surg 2000;232:646703.
5. Cohen, DJ, et al. Kidney and pancreas transplantation in the United States, 19952004.
Am J Transpl 2006:6(Pt 2):11531169.
6. Sutherland, DE, et al. Lessons learned from more than 1,000 pancreas transplants at a
single institution. Ann Surg 2001;233:463501.
7. Gruessner, AC, et al. Pancreas after kidney transplants in posturemic patients with type 1
diabetes mellitus. J Am Soc Nephrol 2001;12:24902499.
8. Port, FK, et al. Recent trends and results for organ donation and transplantation in the
United States, 2005. Am J Transpl 2006;(pt 2):10951100.
9. Venstrom, JM, et al. Survival after pancreas transplantation in patients with diabetes and
preserved kidney function. J Am Med Assoc 2003;290:28172823.
10. Gruessner RWG, Sutherland DER, Gruessner AW. Mortality Assessment in Pancreas
Transplants. Am J Transpl 2004;4:20182026.
11. Feng, S, et al. Developments in clinical islet, liver, thoracic, kidney and pancreas transplantation in the last 5 years. Am J Transpl 2006;6:17591767.
12. Sutherland, DER. Beta-cell replacement by transplantation in diabetes mellitus: which
patients at what risk; which way (when pancreas, when islets), and how to allocate deceased
donor pancreases. Curr Opin Transplant 2005;10:147149.
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Islet Cell Transplantation

How Effective Is It?
Eric H. Liu, MD
and David M. Harlan,
MD
CONTENTS
History
Islet Isolation
Limits of the Procedure
Clinical Islet Transplantation
Immunosuppression
The Edmonton Advance
Islet Transplantation Outcome Follow-Up
Benets, Risks, and Limitations
Novel Methods of -cell Replacement
and Encapsulation
Endogenous -Cell Regeneration?
Conclusions
Acknowledgment
References
Summary
Islet cell transplantation as a treatment for diabetes has shown great
promise, but has significant limitations. Since early animal studies in rats
demonstrated its ability to restore euglycemia, islet transplantation has not
proven to be a durable or practical therapy for type 1 diabetes. Here we review
some of the history, technique, clinical outcomes, and potential alternatives
of islet transplantation.
11
12
Liu and Harlan
Key Words: Islet, transplantation, beta-cell, liberase, immunosuppression, adverse events, encapsulation, progenitors, regeneration, isolation,
technique, edmonton protocol, risks, benefits.
Cell-based transplantation has long held great promise as a diabetes

treatment alternative. Since islets were first identified in the pancreas by
Paul Langerhans in 1869, and after von Mering and Minkowski demonstrated
that total pancreatectomy in dogs resulted in diabetes, several attempts have
been made to use pancreatic tissue to reverse diabetes (14). For instance,
in 1894, Williams grafted pancreatic tissue from a slaughtered sheep into the
subcutaneous tissue of a 15-year-old boy with diabetes but failed to revive
him; the boy died 3 days later (5). Insulins discovery and first clinical use
in 1922 temporarily deflated pressure for transplant approaches. However,
with increasing awareness that insulin neither cures diabetes nor absolutely
prevents its complications, interest in tissue transplant was revived when Lacy
and his colleagues in St. Louis demonstrated in the 1960s and 1970s that
isolated pancreatic islets could reverse diabetes in experimental rodent models.
That early laboratory animal success was tested in clinical trials, but with
minimal success. Another generation passed before enthusiasm was reinfused
in clinical islet transplantation with the Edmonton Protocol report in 2000.
Since then, islet transplantation euphoria again waned when new limitations
with the technique were recognized. Thus, although the field has advanced
considerably, several barriers must be overcome before cell transplantation as
a diabetes treatment can fulfill its long-standing promise.
HISTORY
Since Lacys early work, a major hurdle was the imperfect technique for
isolating viable islets in sufficient numbers and with preserved function (6).
Early investigators used a laborious and inefficient microdissection technique
but only produced enough tissue to study islet physiology (7,8). A major
advance came with the use of collagenase to enzymatically dissociate the
pancreas to yield isolated islets (9,10). The techniques were refined, for
instance, by injecting the collagenase into the pancreatic duct, and allowed
Ballinger and Lacy (11) to transplant syngeneic rat islets intraperitoneally to
cure experimental diabetes. The Lacy team further refined the technique by
using density gradients to separate islets from pancreatic acinar tissue and
implanting the purified islets into the liver by portal vein infusion (12,13).
This critical early work, all accomplished in the 1970s, established the basic
techniques that while refined since, remain largely unchanged. That is, islet
transplantation as currently practiced in both large animal trials and clinical
studies isolates islets and infuses them more or less as worked out by those
13
early pioneers. More recent improvements have been to automate, in part, the
islet isolation process and to improve the purity and activity of the critical
collagenase enzyme (e.g., Liberase made by Roche).
ISLET ISOLATION
Although the islet isolation technique, using broad brushstrokes, is quite
similar to that developed over 20 years ago, a fair amount of variation in
technique exists between islet isolation centers (14). We will review the
isolation technique in more detail and discuss some of the finer points related
to the technique.
The majority of isolated human islets are derived from cadaveric organ
donors. As with whole organ procurement, the pancreas is flushed with preservation solution (e.g., University of Wisconsin Solution) and kept on ice. The
pancreas is typically procured along with the donors duodenum and spleen,
and special care is given to avoid damaging the pancreatic capsule (15). The
organ is then transported to the laboratory on ice in either preservation solution
alone or using the more recently developed two-layer method that adds the
oxygen-carrying solution perfluorocarbon (PFC) (1618).
Once the organ arrives in the laboratory, isolation proceeds in four general
stages. One, the pancreas is isolated from extraneous tissues and inflated
with collagenase by injecting the enzyme into the pancreatic duct. Two, the
collagenase digests the pancreas. Three, small pancreatic cell aggregates
continuously released by the collagenase digestion are collected and washed
to stop continued digestion. Four, islets are isolated from other pancreatic cell
aggregates (taking advantage of acinar tissues greater density) using density
gradient separation techniques. All procedures are performed in biological
safety cabinets and under otherwise sterile and controlled conditions.
After the organ is cleaned and the pancreatic duct cannulated, cold collagenase (typically Liberase ) solution is injected to inflate the pancreas with
enzyme. The gland is then often cut into smaller fragments and is transferred into the digestion chamber (named Ricordi chamber in honor of
Dr. Camillo Ricordi who played an instrumental role improving isolation
techniques). The digestion step consists of a closed fluid circuit that includes
the Ricordi chamber, a heating coil, a peristaltic pump, a sampling port, and a
collection flask (Fig. 1). The inflated pancreas segments and several marbles
are placed together into the Ricordi chamber. A screen with 500-m opening
filters the chamber allowing only small pieces of tissue to escape. A pump is
started to circulate the fluid, and the chamber is shakeneither by hand or by
placing the chamber in a shaker machine. The circulating fluid is warmed to
37C and then fluid samples are repeatedly taken and examined microscopically to determine when the digestion is complete. The trained islet isolator
14
Liu and Harlan
knows when the islets are sufficiently liberated from the acinar tissue but not
over digested. Over digestion, to be avoided, means that the collagenase has
disrupted the islets themselves into smaller cellular fragments thought to be
be less viable and functional. Once the digestion is considered complete, the
circuit is converted into a linear system design to quickly dilute and inactivate
the collagenase, drawing in cold media (inactivating the enzyme with temperature) and adding human albumin to the fluid flowing through the chamber (to
chemically inactivate the enzyme). The fluid is collected into multiple chilled
conical flasks, pooled, and prepared for the density gradient separation step.
Density gradient separation techniques vary. Most laboratories rely on
Ficoll gradients, but some use non-sucrose-based solutions (e.g., Optiprep ).
Either a continuous or a discontinuous gradient can be used as acinar cell
aggregates will migrate into the most-dense gradient, whereas islets tend to
gravitate to a less-dense layer. After a short centrifugation, the gradient is
expelled and collected into chilled tubes to promptly dilute the polysucrose
gradient. Each tube is sampled and assessed for islet content and purity.
Fractions enriched in pure or relatively pure islets are pooled, samples are
taken, and the islets are counted and assessed. The cells are ready now ready
for culture or transplantation.
LIMITS OF THE PROCEDURE

Although the islet isolation procedure has been successfully performed in
dozens of laboratories around the world, the technique remains imperfect. As
many as half the isolation attempts are considered failed because too few
islets are isolated, or the isolated islets are overly digested, not sufficiently
viable, or unsatisfactorily purified from acinar tissue (19). Several issues may
contribute to failed islet isolation efforts, starting with the donor. Lakey and
colleagues looked retrospectively at several of their isolation efforts, and using
a relatively generous definition of success [150,000 islet equivalents (IEQs)
to be defined later in this section], they reported that increased donor age,
higher donor body mass index, and a local procurement team all correlated with
a more successful outcome. On the contrary, donor hyperglycemia, cardiac
arrest, donor reliances on high dose pressors to maintain blood pressure, and
prolonged cold storage had a negative impact (20). Moreover, careful surgical
technique and particular attention to keeping the pancreas chilled during the
procurement also affected the islet yield (21). While these factors can be used
to screen for higher quality donors, recall that all donors are brain dead, and
brain death itself has been shown to negatively impact islet yield and function,
perhaps through up-regulation of inflammatory cytokine [tumor necrosis factor
(TNF)-, interleukin (IL)-1, and IL-6] levels (22). To a limited degree, islets
have been isolated from living donors (partial pancreatectomy in a single
15
allogeneic donor case report or complete pancreatectomy for autotransplantation), and such efforts appear to generate a higher islet yield and islets with
better function (2327). These data further support the concept that brain death
is bad for islet isolation efforts and for ultimate isolated islet function. Unfortunately, until other sources are found, cadaveric pancreas donation will remain
the major islet source for clinical transplantation efforts.
Research to refine isolation techniques continues to progress, but the
technique remains quite expensive, requires an experienced team, and demands
considerable resources. The reagents themselves can be variablestarting with
the collagenase enzyme. Many centers use an enzymatic blend (Liberase ) that
effectively digests the pancreas, but suffers from some lot-to-lot variability, and
many investigators believe the shelf life is relatively short. Furthermore, centers
often disagree about which enzyme lots are effective and which are not. And as
mentioned above, determining the optimal time to end the pancreas digestion
during the isolation procedure requires an experienced islet isolator. This endof-digestion call remains as much an art as it is a science. Most recently on April
18, 2007, groups around the world using Liberase (R) to isolate islets were
informed that the reagent was exposed to cow brain extract during manufacturing. While the risk of transmitting bovine spongiform encephalopathy is
quite low, it is not zero. Programs using Liberase (R) have curtailed clinical
islet transplantation, thus pointing out the techniques experimental nature.
Investigators have tested many different techniques for quantifying islet
quality but none is yet absolutely predictive of clinical function. Even determining the islet yield remains a challenge. As isolated islets vary significantly
in size, standard procedure calls for estimating the IEQs, resulting from
the isolation. To assess IEQ number, an aliquot of the digested pancreas is
taken, and the number of islets falling within several size ranges is counted
(for example, 050 m in diameter, 51100 m, 101150 m, etc.). Using
these counts, the cumulative islet volume is calculated by a mathematical
formula to convert that volume into a theoretical IEQ number where all the
islets are 150 m in diameter. Unfortunately, the process is user and sampling
dependent, making it a relatively subjective technique (28). Purity has also
been a challenging parameter to measure with precision. Currently, islet preparations are stained with dithizone, a dye that takes advantage of cells high
zinc content by binding to that metal to stain the islets red. The islet isolator
then estimates the percentage purity by examining an aliquot of the pancreas
digest. This method is even more subjective than islet counting such that
different observers islet purity assessments vary considerably. A variety of islet
functional assays also exist including in vitro glucose-stimulated (either using
static glucose incubations or perifusion assays in which glucose concentrations vary over time) insulin release assays and oxygen consumption assays
(2931). These in vitro assays have the great advantage of generating a result
16
Liu and Harlan
quickly to help decide which islet preparations are of sufficient quality for
transplant. The problem is that no assay is yet well validated for its clinical
predictive power. That is, some islet preparations measured to be of high
quality by in vitro assay results fail to function well in vivo. Many believe
that a more laborious and time-consuming in vivo assay for islet function is a
better predictor of clinical function. For this in vivo assay, isolated islets are
transplanted into diabetic immuno-incompetent mice to see whether the islets
restore normal glucose homeostasis to the animal. This type of assay does not
provide its information in a timely enough fashion to dictate which islets can
be used clinically and is limited by the large number of islets needed. New
techniques are being tested in hopes of improving the islet assessment process.
CLINICAL ISLET TRANSPLANTATION

By the late 1980s, improved isolation techniques and breakthroughs in
immunosuppression made possible clinical trials to test islet transplantation
in patients with type 1 diabetes mellitus (T1DM). Following some not well
documented and unsuccessful clinical islet transplantation efforts by others,
David Scharp and Paul Lacy of Washington University in St. Louis first
reported a clinical islet transplant success when they transplanted islets into
the portal vein of a diabetic kidney transplant recipient (32). This patient
received nearly 800,000 IEQs (obtained from several donors) and was immunosuppressed with anti-lymphocyte globulin and cyclosporine. Following the
islet infusion, the patient was given intravenous insulin for a few days to
maintain tight blood glucose control. Once the insulin infusion was stopped, the
patient retained C-peptide production with near-normal fasting blood glucose
and significantly improved blood glucose control. All exogenous insulin was
stopped 10 days after the islet infusion, and the patient continued to have normal
glucose levels until day 25, when insulin therapy was reinstituted because of
gradually worsening glycemia control. The St. Louis group expanded their
study to include diabetic patients with preserved kidney function, and they
tested different immunosuppressive approaches. In most cases, subjects were
able to achieve partial graft function with increased C-peptide production.
However, only one patient was able to maintain sustained insulin independence; most patients rejected their grafts. As demonstrated by Scharp and
Lacy, patients who only received 6000 IEq/kg body weight were never restored
to insulin independence, whereas those who received almost 14,000 IEq/kg
were occasionally able to achieve at least temporary insulin independence.
With regard to cell quality, all the preparations demonstrated good glucosestimulated insulin release, reflecting standard assays inability to predict
clinical outcome.
17
After this initial case series, the procedure was tested at other institutions but
with similar mixed results (3335). The International Islet Registry documented
several cases of short-term insulin independence but no long-term success (36).
An overall conclusion of these studies was that in addition to the difficulty of
obtaining sufficient numbers and quality of islets for clinical transplantation,
perhaps a more significant barrier limiting transplant-based approaches to
diabetes was the imperfect efficacy and safety of existing immunosuppressive
therapies.
IMMUNOSUPPRESSION
T1DM, at least in theory, represents a most difficult challenge for immunosuppression because, following the transplant of allogeneic cells (using
either a whole organ transplant or isolated islets) both an alloimmune and an
autoimmune response may exist to destroy those islets. That is, T1DM is caused
by a T-cell-mediated autoimmune killing of cells (and data suggest that
this autoimmune response never wanes), and in addition to that autoimmune
response, transplanting tissues from a cadaveric human donor always generates
an alloimmune response. In an effort to control both, combination immunosuppression was employed (3739). Initial approaches used cyclosporine, one
of various anti-lymphocyte antibodies, anti-proliferative agents (e.g., azathioprine), and corticosteroids. Steroids were appropriately deemed particularly
detrimental to the graft, because of the well-known nature of glucocorticoids
to raise the blood sugar level. Current data suggest that calcineurin inhibitors
(e.g., cyclosporine) probably exacerbated the unfavorable environment for
transplanted beta-cell survival and function (40).
THE EDMONTON ADVANCE

On the basis of these early studies, the group from Edmonton, Alberta,
Canada, developed a protocol to assess whether four modifications to the
standard clinical islet transplant approach could improve overall outcome. The
Edmonton protocol modifications included (i) transplanting more islets from
multiple pancreas donors, (ii) using a novel and less diabetogenic immunosuppressive regimen, (iii) avoiding animal products (i.e., fetal calf serum) during
cell processing, and (iv) minimizing cell culture and transplanting the isolated
islets as soon as possible after their isolation. In 2000, they reported a series
of seven consecutive cadaveric islet transplant recipients all rendered insulin
independent for at least 1 year, and with normal blood sugar control (41).
For the first time, islet transplantation resulted in relatively sustained insulin
independence and in a consistent fashion.
18
Liu and Harlan
Widespread experience since that publication now suggests that of the

four modifications made by the Edmonton group, the islet number infused
and the immunosuppression employed after the transplant were the most
important factors underlying their success. Since Edmonton, additional
technical advances have been reported. The two-layer pancreas preservation
method has become more widely used as it appears to reproducibly promote
good islet isolation results (17). And centers have resumed culturing islets
before transplant. Islets not cultured are comparable with cultured cells for a
limited period with regard to function post-transplant, and the culture period
allows for more complete testing of the isolated islet product and to orchestrate the islet transplant procedure during regular working hours and with a
stable and rested transplant team. Moreover, culture time allows unpurified
acinar tissue to degrade. A few centers have reasoned that the islet transplant
procedure may be feasible wherever a hospital has a trained and equipped
interventional radiology suite but that islet isolation may be best performed at
centers well versed in that fine art. To that end, a few groups have collaborated
by transporting cadaveric pancreata to a specialized center for the isolation
procedure, then returning the isolated islets to the original center for transplantation (4245). Such a strategy would allow the transplant center to focus
on patient care and relatively quickly offer a novel therapy, without having
to make the significant investment required to build, staff, and equip an islet
isolation facility.
ISLET TRANSPLANTATION OUTCOME FOLLOW-UP

The success of the Edmonton Protocol infused the islet transplantation
field with tremendous energy. And the excitement was appropriate. The
glucocorticoid-free immunosuppressive regimen they employed had enjoyed
some limited success in kidney allograft recipients, relying on a monoclonal
antibody against the IL-2 receptor (daclizumab) every 2 weeks for five doses
as an induction therapy, in conjunction with tacrolimus (FK506) and sirolimus
(rapamycin) (4649). Like cyclosporine, tacrolimus also has significant diabetespromoting effects, but the Edmonton group used lower doses than typically
employed for other organ transplants. In that original series, seven consecutive patients became insulin free after a sufficient number of islets were
infused, the patients suffered no significant hypoglycemia, the mean amplitude
of glycemic excursion was decreased, and the percentage of glucose values
within the normal range markedly improved. There were some complications from the infusion procedure and the immunosuppression, but no patients
died from their islet transplants. Islet transplantation had finally succeeded.
Islet transplantation not only offered the reality of insulin independence, it
also offered a new model for testing transplant tolerance. Everyone reasoned
19
that if a cell transplant was rejected because an experimental therapy failed,

the only risk for the patient was going back on insulina much better option
compared with dialysis (kidney) or death (liver, heart, lungs). Other centers
attempted to replicate Edmontons historic results. Thanks to significant helpful
input from both Edmonton and the University of Miami, our National Institutes
of Health (NIH) group quickly replicated the protocol, with results similar
to that since reported by centers around the world, including longer followup results reported from Edmonton (50). Networks around the world were
created to perform more islet transplants. The Immune Tolerance Network
(ITN), sponsored by the NIH and the Juvenile Diabetes Research Foundation
(JDRF), initiated a multi-center trial to test whether Edmontons results could
be reproduced at other centers, then serve as a model for the testing of novel
therapies designed to achieve immunological tolerance (51). Islet Cell Resource
centers were created around the USA to provide good quality isolated islets
for both research and transplant studies. It was an exciting time.
Gradually however, a more sober view of the field evolved. For the multicenter ITN trial, centers with islet isolation and transplantation experience
enjoyed results similar to Edmontonsbut other centers were not so fortunate.
Furthermore, follow-up data showed that long-term insulin independence was
difficult to maintain. After 1 year, the Edmonton group still had promising data
most patients were insulin free or treated with oral hypoglycemic agents and
low-dose insulin (34). But most recently Edmonton reported on 65 islet transplant recipients and reported a 1-year insulin independence rate of 64%, a 3-year
insulin independence rate of only 20%, and a 5-year insulin independence rate of
<10% (median 15 months) (35). On the contrary, 80% of the patients maintained
circulating C-peptide levels suggesting that some of the islets continued
to function, and at 5 years, the vast majority enjoyed normal HgA1c values.
Of great concern to many however have been the risks associated with
the immunosuppressive therapy and the transplant procedure itself. With
longer follow-up, Edmonton protocol immunosuppression with both tacrolimus
and sirolimus has been found to produce significant side effects. Common
adverse effects of tacrolimus include neurotoxicity (tremor, headache, motor
disturbances), gastrointestinal (GI) complaints, hypertension, and hyperkalemia. But the greatest concern is the nephrotoxicity and specific beta-cell
toxicity. Patients on sirolimus can exhibit hyperlipidemia, oral ulcers, anemia,
leukopenia, thrombocytopenia, hypokalemia or hyperkalemia, fever, gastrointestinal effects, delayed wound healing, and edema. Although not nephrotoxic itself, sirolimus appears to exacerbate the nephrotoxicity of calcineurin
inhibitors (cyclosporin and tacrolimus). In the original Edmonton series, 2 of
15 procedures required transfusion secondary to bleeding from the hepatic
cannulation, and all patients had at least some minor buccal ulceration from the
20
Liu and Harlan
sirolimus. They reported no changes in lipids and no patients required lipidlowering therapy, but their follow-up was only 415 months. With the more
recent report including 5-year follow-up, 15 of 65 subjects had major bleeding
from the cannulation requiring intervention (transfusion or laparotomy). Over
half of the patients had transient elevations in their liver enzymes that lasted
approximately 4 weeks, but 8 of 36 patients who underwent abdominal
magnetic resonance imaging were found to have (MRI) developed fatty liver.
With regard to the immunosuppression, mouth ulcers were highly prevalent
(89%), while also prevalent were diarrhea, acne, edema, ovarian cysts, and
anemia. Three patients developed pneumonia and one developed thyroid
papillary carcinoma. The use of lipid-lowering medications also increased
from 23% of patients pre-transplant to 86% after 5 years. A recent report
from Edmonton showed that Islet transplant recipients inexorably lost kidney
function over time, from an initial creatinine clearance of 89 ml/min/1.73m2
at baseline, to 58 ml/min/1.73m2 four years post transplant (52). The authors
attributed the worsening kidney function to the patients underlying chronic
diabetes, but recent reports from others call that interpretation into question.
For instance, a report from Finland that included nearly every patient diagnosed
with T1DM in that country since 1965 found a remarkably low incidence of
renal failure (53). On the contrary, myriad studies now suggest that modern
immunosuppressive regimens significantly increase the risk of renal insufficiency, suggesting that the declining renal function seen in the islet transplant
recipients may have been caused by the immunosuppression given to preserve
the allogeneic islets and not the underlying diabetes (54).
Other centers have tried various islet transplantation strategies. At the
University of Minnesota, subjects and donor pancreata were carefully selected
and eight of eight patients achieved insulin independence, with five of the eight
lasting 1 year (55). At the University of Miami, 14 of 16 patients achieved
insulin independence, with 11 remaining off insulin for at least 1 year and six
off insulin for at least 18 months (56). Other large centers achieved similar
results (50,57).
BENEFITS, RISKS, AND LIMITATIONS

The patient with difficult-to-control T1DM facing the option of an islet
transplant must ask themselves how much risk is justified in return for shortterm relief from insulin injections and longer term improved glycemia control.
The patient can reasonably count on fewer to no daily insulin injections (for up
to several months), would likely check blood glucose values less frequently,
and could expect much less risk of hypoglycemia (58). On the contrary, the
patient need recognize the risks associated with: the procedure, the immunosuppression, and with islets placed within the liver.
21
Let us then discuss the risk/benefit equation from the most global perspective
and based on ever evolving but still incomplete knowledge (59). The benefits
of good glucose control to lower both the risk of microvascular complications
(retinopathy, nephropathy, and neuropathy), and more recently macrovascular
complications (myocardial infarctions, cerebrovascular accidents), have been
clearly demonstrated by the diabetes control and complications trial (DCCT)
and follow-up studies (6062). These data, coupled with the improved glycemia
control most pancreas or islet transplant recipients achieve, have suggested
to some that these transplant therapies may too decrease or reverse microand macrovascular complications. Indeed, patients with pancreas allografts
functioning for 10 years or more have been reported to display less histological evidence of diabetic nephropathy than was present before their pancreas
transplant (63).
The question of transplant-based therapys effects on long-term diabetes
complications is more nuanced however. For instance, the DCCT did not study
patients with long-standing, complicated diabetes (i.e., those with advanced
microvascular or macrovascular complications) and therefore should be viewed
more as a prevention study for those complications. As importantly, no patient
in the DCCT was treated with immunosuppressive agents and clearly transplant
recipients must be so treated. The question then becomes one of comparing
the benefits achieved by transplant-based improved glycemia control weighed
against the known toxicities associated with immunosuppression. Indeed, even
the report studying patients with long-standing pancreas allografts noted that
although the kidney biopsies showed less evidence of diabetic nephropathy, the
patients kidney function was actually worse than that pre-transplant (63). And
a previous study by the same group evaluating kidney function in pancreas
transplant recipients compared patients with functioning pancreas grafts to
those who had no transplant or a transplant but lost it (and therefore discontinued immunosuppression). The group with the failed pancreas allografts that
never received a transplant had better kidney function, whereas the transplant
patients had declining renal function proportional to cyclosporine levels (64).
The point is that the net effect of transplant-based and immunosuppressionrequiring treatments on diabetes complication endpoints remains unknown and
that we must guard against assuming benefit.
Even with regard to patient survival following transplant-based treatments
for diabetes, there is uncertainty. An analysis we performed comparing the
survival of pancreas allograft recipients with those listed for but still awaiting
their pancreas transplant demonstrated a significantly worse survival in the
transplanted groupat least for the T1DM patients with preserved kidney
function (i.e., serum creatinine less than 2.0 mg/dl) (65). A similar analysis
by the Minnesota group did not find the survival disadvantage we reported,
22
Liu and Harlan
but for that analysis patients with renal insufficiency were not excluded, and
everyone agrees that patients with diabetes and renal insufficiency have a poor
prognosis (66). Indeed, our original paper and other similar analyses found that
patients with diabetes and kidney failure did enjoy a transplantation-associated
survival benefit but that most if not all of that benefit was attributable to the
transplanted kidney with little or no effect of the simultaneously transplanted
pancreas.
Considering the fact that most patients undergo islet transplantation for
hypoglycemia unawareness, and that intensive insulin therapy is associated
with more hypoglycemia, one cannot ignore the difficult challenge facing the
brittle diabetic (67). But recent data suggest that hypoglycemia unawareness
can often be reversed by careful avoidance of low blood sugars for a relatively
short period of time (6870).
Overall then, although islet transplantation can often, for many months,
decrease insulin requirements, improve glycemia control, and markedly reduce
the severity and frequency of hypoglycemia, long-term islet allograft survival
remains limited. This coupled with the complications of the cannulation
procedure itself, the immunosuppressive agent-associated complications, and
long-term effects of the islets on liver structure and function all conspire to
warrant great caution to those considering the experimental treatment. As islet
transplantation continues to be performed and more patient data are collected
through the Collaborative Islet Transplant Registry so that the long-term
benefits and consequences will be better understood (71,72).
If islet transplantation is to be a widely available clinical therapy, it faces yet
another major challengethe severely limited supply of organ donors. In the
USA, each year, approximately 12,000 brain dead patients are suitable for organ
donation. Of these, consent for donation is obtained from about half, resulting
in about 6000 organs. As discussed in the islet isolation section, using current
techniques, about half the organs subjected to the islet isolation procedure
would yield islets deemed suitable for transplantation, reducing the number
to 3000 transplantable islet preparations. As most recipients currently require
islets from multiple donors, a realistic estimate is that approximately 1500 islet
transplants could be performed each year in the USA. And yet, current estimates
suggest over one million Americans have T1DM. Moreover, as insulin independence wanes by 25 years post-transplant, patients would be queuing up for
subsequent transplants (assuming repeated islet infusions are safe) (73). Given
the shortage of suitable donors, the possibility of living donation has been
offered (25). In one case, Japanese investigators performed a distal pancreatectomy from a mother then transplanted islets from her pancreatic segment
to her daughter, who suffered from diabetes secondary to chronic pancreatitis
(not T1DM). The pancreas digest was not subjected to gradient separation such
23
that all the pancreas cell aggregates (including islets and acinar cell clusters)
were infused into the recipient. The patient became insulin free, and neither
she nor her donor suffered acute complications. Although this case report
demonstrates the plausibility of the procedure, the risk to the donor from the
distal pancreatectomy, the possibility of a failed islet isolation, and the high
risk of graft failure is generally considered too great to make living donation
a realistic source of tissue for the foreseeable future.
NOVEL METHODS OF -CELL REPLACEMENT

AND ENCAPSULATION
Although still highly experimental, various cellular sources for physiologically regulated insulin production have been proposed including stem cells,
xenogeneic islets, cells grown in vitro from mature islets, and cells transdifferentiated from various cell sources. None of these sources has generated
cells that produce insulin to a degree and with the physiological regulation
characteristic of a pancreatic islet cell however. For example, although
promoting embryonic stem (ES) cells to differentiate to a -like cell could
completely eliminate the need for cadaveric donors and some techniques have
been described that generate insulin-producing clusters from these ES cells,
they fall far short of the cell, and some data suggest the insulin found in
such clusters was simply taken up from the growth media (7476). Still other
cell types, such as bone marrow resident stem cells and splenocytes, have been
tested as possible -cell progenitors, but such studies have been limited to
rodent models and have not been easily reproduced (77,78). One group has
taken human ductal tissue, normally discarded from a human islet isolation,
and under certain culture conditions, reported budding islet-like clusters that
appeared to secrete insulin (79). Even so, only a limited number of cells could
be produced, and investigators disagree about the source of new cells in
vivo. To test the question of cell source, Dor et al. created an elegant mouse
model that allowed for -cell lineage tracing (80). They concluded that in adult
mice, only one cell type is capable of replenishing cellsand in their model
it was cells themselves.
Pigs have been particularly attractive as a potential islet source because the
animals are plentiful, are already widely used for human purposes (alleviating
some of the animal rights concerns raised for other species), have large litters,
grow quickly to adult size, display regulated insulin secretion similar to that of
man, and express an effective form of insulin in humans (porcine insulin was
used for decades to treat patients with diabetes). Clinical trials performed, most
notably by Groth et al. (81), in which fetal porcine islets were infused into the
portal vein or in the renal capsule of diabetic patients did not reverse diabetes
24
Liu and Harlan
but resulted in detectable porcine C-peptide levels. More recently, ValdesGonzalez et al. reported a series of patients given a mixture of neonatal porcine
islets and Sertoli cells within abdominal subcutaneous membrane sheaths. In
that report, a few patients achieved temporary insulin independence with no
immunosuppression (82). The major limitations of pigs as a tissue source are
the aggressive anti-porcine immune response and the possible transmission
of animal pathogens (83). Progress that may overcome the first problem has
been made. Humans rapidly reject pig tissue (hyperacute rejection) because of
high titer antibodies against galactose (1,3)galactose, a carbohydrate residue
expressed on porcine cells. With advances in animal cloning, a genetically
modified pig that does not express the residue is under investigation (84). Even
if hyperacute rejection were solved, many remain concerned that a human host
with an immune system weakened by immunosuppressive agents, and then
given a large unnamed inoculum from the transplanted tissue, might be the
ideal breeding ground for a pathogen to develop into one suited to human
hosts. One must quickly add that porcine endogenous retroviruses have not
been detected in man despite years of husbandry experience with the species.
Other groups have tested whether other endoderm-derived cells (hepatocytes, pancreatic acinar cells, intestinal cells, etc.) can be coaxed to transdifferentiate into glucose-sensing and insulin-producing cells (85). Several
groups have tested adenoviral gene vectors designed to drive the expression of
various transcription factors (e.g., PDX1) in mouse liver with some evidence
that the liver cells begin secreting insulin (86,87). We have reported, however,
that such transformed hepatocytes produce only minimal amounts of insulin
(88). Another group induced the expression of glucose-dependent insulin-like
polypeptide in gut cells to reverse diabetes (89). These techniques still require
significant investigation at the basic level before any attempts at larger animal
models can be made.
Many groups have attempted to grow cells capable of physiological insulin
secretion using mature islets as the starting material. Many have succeeded
in establishing conditions that support proliferating cell populations, but these
cells generally lose insulin production (90,91). Recently, Gershengorn et al.
(92) described cells grown from mature human islets. They contend that
under certain culture conditions (serum based), islet cells convert to a more
mesenchymal phenotype, no longer producing hormone but capable of proliferating thousands of fold. They reported that cells reaggregate and redifferentiate
into more mature hormone-producing cells once serum is removed, but this
technique has yet to be validated in a relevant in vivo model and is still a topic
of extreme controversy.
Through the years, many have attempted to create an immunological barrier
between the islet and the recipient such that the insulin-producing cell can sense
25
ambient glucose levels and secrete insulin with near-physiological kinetics,

and yet be hidden from the cell-mediated immune response (93,94). For
instance, porcine islets have been encapsulated and shown to reverse diabetes
in small and large animal models (95). In general, however, these studies have
been hampered by decreased viability of the encapsulated cells, difficulties
associated with the volume of encapsulated material required to restore normal
glucose homeostasis in larger animals, capsule fragility in vivo such that the
cellular contents are exposed and stimulate an immune response, and other
issues.
ENDOGENOUS -CELL REGENERATION?

Circumstantial evidence from various sources suggests that the endocrine
pancreas, even in patients with long-standing T1DM, has the ability to replenish
its cells (96). For instance, serum from most patients with even longstanding T1DM continues to contain islet autoantibodies. In other diseases,
such as autoimmune thyroiditis, organ-specific autoantibody levels wane after
removal of the target organ. Thus, the persistent anti-islet antibodies suggest
that the target cell may persist. Indeed, another recent study looking at
pancreatic draining lymph nodes from two patients dying 15 and 29 years
after T1DM onset found a high proportion of the T cells reacted, in a human
leukocyte antigen (HLA)-restricted fashion, to an insulin peptide (97). The
high proportion of anti-insulin peptide-specific T cells remaining in those
patients pancreatic lymph nodes leads one to ask what attracted and held the
T cells to that location unless the pancreatic lymph nodes continued to be
bathed in islet -cell antigens. Furthermore, a recent autopsy study by Meier
et al. (98) examined fresh pancreatic tissue from 42 patients dying years after
their initial T1DM diagnosis. Although -cell mass was clearly diminished
relative to control pancreata, insulin-staining cells were detected in 88% of
the subjects and many displayed a low-grade T-cell islet infiltration, consistent
with persistent autoimmunity. In a related autopsy study, Butler et al. (99)
examined the fresh pancreatic tissue from a mixture of individuals: some lean,
some obese but without diabetes, and some with type 2 diabetes. Obese cases
exhibited a higher relative -cell volume with evidence suggesting increased
neogenesis, whereas the pancreata from patients with type 2 diabetics had
an increased rate of -cell apoptosis. All these data suggest a battle between
a slow and plodding pancreatic capacity to generate new cells, but that
regenerative process is outmatched by an immune system quite efficient at
-cell killing. Indeed, a case report by Kuroda et al. (100) also supports this
concept. They described a gentleman with a 19-year history of T1DM who had
been given an allogeneic pancreas transplant. When the native pancreas was
26
Liu and Harlan
biopsied 2 years after the pancreas transplant, many insulin-immunostaining

cells were present in the native pancreas. The authors reasoned that perhaps
the immunosuppression preventing pancreas allograft loss, the normal blood
glucose control mediated by the pancreas allograft, or perhaps other unknown
factors, allowed the native pancreas to regenerate some new cells. In our own
experience, while screening for patients for islet transplantation at the NIH, we
also observed that at least 40% of patients with long-standing T1DM still had
detectable serum C-peptide (101). Given these data, we have designed several
clinical protocols to test whether patients with long-standing T1DM can, under
proper circumstances, be coaxed into making physiologically relevant amounts
of insulin again, even years after their first insulin injection.
CONCLUSIONS
Islet transplantation can restore insulin independence to the patient with
T1DM. Even so, while far superior to results obtained just a decade ago,
islet function is inexorably lost, such that nearly all must return to insulin
therapy by 5 years post-procedure. What is worse, both allogeneic islet rejection
and recurrent anti-islet autoimmunity need be controlled but the immunosuppression presently available remains incompletely effective and intolerably
toxic to be considered appropriate for the vast majority with T1DM. In addition,
many other factors point out islet transplantations still experimental nature
including the inadequate islet supply, risks associated with the portal vein
cannulation, host sensitization against the donor islets making subsequent transplantation more difficult, allogeneic islet effects on the surrounding host liver
tissue, and the procedures great expense (102). Last, patients considering an
islet transplant should be informed that no good data suggest it reduces the
risk of secondary diabetic complications or prolongs survivalso far, only
insulin therapy can make that claim. Even so, all worthwhile ventures require
pioneers risking much in the cause of progress. Properly informed patients and
diligent, well-motivated clinical investigators, will continue making progress
so that transplanting cells capable of regulating a patients blood glucose may
fulfill its long promise of a world free from injected insulin and without
diabetes.
ACKNOWLEDGMENT
This research was supported by the Intramural Research Program of the
NIH, NIDDK.
27
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Metabolic Syndrome
Is There Treatment that Works?
James B. Meigs,
MD, MPH
CONTENTS
Overview
Risk Factor Clustering and Criteria
for Metabolic Syndrome
Metabolic Syndrome as a Risk Factor
for Type 2 Diabetes and CVD
Therapeutic Lifestyle Change to Prevent
Metabolic Syndrome, Type 2 Diabetes,
and CVD
Drug Therapies for Metabolic Syndrome
Conclusions
Acknowledgments
References
Summary
Metabolic syndrome refers to the phenomenon of risk factor clustering
and is presumed to reflect a unifying underlying pathophysiology. Clustering
commonly occurs in the setting of obesity, insulin resistance and a sedentary
lifestyle. Currently there are five different criteria for metabolic syndrome,
all of which are associated with increased risk of diabetes or cardiovascular
disease. Therapeutic lifestyle change that focuses on obesity and physical
inactivity to reduce disease risk has a good evidence base. There is no specific
drug therapy recommended for metabolic syndrome beyond medications
that lower levels of its component risk factors, especially hypertension and
dyslipidemia.
33
34
Meigs
Key Words: metabolic syndrome, type 2 diabetes, cardiovascular

disease, prevention
OVERVIEW
Metabolic syndrome refers to the phenomenon of risk factor clustering
an aggregation of metabolic traits occurring in the same individual with
frequencies greater than expected by chance, and presumably reflecting a
unifying underlying pathophysiology. Traits that cluster include elevated
glucose, triglyceride and blood pressure levels, and/or low high-density
lipoprotein cholesterol (HDL-C) levels. Clustering commonly occurs in the
setting of obesity (particularly central obesity, commonly assessed by waist
circumference) as well as a sedentary lifestyle (1). Markers of an inflammatory,
hypercoagulable state also cluster with metabolic traits (24).
It has long been recognized that type 2 diabetes and cardiovascular disease
(CVD) share many risk factors in common and that their co-occurrence is
probably linked to insulin resistance and obesity (5,6). The concept of trait
clustering and shared risk for type 2 diabetes and CVD has been codified into
formal criteria for metabolic syndrome. As of 2005, there are five different
proposed criteria for metabolic syndrome (Table 1) (711). The metabolic
syndrome appears to be increasingly common. For instance, in the communitybased Framingham Study, the prevalence of the ATP3 metabolic syndrome in
1990 was about 1321% in women and men aged an average of 50 years;
after 8 years of observation, the prevalence was 2434% (12). On a population
level, metabolic syndrome by various criteria predicts risk of diabetes or CVD,
but at an individual patient level, these criteria identify many substantially
different phenotypes, so general drug treatment recommendations for metabolic
syndrome are very problematic. Conversely, therapeutic lifestyle change (TLC)
that focuses on obesity and physical inactivity to reduce diabetes and CVD
risk has an emerging evidence base. In this chapter, we will briefly review
the evidence for risk factor clustering and metabolic syndrome definitions, the
evidence that metabolic syndrome is a type 2 diabetes and CVD risk factor,
evidence for TLC to treat metabolic syndrome and prevent diabetes and CVD,
and emerging data for drug therapy of the metabolic syndrome.
RISK FACTOR CLUSTERING AND CRITERIA

FOR METABOLIC SYNDROME
The major traits of the metabolic syndrome [elevated waist circumference or
body mass index (BMI) and glucose, triglyceride and blood pressure levels, and
low HDL cholesterol levels] are common and could co-occur in some subjects
independent of any unifying physiology (13). However, in population-based
5.6 mmol/L
(100 mg/dL) or
diagnosed
diabetes
5.6 mmol/L
(100 mg/dL) or
drug treatment
for elevated
blood glucose
<1.0 mmol/L
<1.0 mmol/L
(40 mg/dL)(men); (40 mg/dL)(men);
<1.3 mmol/L
<1.3 mmol/L
(50 mg/dl)(women) (50 mg/dl)(women)
or drug
or drug
treatment for
treatment for
low HDL-C
low HDL-Ca
Glucose
HDL cholesterol
No. of
abnormalities
And 4 2 of:
Waist 94 cm
(men) or t 80 cm
(women)c
IDF 2005
3 of:
Required:
NCEP ATP3
2005
<1.0 mmol/L
(40 mg/dL)
6.1 mmol/L
(110 mg/dL)
6.9 mmol/L
(125 mg/dL)
And 4 2 of:
Insulin resistance or
fasting
hyperinsulinemia in
top 25%
EGIR 1999
WHO 1998
6.1 mmol/L
(110 mg/dL); /
2-hour glucose
7.8 mmol/L
(140 mg/dL)
And 4 2 of:
High risk of
insulin resistancee
or BMI 25 kg/m2
or waist 102 cm
(men) or 88 cm
(women)
ACE 2003
(Continued)
<0.9 mmol/L
<1.0 mmol/L
(35 mg/dL)(men); (40 mg/dL)(men);
<1.0 mmol/L
<1.3 mmol/L
(40 mg/dl)
(50 mg/dl)(women)
(women)
Insulin resistance
in top 25%d ;
glucose
6.1 mmol/L
(110 mg/dL);
2-hour glucose
c 7.8 mmol/L
(140 mg/dL)
And 4 2 of:
Table 1
Five Current Definitions of the Metabolic Syndrome
130/85 mm Hg
1.7 mmol/L
(150 mg/dL)
ACE 2003
Treatment with one or more of fibrates or niacin

In Asian patients, waist s 90 cm (men) or 80 cm (women)
c
For South Asian and Chinese patients, waist 90 cm (men) or 80 cm (women); for japanese patients, waist e 90 cm (men) or t 85 cm
(women)
d
Insulin resistance measured using insulin clamp; the presence of microalbuminuria is also counted as one of the 2 or more qualifying traits
e
High risk of being insulin resistant is indicated by the presence of at least 1 of the following: diagnosis of CVD, hypertension, polycystic
ovary syndrome, nonalcoholic fatty liver disease,or acanthosis nigricans; family history of type 2 diabetes, hypertension, or CVD; history of
gestational diabetes or glucose intolerance; nonwhite ethnicity; sedentary lifestyle; BMI 25 kg/m2 or waist circumference 94 cm for men and
80 cm for women; and age 40 years.
140/90 mm Hg
140/90 mm Hg
or drug treatment
for hypertension
130/85 mm Hg
or drug treatment
for hypertension
130/85 mm Hg
or drug treatment
for hypertension
Hypertension
Waist/hip ratio
>0.9 (men) or
>0.85 (women) or
BMI m30 kg/m2
Waist 1 94 cm
(men) or 8 80 cm
(women)
Waist e 102 cm
(men) or 7 88 cm
(women)b
Obesity
WHO 1998
or 1.7 mmol/L
(150 mg/dL)
1.7 mmol/L
(150 mg/dL) or
drug treatment for
high triglycerides
1.7 mmol/L
(150 mg/dL) or
drug treatment for
elevated
triglyceridesa
Triglycerides
EGIR 1999
or 2.0 mmol/L
(180 mg/dL) or
drug treatment for
dyslipidemia
IDF 2005
NCEP ATP3 2005
Table 1
(continued)
Metabolic Syndrome
37
studies groups of two or three or more of these traits occur from 2- to over
1000-fold more commonly than would be expected by chance association alone
(1,14,15). Data from diverse studies show that weight gain, hyperinsulinemia,
and central obesity are key determinants of risk factor clustering (1,1621).
The challenge has been to define diagnostic criteria for risk factor clustering
or metabolic syndrome. Uncertainty in this regard has led to the five different
views of the syndrome shown in the Table 1. The National Cholesterol
Education Programs 3rd Adult Treatment Panel (ATP3) definition is most
widely used. ATP3 criteria diagnose metabolic syndrome if any 3 or more
of 5 traits are present. As no specific trait is required, the ATP3 definition
is something of a grab bag syndrome, as any 3 or more of 5 defines 10
distinct phenotypes, each with modestly common frequency (12). However, as
the definition gives equal weight to either high triglyceride or low HDL-C level,
such that 9 of 10 possible combinations of any 3 or more of 5 include a lipid
abnormality, the ATP3 criteria tend to be a lipid-centric atherogenic dyslipidemia syndrome. The International Diabetes Federation (IDF) definition is
similar to that of ATP3 but requires a large waist circumference for diagnosis,
making this a central obesity syndrome. The European Group for the Study of
Insulin Resistance (EGIR) requires the presence of insulin resistance, making
this definition the closest to that of an insulin resistance syndrome. The
World Health Organization (WHO) requires insulin resistance and/or impaired
or diabetic hyperglycemia, creating a type 2 diabetes/prediabetes syndrome.
The American College of Endocrinology (ACE) insulin resistance syndrome
definition is the least specific of the five, as it specifies that two or more of the
usual abnormalities are present in a very heterogeneous group of high risk
subjects, making this an all-purpose diabetes risk syndrome.
It is apparent from the heterogeneity of syndrome definitions and the phenotypes they produce that the nature of metabolic syndrome is more a function
of perspective than of unifying physiology. These diverse perspectives have
led to a great deal of controversy over the value of metabolic syndrome for
clinical practice or to understand disease etiology (7,8,2225). Some of the key
controversial issues focus on which definition best captures the phenomenon of
risk factor clustering, whether a diagnosis of metabolic syndrome carries any
clinical information beyond that indicated by abnormal levels of its component
traits, whether type 2 diabetes is a component or a consequence of metabolic
syndrome, and what, if any, unifying pathophysiology underlies risk factor
clustering. Some have argued that metabolic syndrome meets criteria for a
syndrome on the basis of an aggregation traits with a common consequence,
regardless of the specific etiology underlying aggregation, while others have
argued that a unifying pathophysiology must be defined before risk factor
clustering can be properly considered a syndrome (8).
38
Meigs
Whether a unifying pathophysiology underlies risk factor clustering is a

critical issue for discussions of therapies for metabolic syndrome. It is widely
assumed that metabolic syndrome is synonymous with insulin resistance.
However, this is only true for the EGIR and WHO metabolic syndromes.
Among subjects with the commonly used ATP3 metabolic syndrome, fewer
than two-thirds are insulin resistant as assessed using insulin clamp or
insulin suppression test methods (26,27). For ATP3 metabolic syndrome,
specific treatment for insulin resistance would not be indicated in most cases,
and treatment implications beyond those already indicated for atherogenic
dyslipidemia are unclear at best. Because of the critical roles of obesity
and physical inactivity in the development of risk factor clustering, the
ATP3 treatment recommendations focus on the treatment of underlying causes
(overweight/obesity and physical inactivity) using TLC and on the treatment of
CVD risk factors if they persist despite lifestyle modification. The implicit goal
of these interventions is to prevent the consequences of metabolic syndrome,
specifically, type 2 diabetes and CVD.
METABOLIC SYNDROME AS A RISK FACTOR

FOR TYPE 2 DIABETES AND CVD
Most studies on the consequences of metabolic syndrome have used variations in the ATP3 or the WHO criteria and assessed risk in groups with versus
those without the syndrome. In a meta-analysis examining metabolic syndrome
as a risk factor for type 2 diabetes or CVD, the syndrome increased risk for
diabetes about threefold based on four studies and increased risk for CVD
by 1.7-fold based on 12 studies (28). A recent analysis from the Framingham
Study extends these data, where metabolic syndrome was associated with a
sevenfold increased relative risk for incident diabetes but a 1.3- to 2.9-fold
increased risk of CVD, confirming that the syndrome is a far stronger risk
factor for type 2 diabetes than for CVD (12).
Metabolic syndrome in the absence of insulin resistance may be a weaker
risk factor than in the presence of insulin resistance. Among Pima Indians,
metabolic syndrome increased the relative risk for incident diabetes by 2.1-fold
using the ATP3 definition and 3.6-fold using the WHO definition (which
requires insulin resistance); ATP3 metabolic syndrome in the absence of insulin
resistance did not increase diabetes risk (29). In the DECODE Study, metabolic
syndrome defined as requiring insulin resistance (defined by an elevated
homeostasis model insulin resistance) plus any two additional ATP3 metabolic
syndrome traits was associated with about a 30% higher relative risk for CVD
compared with risk associated with the standard ATP3 3 or more of 5 traits
definition (30). In the Framingham Study, both ATP3 metabolic syndrome and
Metabolic Syndrome
39
insulin resistance independently predicted incident CVD (31), but in the Hoorn
Study, various metabolic syndrome definitions specifically including elevated
insulin level were not more strongly associated with risk than definitions where
hyperinsulinemia was implied but not specifically required (32).
The data in aggregate support metabolic syndrome as a population-level risk
factor for type 2 diabetes or CVD. This is not a surprise, as metabolic syndrome
comprises most well-accepted risk factors for diabetes or atherosclerosis. The
role of insulin resistance as an underlying factor or independent contributor
to metabolic syndrome consequences remains unresolved. However, it is
generally accepted that obesity and physical inactivity play a role in the development of metabolic syndrome and are also CVD risk factors, and so the best
evidence for treatments of metabolic syndrome centers on TLC.
THERAPEUTIC LIFESTYLE CHANGE TO PREVENT

METABOLIC SYNDROME, TYPE 2 DIABETES, AND CVD
Several lines of evidence suggest that TLC, through improved physical
activity and fitness, weight control, and healthy dietary habits, can prevent or
alleviate metabolic syndrome or its consequences.
In an observational study of physical fitness, LaMonte et al. (33) followed
about 11,000 healthy men and women for 6 years for incident ATP3 metabolic
syndrome, conditioned on baseline measurement of physical fitness using an
exercise treadmill test. They found a very strong doseresponse relationship
between physical fitness and reduced incidence of metabolic syndrome, with
those in the highest tertile of fitness having about one-third the rate of metabolic
syndrome compared with those in the lowest tertile of fitness. In another
observational study, metabolic syndrome increased risk for all-cause mortality,
but this association was largely explained by low physical fitness among
subjects with metabolic syndrome, implying that increased physical fitness
could completely prevent mortality associated with metabolic syndrome (34).
Similar observations have been made with respect to physical activity and
fitness and risk of type 2 diabetes (35) or CVD (36,37), implying that reversal
of physical inactivity may be a key treatment for preventing the ultimate
complications of metabolic syndrome.
Recent dietary intervention studies have specifically addressed treatment and
prevention of metabolic syndrome. Esposito and colleagues (38) randomized 180
Italian men and women with ATP3 metabolic syndrome to a Mediterranean-style
diet (foods rich in mono- and polyunsaturated fat, fiber, a low ratio of omega6 to omega-3 fatty acids) or to an ad lib diet, and followed them for 2 years.
Subjects in the Mediterranean diet arm lost more weight than those in the ad
lib arm, but even after accounting for this difference, the Mediterranean diet
40
Meigs
was associated with a 39% reduction in the prevalence of metabolic syndrome.

In addition, the Mediterranean diet was associated with significant reductions
in the levels of inflammatory markers and improved indices of endothelial
function, suggesting both a close relationship of these traits with metabolic
syndrome and identifying a more vascular global benefit of Mediterranean-style
diets. As for physical fitness, Mediterranean-style diets may be beneficial for
prevention of type 2 diabetes or CVD as well as metabolic syndrome (39,40),
pointing to dietary change as a key treatment for preventing the ultimate complications of metabolic syndrome. Another recent trial showed that the DASH
diet (reduced calories and increased consumption of fruit, vegetables, lowfat dairy, and whole grains and reduced saturated fat, total fat, and cholesterol, and restricted to 2400 mg sodium) beneficially lowered all metabolic
syndrome trait levels (41). Exactly which components of these healthy diets
are beneficial, or their mechanism of metabolic benefit, remains uncertain.
For instance, diets high in dietary fiber and low in simple sugars have been
associated with a lower prevalence of insulin resistance and of metabolic
syndrome (42). These diets may also act by reducing inflammatory stimuli
leading to metabolic syndrome (43). More research is required to specify optimal
dietary patterns and mechanisms for dietary treatment of metabolic syndrome.
Global benefits on metabolic syndrome of TLC combining physical activity
and dietary treatment have been shown in two diabetes prevention trials. The
Diabetes Prevention Program (DPP) was a 3-year randomized controlled trial
comparing the ability of structured therapeutic lifestyle change, metformin,
or placebo and basic diet and exercise advise for the prevention of type 2
diabetes. A post hoc analysis of metabolic syndrome in the DPP has recently
been published (44). At baseline, 47% of enrollees did not have metabolic
syndrome. Structured lifestyle change was associated with a 41% reduction in
the incidence of metabolic syndrome compared with the placebo group. Among
DPP subjects with metabolic syndrome at baseline, the lifestyle intervention
was associated with a small but significant decrease in the prevalence of the
syndrome. The Finnish Diabetes Study (FDS) also demonstrated that TLC
reduced the risk of type 2 diabetes by about 58%. At baseline, about 75%
of participants had WHO metabolic syndrome, suggesting that many subjects
with metabolic syndrome will benefit from TLC to prevent diabetes (45).
DPP and FDS data strengthen the evidence base for TLC to prevent or treat
metabolic syndrome.
DRUG THERAPIES FOR METABOLIC SYNDROME

Discussion of drug therapies for metabolic syndrome would be more
straightforward if there were agreement on a case definition that
produced a consistent phenotype with an identifiable, treatable underlying
Metabolic Syndrome
41
pathophysiology, and if there were evidence that treatment of the syndrome

per se produces equivalent or better outcomes than treatment to lower levels
of the syndromes component risk factors. Theoretically, the goals of drug
treatment for metabolic syndrome are similar to those of TLCto reduce
risk factor clustering, reduce absolute levels of component risk factors, and
prevent the diabetes and CVD consequences of the syndrome. Whether it
is sensible or ethical to expose otherwise well asymptomatic people with a
controversial diagnosis to long-term prophylactic drug therapy is an important,
unresolved question. Clearly, there is a strong evidence base for treatment of the
component traits of the syndrome, especially hypertension, hyperlipidemia, and
glucose intolerance, to prevent diabetes or CVD (4648). It remains entirely
unclear whether therapies aimed at risk factor clustering per se offer any
benefits beyond those offered by TLC or drug therapy for specific, abnormal
trait levels. Nonetheless, one might consider drug therapies specifically for
metabolic syndrome target insulin resistance, the endocannabinoid system, and
endothelial dysfunction.
Metformin is an insulin-sensitizing drug that acts primarily to reduce hepatic
insulin resistance. In the DPP, metformin therapy was associated with a 17%
reduction in incident metabolic syndrome compared with the placebo group (44),
as well as a 31% reduction in the incidence of type 2 diabetes (48). In a post
hoc analysis of the UK Prospective Diabetes Study, metformin significantly
reduced the risk of diabetes-related death (most of which were CVD deaths) in
obese diabetics by 42% (49). However, in the DPP, TLC but not metformin was
associated with improved levels of CVD risk factors (50). Although post hoc
subgroup analyses only provide indirect evidence, metformin appears to prevent
the metabolic syndrome and consequent diabetes, but its role in preventing CVD
associated with insulin resistance remains uncertain.
Thiazolidinediones (TZDs), agonists of the peroxisome proliferatoractivated receptor (PPAR ), reduce insulin resistance in skeletal muscle and
liver. TZDs lower blood glucose in type 2 diabetes, and improve levels of
many CVD risk factors associated with metabolic syndrome. TZDs raise the
levels of HDL-C and reduce the levels of triglycerides and markers of inflammation, oxidative stress, and endothelial dysfunction (5155). However, TZDs
are also associated with fluid retention, weight gain, and central (primarily
subcutaneous) fat redistribution.
TZDs may reduce the risk of type 2 diabetes in high-risk individuals. In
Hispanic women with a history of gestational diabetes, troglitazone (now
unavailable in the USA) reduced risk for subsequent type 2 diabetes by 56%
(56). During the brief (less than a year) use of troglitazone in the DPP, TZD
therapy was associated with a 75% reduction in the incidence rate of type 2
diabetes compared with placebo. This beneficial effect did not persist once
troglitazone therapy was discontinued (57).
42
Meigs
TZDs may also have CVD benefits. In nondiabetic subjects with angiographic CVD, therapy with rosiglitazone prevented the progression of common
carotid artery atherosclerosis over about 4 years of treatment (58). In the recent
PROactive trial, type 2 diabetes patients with clinical CVD were randomized
to placebo or pioglitazone added to standard diabetes care. Although pioglitazone did not significantly reduce the main endpoint (all-cause mortality and
all CVD events), pioglitazone reduced the prespecified secondary composite
event rate (all-cause mortality, nonfatal myocardial infarction, and stroke)
by 16% (P = 0.03) compared with placebo (59). In PROactive trail, pioglitazone also reduced levels of many CVD risk factors, and modestly improved
glycemia. Whether pioglitazones CVD benefit is mediated via risk factor
reduction or improved insulin sensitivity is uncertain. In addition, whether
benefits of TZDs can be extended to diabetes patients without clinical CVD
or to nondiabetic subjects is unknown. Thus, TZDs have promising effects on
diverse metabolic syndrome components and would seem an attractive drug
therapy. However, there is currently no direct evidence that TZDs reduce
risk for the syndrome or risk for diabetes or CVD in patients with metabolic
syndrome. In addition, TLC promotes weight loss and improves insulin sensitivity to a greater degree than pioglitazone (60), further emphasizing the value
and preference for TLC over insulin sensitization as current, evidence-based
therapy for metabolic syndrome.
Beyond TZD PPAR- agonists, PPAR- agonists, including the fibric acid
derivatives fenofibrate and gemfibrozil, have been shown in clinical trials
to reduce cardiovascular events or slow atherosclerosis progression (6163).
Thus, dual PPAR-- agonists would seem a reasonable drug strategy to
treat metabolic syndrome and prevent its diabetes and CVD consequences.
Unfortunately, the only dual agonist yet studied in the USA, muraglitazar,
was recently shown to be associated with an excess incidence of death and
major adverse CVD events in patients with type 2 diabetes compared with
placebo or pioglitazone. Thus, at this time, dual PPAR-- agonists cannot
be recommended for the treatment of either type 2 diabetes or its precursor
metabolic syndrome.
Clinical trial data indicated that several other specific drugs have potential
use in the treatment of metabolic syndrome. Acarbose, an -glucosidase
inhibitor with modest blood-glucose-lowering effects, has been shown to
prevent type 2 diabetes as well as CVD events in prediabetics (64,65). Orlistat,
a gastrointestinal lipase inhibitor that reduces dietary fat absorption, has been
shown reduce the risk of developing glucose intolerance and type 2 diabetes
in obese subjects. Its benefits on CVD risk have not been established.
Rimonabant, a cannabinoid CB-1 receptor blocker currently in clinical development, acts in the newly discovered endocannabinoid system to reduce food
Metabolic Syndrome
43
intake and body weight and increase blood adiponectin levels. Adiponectin, a
hormone derived from adipose tissue, has potentially important effects on insulin
sensitivity and atherogenesis and may play a role in the pathogenesis of risk factor
clustering (6669). Rimonabant therefore appears to be a unique drug targeted
at fundamental abnormalities putatively underlying risk factor clustering and the
metabolic syndrome. The potential benefits of Rimonabant have been shown in
the RIO-Europe (obese subjects) and RIO-Lipid (obese subjects with dyslipidemia) trials (70,71). In these trials, as compared with placebo, 20 mg/day of
Rimonabant was associated with a significant weight loss (about 6 kg), a reduction
in waist circumference (about 5 cm), an increase in HDL cholesterol (about 9%),
a reduction in triglycerides (about 12%), and an increase in plasma adiponectin
levels (about 50%). The rise in adiponectin was partly independent of weight
loss alone. In RIO-Lipid, about 50% of the participants had ATP3 metabolic
syndrome. The prevalence of metabolic syndrome at study end in subjects in the
Rimonabant 20 mg/day arm was 26%, compared with 45% in the placebo arm
(p-value for difference in prevalence 0.001). Reduced prevalence of metabolic
syndrome was attributed mainly to the reduction in waist circumference and the
increase in HDL cholesterol levels. These data suggest that Rimonabant may be
uniquely useful for the treatment of metabolic syndrome, but greater experience
with the drug, especially safety experience, is required. In addition, data bearing
on Rimonabants effects on the long-term incident of type 2 diabetes and CVD
are needed before definitive recommendations can be made for or against Rimonabant for the treatment of metabolic syndrome.
Drugs with beneficial effects on endothelial function also offer potential for
treatment of metabolic syndrome. Vascular endothelial dysfunction is marked
by abnormal endothelial nitric oxide synthase function, impaired brachial artery
flow mediated dilation, and elevated levels of cellular adhesion molecules.
Endothelial dysfunction has been associated with insulin resistance and increased
risk of diabetes and CVD and may play a role in the development of risk factor
clustering (7275). Reninangiotensin system-acting drugs [ACE inhibitors
and angiotensin receptor-blockers (ARBs) and HMG CoA reductase inhibitors
(statins)] both are well-established drugs for the prevention of CVD (47,76,77).
ACE/ARBs and statins have also been shown to reduce markers of systemic
inflammation and oxidative stress, improve insulin sensitivity and markers of
endothelial dysfunction, and in post-hoc subgroup analyses, have been associated
with reduced incidence of type 2 diabetes (57,7884). As these drugs act on
traits of the metabolic syndrome as well as its potential underlying pathophysiology, it will be difficult to unequivocally determine whether they are beneficial
for metabolic syndrome per se. Nonetheless, both ACE inhibitors/ARBs and
statins have proven benefits for treatment of hyperglycemia, hyperlipidemia, and
44
Meigs
hypertension and can be recommended for most patients with these conditions,
regardless of the presence or absence of metabolic syndrome.
CONCLUSIONS
Risk factor clustering occurs in individuals and when present is called
metabolic syndrome. On a population basis, metabolic syndrome is a strong
risk factor for type 2 diabetes and a somewhat weaker but significant risk factor
for CVD events. Metabolic syndrome appears to be increasingly common
and driven primarily by obesity and physical inactivity. Its specific underlying pathophysiology has not been determined, although insulin resistance
and perhaps endothelial dysfunction play an important role in many cases.
There are several metabolic syndrome diagnostic schemes, the most commonly
used of which is the ATP3 metabolic syndrome criteria. A limitation of ATP3
metabolic syndrome with respect to drug therapy recommendations is that
individual patients may have one of many fairly distinct phenotypes, and only
about half with ATP3 metabolic syndrome have substantial insulin resistance.
As of 2005, no drug or drug class can be recommended for specific treatment of
the metabolic syndrome. Additional clinical trials efficacy and safety data for
insulin-sensitizing drugs, Rimonabant, and ACE inhibitors/ARBs and statins,
specifically for treatment of metabolic syndrome or prevention of diabetes or
CVD in metabolic syndrome, are required before firm recommendations can
be made. On the contrary, there is strong evidence that TLC, especially weight
loss and healthy weight maintenance, healthy dietary habits, and increased
physical activity, improves metabolic syndrome trait levels, lowers the prevalence of metabolic syndrome, are safe for most people, and have other,
nonobesity health benefits. When TLC fails to favorably benefit levels of blood
pressure, cholesterol, and blood glucose, drugs targeted specifically at these
risk factors to prevent CVD, and perhaps diabetes, are warranted. In summary,
there does appear to be treatment that works for risk factor clustering, called
metabolic syndrome. Providers and patients should work to treat the underlying
causes of overweight, obesity, and physical inactivity by intensifying weight
management and increasing physical activity, and to treat cardiovascular risk
factors if they persist despite lifestyle modification.
ACKNOWLEDGMENTS
Dr. Meigs is supported by an American Diabetes Association Career Development Award, has received unrestricted research support from Aventis-Sanofi,
Glaxo-Smith-Kline, Novartis, Pfizer, and Wyeth, and has served on safety
monitoring or advisory boards for GSK, Lilly, Pfizer, and Merck.
45
Metabolic Syndrome
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Intensive Treatment
and Complications of Diabetes
Can They Be Effectively Reduced?
Vivian Fonseca MD,

and Ali Jawa, MD
FRCP
CONTENTS
Introduction
Pathophysiology of Diabetic Vascular Disease
Intensive Therapy
Advantages of Intensive Therapy: Data
from Clinical Trials
Multiple Risk Factor Approach
to Intensive Therapy
Mechanisms of the Benet of Intensive
Therapy
Approaches to Intensive Therapy
to Prevent Complications
Intensive Lifestyle Change
Intensive Pharmacological Therapy
with Oral Agents
Current Clinical Trials in Progress
References
Summary
Diabetes mellitus (DM) is a growing health problem in the USA, afflicting
over 18.2 million Americans. Morbidity and mortality from DM most
commonly result from the long-term complications of the disease. Intensive
therapy reduces blood sugars to near normal and effective management
51
52
Fonseca and Jawa
of other associated risk factors such as lipid abnormalities and blood

pressure (BP). New clinical trials are being carried out to determine whether
goals for intensive therapy should be lower than current goals and to test
various therapeutic strategies to determine the optimum methods to prevent
diabetes complications. Cardiovascular disease (CVD) disproportionately
affects people with diabetes and is a leading cause of death. So far, intensive
glycemic control has not been conclusively shown to decrease cardiovascular
events. The therapeutic agents used in treating glycemia have different effects
on cardiovascular risks and therefore may have different effects on outcome.
Metformin was the only oral anti-diabetic medication shown to decrease
cardiovascular events independent of glycemic control. Thiazolidinediones
improve insulin resistance and lower insulin concentrations, which may be
beneficial because hyperinsulinemia is an independent predictor of CVD. In
the recent PROACTIVE study, a pioglitazone treatment was associated with
a significant reduction in myocardial infarction and cardiovascular mortality,
although that was not the primary endpoint of the study. Insulin therapy
acutely reduces mortality and morbidity in patients with hyperglycemia when
critically ill, but the effect on cardiovascular events is unclear. In contrast,
insulin secretagogues have very little effect on both cardiovascular risk
factors and outcomes. Thus, the role of intensive glycemic control and the
choice of therapeutic agents to reduce the macrovascular complications of
diabetes are unclear.
Key Words: Diabetes, cardiovascular disease, insulin resistance.
INTRODUCTION
Diabetes is a leading cause of morbidity and mortality related to its longterm complications. The microvascular complications of diabetes are specific
to the condition, and diabetes is the leading cause of blindness and endstage kidney disease in the USA. However, for patients with type 2 diabetes,
cardiovascular disease (CVD) occurs at a younger age and is associated with
more complications making it the cause of mortality in most of these patients.
Data from several studies suggest that aggressive management of diabetes
and its associated risk factors will lead to a reduction in these long-term
complications.
CVD, including coronary artery disease (CAD), peripheral arterial disease
(PAD), and cerebrovascular disease, disproportionately affects people with
diabetes and is a leading cause of death. There is a significantly increased
risk of CAD with type 2 diabetes (1). Diabetes is considered a coronary heart
disease risk equivalent, and people with diabetes have not experienced similar
reductions in cardiovascular mortality, as observed in non-diabetic patients,
Intensive Treatment and Complications of Diabetes
53
with improvements in treatment of heart disease (2). Thus, novel approaches to

treatment and perhaps lower treatment goals for risk factor reduction may be
needed to decrease the burden of the macrovascular complications of diabetes.
PATHOPHYSIOLOGY OF DIABETIC VASCULAR DISEASE

Although the pathogenesis of diabetes is variable and complex, the resultant
hyperglycemia, elevated free fatty acids, and insulin resistance all contribute
to increased cardiovascular morbidity and mortality. Together, these lead to
decreased endothelial function, oxidative stress, and other biochemical abnormalities. Therefore, treatments that do not address these abnormalities may not
impact CVD.
Nitric oxide (NO) is produced by endothelial cells and is an important marker
of vascular health. It is a potent vasodilator, limits platelet activation, limits
inflammation by reducing leukocyte adhesion to endothelium, and migration
into the vessel wall (3). It also diminishes smooth muscle cell proliferation
and migration (3). Insulin resistance and hyperglycemia are associated with
decreased NO production and availability by increasing oxidative stress (4).
Free fatty acids are increased in obesity and are closely linked with the pathogenesis of diabetes and insulin resistance. The increased FFA contributes to
dyslipidemia by stimulating very-low-density lipoprotein (VLDL) production
from the liver (4). Free fatty acids also contribute to elevated triglycerides,
lowered high-density lipoprotein (HDL), and increased small dense LDL.
Insulin resistance leads to hyperinsulinemia in diabetes. In healthy people,
insulin increases NO-mediated vasodilatation, but this is reduced in diabetes (4).
Atherogenesis begins with migration of T-cell lymphocytes and monocytes
into the intima, which is enhanced in diabetes (5). T cells secrete cytokines and
monocytes ingest oxidized LDL and become foam cells. There is increased
activation of transcription factors nuclear factor B and activator protein
1, which regulate other mediators of atherogenesis including leukocyte cell
adhesion molecules, leukocyte-attracting chemokines, and proinflammatory
mediators such as interleukin 1 and tumor necrosis factor (5).
Impaired platelet function in diabetes can exacerbate the progression of
atherosclerosis and the enhanced thrombotic potential (4). In addition to
impaired platelet function, there is impaired fibrinolytic ability because of
elevated plasminogen activator inhibitor type 1 (PAI-1) in diabetes. Therefore,
the combination of impaired endothelial cells, vascular smooth abnormalities,
and impaired coagulation and fibrinolysis favors formation and persistence of
thrombi (4).
In this review, we will focus on anti-diabetic therapies and their impact
on atherosclerosis either through direct effects on hyperglycemia, free fatty
54
Fonseca and Jawa
acids, and insulin resistance or through indirect influence on non-traditional

cardiovascular risk factors.
INTENSIVE THERAPY
The term intensive therapy began to be widely used after publication
of the results of the Diabetes Control and Complications Trial (DCCT) (6).
The DCCT was carried out in patients with type 1 diabetes, and the intensive
therapy group attempted to maintain normoglycemia, but managed to achieve
an HbA1c of 7%, which was 2% lower than the conventional treatment group,
and resulted in a very significant reduction in complications of diabetes. The
strategy used for intensive therapy in the DCCT consisted of three to four
injections of insulin per day (usually using a basal-bolus approach) or a
continuous infusion of insulin using a pump compared with less frequent
injections of mixed insulin (6). The term intensive therapy was initially
widely used to this approach of multiple injection insulin therapy. However, in
the United Kingdom Prospective Diabetes study (UKPDS), the term was used
even for oral agent therapy if the aim was to keep the HbA1c as low as possible
(6). Increasingly (and perhaps rightly so), the term is now being used for
whatever strategy is used to keep blood sugars near normal as well as aggressive
management of other associated risk factors such as lipid abnormalities and
blood pressure (BP) as in the Steno-2 Diabetes Study(7).
ADVANTAGES OF INTENSIVE THERAPY: DATA

FROM CLINICAL TRIALS
The DCCT examined whether intensive treatment with the goal of
maintaining blood glucose concentrations close to the normal range could
decrease the frequency and severity of microvascular complications in patients
with type 1 diabetes (6). In the primary-prevention cohort, intensive therapy
reduced the risk for the development of retinopathy by 76% compared with
conventional therapy. In the secondary-intervention cohort, intensive therapy
slowed the progression of retinopathy by 54%. Intensive therapy reduced the
occurrence of microalbuminuria by 39%, albuminuria by 54% and that of
clinical neuropathy by 60%. Thus, intensive therapy effectively delays the onset
and slows the progression of diabetic complications in patients with IDDM.
To determine the long-term effects of intensive versus conventional diabetes
treatment during the DCCT, researches have examined the DCCT cohort
annually for another 8 years as part of the follow-up Epidemiology of Diabetes
Interventions and Complications (EDIC) study (8,9). During the EDIC study,
glycemic levels no longer differed significantly between the two original
treatment groups, with an HbA1c of approximately 8% in both groups. Results
55
were analyzed by intention-to-treat analyses, comparing the two original DCCT

treatment groups. New cases of microalbuminuria occurred during the EDIC
study in 6.8% of the participants originally assigned to the intensive-treatment
group versus 15.8% of those assigned to the conventional-treatment group, for
a 59% reduction in odds, which was very similar to the reduction at the end
of the DCCT (9). Similarly, there was a significant reduction in odds for the
development of clinical albuminuria and retinopathy (8).
Thus, intensive management of glycemia may have long-lasting benefits
over conventional therapy. This finding has far-reaching implications for how
diabetes is or should be managed. The term metabolic memory has been
used to propose the hypothesis that a period of near normoglycemia will lead
to long-term benefits even if loss of control subsequently occurs (10).
Although cardiovascular events remain too low in this cohort, significantly
fewer cases of hypertension have developed in the original intensive-treatment
group and the carotid intimamedia thickness (a surrogate for atherosclerosis)
is also significantly lower in the intensive group (11). Thus, it is possible that
a few years of good glycemic control, using insulin exclusively, may reduce
the risk for cardiovascular events several years later.
In the UKPDS, patients randomized to intensive therapy had a significant
reduction in microvascular complications with whatever therapy was used,
although because of the progressive nature of type 2 diabetes, diabetic control
was sub-optimal for many patients in the trial. Furthermore, the difference in
HbA1c between intensive and conventional therapy groups was only 0.9%.
In obese patients, in the UKPDS, randomization to metformin resulted in
a reduction in not only microvascular but also macrovascular complications
(12). However, when the UKPDS results were analyzed according to HbA1c
achieved rather than an intent-to-treat basis, macrovascular complications were
also reduced significantly in patients who achieve good glycemic control (13).
To determine the relation between exposure to glycemia over time and the
risk of macrovascular or microvascular complications in patients with type
2 diabetes, Stratton et al. analyzed data from UKPDS patients independent
of their randomization in the study. The incidence of clinical complications
was significantly associated with glycemia. Each 1% reduction in HbA1c was
associated with reductions in risk of 21% for any endpoint related to diabetes,
21% for deaths related to diabetes, 14% for myocardial infarction (MI), and
37% for microvascular complications. No threshold of risk was observed for
any endpoint. Thus, any reduction in HbA1c is likely to reduce the risk of
complications, with the lowest risk being in those with HbA1c values in the
normal range (<6.0%). Whether such a reduction can be achieved without
risk of hypoglycemia is currently being tested in prospective clinical trials,
attempting normoglycemia.
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Fonseca and Jawa
In the Kumamoto study, only insulin therapy was used in patients with type
2 diabetes. Patients randomized to intensive treatment received multiple insulin
injections and had a significant reduction in microvascular and macrovascular
complications of diabetes compared with the conventional treatment group
(14). These results as well as analysis of the DCCT treatment approach suggest
that multiple insulin injections by reducing fluctuations in glucose for the
same level of HbA1c may lead to a greater reduction in complications than
that suggested by HbA1c reduction alone. Whether this difference is due to a
reduction in postprandial excursions or just random fluctuation in glucose is not
clear, as continuous measurements of glucose were not made in these studies.
Recently, studies have focused on the role of intensive therapy to prevent
cardiovascular eventsespecially as secondary prevention. Stress hyperglycemia with MI is associated with an increased risk of in-hospital mortality
in patients with and without diabetes; the risk of congestive heart failure or
cardiogenic shock is also increased in patients without diabetes (15). Insulin
infusions have been shown to decrease mortality and events in intensive care
units. Thus, in this setting of critical illness and MI, intensive therapy of
diabetes may mean infusions of insulin intravenously while in hospital.
In the DIGAMI study, patients presenting with a MI were randomized to
an insulin infusion while in hospital followed by 36 months of multiple
insulin injections (16). This treatment resulted in a 25% reduction in mortality
following MI at the end of 1 year, and this benefit was maintained for a
further 4 years. The effect was most apparent in patients who had not previously received insulin treatment and who were at a low cardiovascular risk.
However, in DIGAMI 2, insulin-infusion therapy following an MI did not
reduce CV events (17). This negative result may have been related to the
fact that the control group had glycemic control as good as the insulin-treated
group, suggesting that glycemic control is also important.
A recent study has demonstrated that an infusion of insulin on admission
with a MI decreases markers of inflammation, oxidative stress, and abnormal
fibrinolysis and leads to a possible reduction in infarct size (18); on the contrary,
the CREATE ECLA study showed no benefit from an infusion of glucose,
insulin, and potassium (19). However, the blood glucose in the treated group
was higher than that in the control group, suggesting that even modest degrees
of hyperglycemia may be detrimental.
Van Den Berghe et al. performed a prospective, randomized, controlled
study on adults admitted to a surgical intensive care unit who were receiving
mechanical ventilation. On admission, patients were randomly assigned to
receive intensive insulin therapy with an insulin infusion (maintenance of
blood glucose at a level between 80 and 110 mg/dl) or conventional treatment
(infusion of insulin only if the blood glucose level exceeded 200 mg/dl and
maintenance of glucose at a level between 180 and 200 mg/dl). Intensive
57
insulin therapy reduced mortality during intensive care from 8.0% with conventional treatment to 4.6% (p < 0.04). Intensive insulin therapy also reduced
overall in-hospital mortality by 34%, bloodstream infections by 46%, acute
renal failure requiring dialysis or hemofiltration by 41%, the median number
of red-cell transfusions by 50%, and critical-illness polyneuropathy by 44%,
and patients receiving intensive therapy were less likely to require prolonged
mechanical ventilation and intensive care (20). Thus, intensive insulin therapy
to maintain blood glucose at or below 110 mg/dl reduces morbidity and
mortality among critically ill patients in the surgical intensive care unit.
MULTIPLE RISK FACTOR APPROACH

TO INTENSIVE THERAPY
The Steno-2 Study involved patients with type 2 diabetes at high risk for
CVD events because they had microalbuminuria (7). The effect of a targeted,
intensified, multifactorial intervention was compared with that of conventional
treatment on modifiable risk factors for CVD in these patients over a mean
follow-up period of 7.8 years. Eighty patients were randomly assigned, with
an open, parallel design, to receive conventional treatment in accordance with
national guidelines and 80 to receive intensive treatment, with a stepwise
implementation of behavior modification and pharmacological therapy that
targeted hyperglycemia, hypertension, dyslipidemia, and microalbuminuria,
along with secondary prevention of CVD with aspirin.
The decline in HbA1c, systolic and diastolic BP, serum cholesterol and
triglyceride levels, and urinary albumin excretion rate were all significantly
greater in the intensive-therapy group than in the conventional-therapy group,
although many patients did not meet pre-determined goals. Patients receiving
intensive therapy had a significantly lower risk of CVD (hazard ratio, 0.47),
nephropathy (hazard ratio, 0.39), retinopathy (hazard ratio, 0.42), and autonomic
neuropathy (hazard ratio, 0.37). Thus, target-driven, long-term, intensive therapy
aimed at multiple risk factors in patients with type 2 diabetes and microalbuminuria reduces the risk of cardiovascular and microvascular events by about
50% (7). Thus, to prevent macrovascular disease, we found that a multiple risk
factor approach using multiple therapies may be necessary for cardiovascular
event prevention.
MECHANISMS OF THE BENEFIT OF INTENSIVE THERAPY

Hyperglycemia leads to multiple biochemical and structural abnormalities
(2022). In the short term, these include development of oxidative stress,
endothelial dysfunction, and activation of coagulation. In the long term, glycosylation of proteins leads to formation of advanced glycosylation end products
(AGEs), which lead to stiffening of the arterial wall and other connective tissue
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changes. Other biochemical abnormalities include accumulation of sorbitol in

tissue such as the nerve, kidney, and ocular lens, and activation of protein
kinase-C, an important mediator of tissue damage particularly in relation
to microvascular disease. Another contributor to macrovascular pathogenesis
is the increased level of free fatty acids present in states of insulin resistance. In addition, as the disease progresses and blood glucose levels rise,
hyperglycemia-induced reactive oxidative species may in turn contribute to
activation of each of the above biochemical pathways.
APPROACHES TO INTENSIVE THERAPY

TO PREVENT COMPLICATIONS
The lack of reversibility of established (clinically detectable) complications
is well recognized. Early and aggressive correction of hyperglycemia may
result in reversal of many of the biochemical abnormalities both in the short
term as well as in the long term, but clinical features are rarely, if ever,
reversed. Thus, clinical trials are needed in patients with very early abnormalities in blood glucose (such as during the stage of pre-diabetes) to determine
whether such early intervention will lead not only to prevention of complications but prevention of diabetes itself. Clinical trials are in progress to test this
hypothesis.
The possibility of preventing the imprinting of target cells with the cellular
and molecular changes described demands the achievement of near normoglycemia early in diabetes. Near-normoglycemic remissions have occurred
following the withdrawal of therapy in patients with type 2 diabetes who had
received intensive treatment after presenting with severe hyperglycemia (24).
Although it is difficult to determine the exact reason for these remissions, they
might be due to amelioration of glucose toxicity by initial intensive glycemic
control (25). In addition, intensive insulin therapy may have a beneficial effect
on insulin resistance and might in part be mediated by insulin-induced lowering
of free fatty acid concentrations and resultant reduction in lipotoxicity.
Intensive therapy can consist of multiple different strategies, including diet,
to induce weight loss, exercise, frequent blood glucose monitoring, oral agents,
and insulin.
INTENSIVE LIFESTYLE CHANGE

Overweight and obesity are major contributors to both type 2 diabetes
and CVD, and lifestyle change may be necessary for the prevention and
treatment of diabetes. The Diabetes Prevention Program randomly assigned
3234 non-diabetic persons with elevated fasting and post-load plasma glucose
59
concentrations to placebo, metformin (850 mg twice daily), or a lifestylemodification program with the goals of at least a 7% weight loss and at
least 150 min of physical activity per week (25). The lifestyle intervention
reduced the incidence of diabetes by 58% and metformin by 31% compared
with that of placebo; the lifestyle intervention was significantly more effective
than metformin. Follow up of this cohort may determine the value of this
strategy in the prevention of CVD. Other clinical trials currently ongoing will
determine whether early use of thiazolidinediones (TZDs), blockade of the
renninangiotensin system, and even the early use of insulin can prevent the
progression of type 2 diabetes and its macrovascular complications.
Although short-term weight loss has been shown to ameliorate obesityrelated metabolic abnormalities and CVD risk factors, the long-term consequences of intentional weight loss in overweight or obese individuals with type
2 diabetes have not been adequately examined. The Look AHEAD clinical
trial is ongoing with a primary objective of assessing the long-term effects (up
to 11.5 years) of an intensive weight loss program delivered over 4 years in
overweight and obese individuals with type 2 diabetes (26). Approximately
5000 male and female participants who have type 2 diabetes, are 4574 years
of age, and have a body mass index 25 kg/m (2) will be randomized to one of
the two groups. The intensive lifestyle intervention is designed to achieve and
maintain weight loss through decreased caloric intake and increased physical
activity. This program is compared to a control condition given diabetes support
and education. The primary study outcome is time to incidence of a major
CVD event.
Hamdy et al. have demonstrated that 6 months of weight reduction and
exercise improve macrovascular endothelial function and reduce selective
markers of endothelial activation and coagulation in obese subjects with the
insulin resistance syndrome (IRS) regardless of the degree of glucose tolerance
(27). These results may have important implications for prevention of CVD in
diabetes.
INTENSIVE PHARMACOLOGICAL THERAPY

WITH ORAL AGENTS
Intensive therapy with oral agents has been shown to lead to long-term
benefits including possible remission of diabetes in a few patients. However,
oral agent therapy has so far not been shown to change the natural history
of diabetes resulting in progressive loss of beta-cell function and thereby
secondary failure of these oral agents. Thus, it may not be possible to
completely eliminate long-term complications by oral agents alone.
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Biguanides
Metformin is the only biguanide available for clinical use. In contrast to the
secretagogues, metformin lowers rather than increases fasting plasma insulin
concentrations. It reduces basal hepatic glucose production in the presence of
insulin and enhances muscle insulin sensitivity. Metformin promotes weight
loss and is preferred in overweight patients with diabetes. Also, there are less
episodes of hypoglycemia (28) with its use compared with that of insulin and
sulfonylureas (SU).
In the UKPDS 34, treatment with metformin was shown to produce greater
reduction in macrovascular complications including MI, stroke, and death than
sulfonylureas and insulin (12). This decrease in cardiovascular events was
independent of glycemic control. In a retrospective analysis of the Prevention of
Restenosis with Tranilast and its Outcomes Trial, patients with diabetes treated
with metformin appeared to have decreased MI and death compared with nonsensitizer therapy (29). This is important as people with diabetes undergoing
coronary interventions have worse outcomes than patients without diabetes,
as mentioned above. However, this concept has not been tested prospectively.
Metformin has been associated with decreased PAI-1 activity (30), leading
to increased fibrinolytic activity and improved endothelial function. Metformin
has a modest favorable effect on plasma lipids, particularly lowering triglycerides and LDL cholesterol (LDL-C); however, it has little, if any, effect on
HDL cholesterol levels (31). Therefore, metformin treatment lowers plasma
insulin levels, decreases hyperglycemia, and positively influences non-traditional
risk factors associated with the insulin resistance syndrome. Gastrointestinal side
effects are most common but lactic acidosis is a rare but serious complication,
so metformin is contraindicated in renal and hepatic disease.
Thiazolidinediones
The TZDs including rosiglitazone and pioglitazone are used for treatment of
type 2 diabetes. The TZDs bind and activate peroxisome proliferator-activated
receptor (PPAR)-, a nuclear receptor that affects differentiation of cells,
particularly adipocytes. This receptor is also expressed in several other tissues,
including vascular tissue. They decrease insulin resistance in skeletal muscle
and fatty tissue and increase peripheral glucose uptake. This is important
because hyperinsulinemia, a marker of insulin resistance, is an independent
predictor of CVD (32). The reduced peripheral insulin resistance results in
increased peripheral glucose utilization, reduced hepatic gluconeogenesis, and
improvement in glucose control.
The TZDs have the potential to alter metabolic conditions beyond the
management of glycemia. Because the TZDs target insulin resistance, these
61
agents may improve many of the risk factors associated with the insulin resistance syndrome including dyslipidemia, hypertension, impaired fibrinolysis,
and atherosclerosis. It appears that the TZDs exert numerous non-glycemic
effects that may improve cardiovascular outcomes.
In this context, the results of the PROACTIVE study are important (33).
PROACTIVE was a prospective, randomized controlled trial in 5238 patients
with type 2 diabetes who had evidence of macrovascular disease. Patients
were assigned to oral pioglitazone titrated from 15 to 45 mg (n = 2605) or
matching placebo (n = 2633), to be taken in addition to their glucose-lowering
drugs and other medications. The primary endpoint was the composite of
all-cause mortality, non-fatal MI (including silent MI), stroke, acute coronary
syndrome, endovascular or surgical intervention in the coronary or leg arteries,
and amputation above the ankle. Over a period of almost 3 years, 514 of 2605
patients in the pioglitazone group and 572 of 2633 patients in the placebo
group had at least one event in the primary composite endpoint (HR 0.90, 95%
CI 0.801.02, p = 0.095). The main secondary endpoint was the composite of
all-cause mortality, non-fatal MI, and stroke. Three hundred and one patients
in the pioglitazone group and 358 in the placebo group reached this endpoint
(0.84, 0.720.98, p = 0.027). Overall safety and tolerability was good with no
change in the safety profile of pioglitazone identified. Those patients in the
pioglitazone and placebo groups [6% (149 of 2065) and 4% (108 of 2633),
respectively] were admitted to hospital with heart failure; mortality rates from
heart failure did not differ between groups. Thus, pioglitazone reduces the
composite of all-cause mortality, non-fatal MI, and stroke in patients with type
2 diabetes who have a high risk of macrovascular events.
However, the better glycemic control in the pioglitazone group and its
increase reported heart failure and weight gain raise many questions about the
role of TZDs in CVD protection. Thus, the study is being interpreted with
some caution (34) and raises several important questions that have implications
for this class of drug, as well as design of diabetes-related clinical trials.
Several ongoing studies may clarify these issues. The mechanisms underlying
the benefits seen in PROACTIVE were not elucidated in the trial. However,
an impressive body of literature sheds some light on possible mechanisms.
Insulin resistance and diabetes are associated with lipid abnormalities
including elevated triglycerides and decreased HDL cholesterol. All the TZDs
raise HDL cholesterol, although only troglitazone and pioglitazone have been
shown to consistently lower triglycerides (3537). Although LDL levels do
not differ, qualitative changes in LDL-C are common in patient with diabetes
and the effects of TZDs on LDL are more complex. TZDs have been shown
to increase total cholesterol and LDL-C but the increase is primarily larger,
more buoyant particles, which may be less atherogenic (38,39).
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B-mode ultrasound is a non-invasive method for evaluating carotid

intimalmedial complex thickness, which is an indicator for early atherosclerosis and is associated with insulin resistance (40,41). This measurement
may serve as a surrogate marker for atherosclerotic events because patients
with increased intimalmedial complex thickness have a higher rate of
cardiovascular events over time. Pioglitazone caused a significant decrease in
the intimamedia thickness in patients with diabetes (42). Rosiglitazone also
decreases intimal hyperplasia after balloon catheter-induced vascular injury in
Zucker rats (43).
Microalbuminuria is a risk factor for cardiovascular morbidity and mortality
in patients with diabetes (49). In patients with diabetes, microalbuminuria
is often associated with hypertension and poor glycemic control. In a
52-week study comparing rosiglitazone and glyburide, only rosiglitazone
significantly reduced urinary albumin excretion from baseline (44). There was
a lack of correlation between glycemic control and changes in the urinary
albumin : creatinine ratio (44), supporting that PPAR- agonists help maintain
vascular health.
Decreased fibrinolytic activity, in association with elevated plasma PAI-1,
is associated with increased risk of atherosclerosis and CVD (45). PAI-1 is
the primary inhibitor of endogenous tissue plasminogen activator (tPA) and is
elevated both in patients with diabetes mellitus and in insulin-resistant nondiabetic individuals (46). Increased PAI-1 levels are now recognized as an
integral part of the insulin resistance syndrome and correlate significantly with
plasma insulin.
Increases in plasma concentrations of markers of inflammation, such as Creactive protein (CRP), are also associated with both the insulin resistance
syndrome and the CVD (47). Multiple studies have demonstrated that all TZDs
reduce CRP levels significantly (4851). These effects may be related to the
decrease in insulin resistance and may have beneficial consequences for long-term
cardiovascular risk. Interestingly, the TZDs have also been evaluated in patients
with CAD without diabetes. Studies have found these patients also experience
a reduction in inflammatory markers including CRP and fibrinogen (52).
Thus, the beneficial effects of PPAR- agonists go beyond controlling hyperglycemia. They have anti-inflammatory and vascular properties and are currently
the subject of numerous studies including the primary and secondary prevention
(33) of macrovascular disease in patients with diabetes and insulin resistance.
Insulin
As indicated above, results from the clinical trials with insulin for patients
with type 2 diabetes are very encouraging. This partly relates to the ability of
insulin to lower glucose substantially more than oral agents.
63
Insulin is a powerful agent with nearly unlimited potential to lower plasma

glucose levels in patients with diabetes and is capable of restoring near
normoglycemiathe primary treatment goal to forestall the onset and
progression of long-term complications. Attainment and maintenance of nearnormal glycemic control can be achieved with the use of insulin replacement
strategies designed to simulate the physiologic, non-diabetic patterns of insulin
secretion in response to 24-h post-absorptive and postprandial glucose profiles.
In addition to its effects on lowering glucose, insulin has been shown to have
many beneficial effects on risk factors for CVD, including markers of inflammation, abnormal fibrinolysis, and oxidative stress (53). This discovery of the
anti-inflammatory effect of insulin coupled with the proinflammatory effect of
glucose has not only provided novel insight into the mechanisms underlying
several disease states but has also provided a rationale for the treatment of
hyperglycemia in several acute clinical conditions (54).
In a pre-planned subanalysis of a large, randomized controlled study,
intensive insulin therapy lowered circulating levels of adhesion molecules
in patients with prolonged critical illness, which reflects reduced endothelial
activation (55). This effect was not brought about by altered levels of
endothelial stimuli, such as cytokines, or by upregulation of endothelial
NO synthase (eNOS). In contrast, prevention of hyperglycemia by intensive
insulin therapy suppressed inducible NOS gene expression in postmortem
liver and skeletal muscle, and lowered the elevated circulating NO levels in
both survivors and non-survivors. These effects on the endothelium statistically explained a significant part of the improved patient outcome with
intensive insulin therapy. Thus, maintaining normoglycemia with intensive
insulin therapy during critical illness protects the endothelium and thereby
contributes to prevention of organ failure and death.
Addition of insulin to oral agent may lead to large drops in blood glucose
as in the Treat-to-Target Trial (56). Systematically titrating bedtime basal
insulin added to oral therapy can safely achieve 7% HbA1c in a majority of
overweight patients with type 2 diabetes with HbA1c between 7.5 and 10.0%
on oral agents alone (56). In this study, insulin glargine caused significantly less
nocturnal hypoglycemia than NPH, thus reducing a leading barrier to initiating
insulin. This simple regimen may facilitate earlier and effective insulin use in
routine medical practice, improving achievement of recommended standards
of diabetes care (56).
Use of a basal-bolus approach (long-acting insulin once daily with rapidacting insulin with meals) may allow physiological insulin replacement that
may not only achieve better HbA1c reduction but less fluctuation in blood
glucose, leading to less complications as in the DCCT and Kumamoto
studies.
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Lipid Management
Recent data suggest that patients with diabetes benefit greatly from
aggressive management of lipid irrespective of baseline cholesterol levels. This
is particularly true with a statin therapy.
The Heart Protection Study provides direct evidence that cholesterollowering therapy is beneficial for people with diabetes even if they do not
already have manifest coronary disease or high cholesterol concentrations (57).
Allocation to 40 mg simvastatin daily reduced the rate of first major vascular
events by about a quarter in a wide range of diabetic patients studied (57).
Statin therapy should now be considered routinely for all diabetic patients
at sufficiently high risk of major vascular events, irrespective of their initial
cholesterol concentrations. The target level for cholesterol remains controversial. Recent data suggest that levels well below the target goal of less than
100 for LDL-C may be desirable.
Blood Pressure
Data from several clinical trials have demonstrated that patients with
diabetes may require a lower level of BP to benefit from BP-lowering therapy.
On the basis of these results, the american diabetes association (ADA) has
recommended a BP goal of 130/80 to prevent microvascular and macrovascular
complications of diabetes.
The Heart Outcomes Prevention Evaluation (HOPE) study demonstrated
that in patients with diabetes aged 55 years or older, who had a previous
cardiovascular event or at least one other cardiovascular risk factor, ramipril
was beneficial for preventing cardiovascular events and overt nephropathy (58).
The cardiovascular benefit was greater than that attributable to the decrease
in BP. This treatment represents a vasculoprotective and renoprotective effect
for people with diabetes.
CURRENT CLINICAL TRIALS IN PROGRESS

Several new clinical trials have recently been launched to determine the
value of intensive therapy in type 2 diabetes. Among these, the Action to
Control Coronary Risk in Diabetes (ACCORD) stands out by its size and
the goals for intensive therapy being attempted. The three specific primary
ACCORD hypotheses are as follows. In middle-aged or older people with type
2 diabetes who are at high risk for having a CVD event because of existing
clinical or subclinical CVD or CVD risk factors: (i) Does a therapeutic strategy
that targets an HbA1c <6.0% reduce the rate of CVD events more than a
strategy that targets an HbA1c 7.07.9% (with the expectation of achieving
a median level of 7.5%)? (ii) In the context of good glycemic control, does
65
a therapeutic strategy that uses a fibrate to raise HDL-C/lower triglyceride

levels and uses a statin for treatment of LDL-C reduce the rate of CVD events
compared with a strategy that only uses a statin for treatment of LDL-C? (iii) In
the context of good glycemic control, does a therapeutic strategy that targets a
systolic BP (SBP) <120 mmHg reduce the rate of CVD events compared with
a strategy that targets a SBP <140 mmHg? The primary outcome measure for
the trial is the first occurrence of a major CVD event, specifically non-fatal
MI, non-fatal stroke, or cardiovascular death.
Finally, ORIGIN is a trial testing whether early (patients with impaired
fasting glucose (IFG), impaired glucose tolerance (IGT), or newly diagnosed
diabetes) intervention with insulin, as opposed to oral agents, will ameliorate
the progression of beta-cell dysfunction and CVD in type 2 diabetes.
In summary, intensive management of glycemia and other risk factors have
been shown to decrease the risk of microvascular and macrovascular complications of diabetes. Ongoing clinical trials are assessing new goals and therapeutic
strategies for intensive therapy to determine whether these complications can
be reduced further.
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Treatment of Type 2 Using Insulin

When to Introduce?
Julio Rosenstock, MD,

and David Owens, CBE,
MD
CONTENTS
Introduction
The Need for Earlier Insulin Replacement
in type 2 Diabetes
Would the New Insulins Overcome
Complexity Barriers for Early Insulin
Initiation?
Conclusions
References
Summary
A major component of the overall glycemic burden to which patients
are exposed reflects the delay in adjusting therapy to meet the increasing
requirement for intervention over timethe average patient accumulates up
to 10 years of glycemic burden (HbA1c of more than 7%) before insulin is
commenced. An urgent change in the approach to glucose-lowering treatment
is clearly required. Because of the overwhelming evidence in support of
glycemic control and an awareness of the long-term consequences of hyperglycemia, in particular the onset and progression of vascular (micro- and
macrovascular) complications, insulin therapy is increasingly seen as a key
intervention in type 2 diabetes mellitus (T2DM).
Although the rationale is strong and the evidence clearly justifies the
early use of insulin, issues of implementation and overcoming barriers to
utilise/introduce insulin remain critical. The recent comparative data between
69
70
Rosenstock and Owens
the third National Health and Nutrition Examination Survey (NHANES III)
(19881994) and the latest NHANES (19992000) strongly support this view.
The report reveals certain changes in the pattern of insulin use in the USA,
with a fall in the use of insulin monotherapy (24 to 16%) and an increase
of insulin plus oral agents (3 to 11%) (Koro CE et al. Diabetes Care 27:
1720, 2004), but the total usage of insulin remained relatively unchanged. Of
note, these data do not however reflect the emerging paradigm of early insulin
replacement when combination oral agents fail to maintain blood glucose
within defined glycemic targets that has gained force over the last 5 years.
Of momentum central concern for physicians and persons with T2DM
is the requirements relating to subcutaneous insulin injection. Historically,
insulin therapy was viewed as reflecting the final stage of the disease, with
all the negative connotations associated with this clinical situation/scenario
and that, with insulin, increased side effects could be expected. The patients
concern is the introduction of often compounded by the physicians reluctance to initiating insulin therapy and thereby, very often, sub-optimal glycemic
control persists as the way forward. What is frequently lacking in these cases
is a clear educational message to patients of the benefits of insulin. Looking
to the ongoing outcome trials, if these studies provide convincing evidence
in terms of cardiovascular event reductions, the task of persuading physicians and patients of the need for early insulin replacement as an expected
strategy to achieve near-normoglycemic control will be made a lot easier.
Furthermore, it may be demonstrated in these trials that the early introduction
of near physiologic insulin replacement within a window of opportunity
is critical for retaining -cell function, which will in turn facilitate longterm maintenance of glycemic control. Whilst this remains to be proven,
patient education remains a key in advancing the message of insulin benefit.
Major advances in insulin therapy include changes in the different formulations of insulin available and in how insulin can be delivered. The advent
of long-acting insulin analogues for early basal replacement and rapid-acting
insulin analogue or inhaled insulin for progressive prandial replacement can
have a major impact as the necessary tools for health care providers to
empower patients to take charge of their own diabetes control along with self
blood glucose monitoring. Inhaled insulin may offer the best opportunity yet
to advance insulin treatment in T2DM by removing the need for injections
in the initial stage of the disease.
Basal insulin provision is intended to inhibit hepatic glucose production
in an attempt to normalize fasting blood glucose. When normalization is
achieved, but the HbA1c remains above the defined HbA1c target of 7%,
attention should then be focused on assessing and correcting the postprandial
glucose excursions. This approach is very simple to understand by health care
providers, to fix fasting first, and then an escalation of therapy to include
prandial insulin as required when the HbA1c exceeds 7%, only when basal
Treatment of Type 2 Using Insulin: When to Introduce?
71
insulin therapy has already been optimized whilst avoiding hypoglycaemia.

In those patients with well controlled fasting glucose <100 mg/dL, it is
the postprandial glucose excursions that are the predominant factor in the
glycemic burden, (Monnier et al. 2003, 2007) and proper intervention with
prandial insulin can further improve glycemic control. Alternatively, patients
who have maximized oral agent therapy and the HbA1c marginally exceeds
7%, perhaps in the 78% range, may find the option of starting first with
inhaled insulin very attractive especially if the long-term safety data are
convincing and glycemic targets can be sustained overtime with inhaled
insulin. Basal insulin replacement will then be eventually added if the HbA1c
remains >7%, especially if the FPG is >100 mg/dL.
The current treatment debate in T2DM is not about insulin, but when
and how to introduce simple insulin regimens, dictated by clear algorithms
and driven by blood glucose monitoring to achieve long-term nearnormoglycemia with minimal effort, and initiated and managed by the
particular in partnership with the diabetes care team. Clearly, patients should
not be left with excess glycemic burden for extended periods and an
aggressive strategy to maintain glycemic control with early insulin introduction to ensure target levels of glycemia will bring well being to the patient
and counter the dreaded long-term complications of diabetes.
Key Words: Insulin therapy, cardiovascular protection, type 2 diabetes
INTRODUCTION
The evidence for improved glycemic control for preventing the onset and
progression of diabetes-related microvascular complications is overwhelming
(15). What is becoming evident is that insulin will play an increasing and
major role in the management of type 2 diabetes mellitus (T2DM), used alone
or in combination with multiple glucose-lowering strategies especially if the
ongoing cardiovascular (CV) outcome trials confirm benefit and that stringent
glycemic targets close to normal can be achieved and sustained (6). Furthermore,
-cell preservation to facilitate maintaining near-normoglycemia may be possible
to demonstrate in some of the ongoing trials where the initiation of insulin
replacement is early relatively when sufficient -cell reserve is still present. It is
well recognized that residual -cell function facilitates the achievement of good
glycemic control in both type 1 (T1DM) and T2DM (Refs.).
Traditionally, the requirement for insulin was seen as a last resort, once
maximal combination oral agent therapy has failed and usually more than
10 years after the diagnosis of T2DM (7). Currently, however, the paradigm
on insulin treatment is in a state of flux and may eventually emerge as the
essential therapeutic tool for achieving glycemic control at even earlier stages
72
in the progression of the disease as we better understand the underlying

pathophysiology and natural history of T2DM. Earlier insulin replacement
may have further benefit and result in a favorable metabolic imprint (8
10), helping to sustain long-term benefits if achieving good glycemic control
thereby reducing progression of microvascular and macrovascular complications, which remain the ultimate objectives in the management of patients
with T2DM.
The increased awareness of the benefits of insulin therapy in T2DM poorly
controlled on oral agents was demonstrated with the introduction of basal insulin
able to achieve fasting blood glucose and hemoglobin A1c (HbA1c ) targets,
with a low risk of hypoglycemia when using long-acting insulin analogues
guided by dose-adjustment treatment algorithms (11) add reference. The treatto-target paradigm offers the basis for a simple, standardized method for the
timely initiation of insulin in clinical practice, governed by specific targets
using safe and effective dose titration algorithms, especially those that can be
applicable for self-adjustments, which makes the treat-to-target paradigm a
feasible approach to a wider patient population in the primary care domain (12).
Furthermore, the recent availability of the inhaled insulin option after many
years of regulatory trials may increase the proportion of patients willing
to accept insulin therapy earlier, but long-term safety and demonstration of
durable near-normoglycemia, as well as patient acceptance and preference,
will ultimately determine the future impact of inhaled insulin (13).
Insulin initiation and optimization through dose escalation once the glycemic
threshold has been exceeded is the driving force for the treat-to-target concept.
Whether it is the use of early basal insulin replacement with long-acting
analogues with special focus on normalizing fasting blood glucose first, or
meal administration of short-acting analogues, or inhaled insulin for early
postprandial control will require further comparative studies to assess the
value of each insulin strategy as an initial approach. (Ref. Feingloss etc)
Both novel insulin options can facilitate earlier insulin initiation, and the
need for optimization may eventually result in convergence of the basal and
inhaled insulin strategies irrespective of which was started first, moving in a
progressive fashion to a basal plus prandial replacement regimen determined
by the glycemic targets achieved.
THE NEED FOR EARLIER INSULIN REPLACEMENT

IN TYPE 2 DIABETES
Worldwide, the number of cases of diabetes is expected to increase exponentially, with current estimates suggesting an increase from around 170 million
in 2000 to approximately 370 million persons by 2030 (1416). Given that
73
T2DM accounts for most cases (>80%), a reevaluation of the approach taken
to effectively manage T2DM, including a reassessment of the role of insulin in
reaching and sustaining glycemic targets to prevent long-term complications
of T2DM, is essential.
When should insulin be started in T2DM depends on two critical scenarios
that will require solid evidence to substantiate any claims of the potential
benefits of early insulin initiation:
1. Can early insulin therapy rest the cell and preserve its function and
integrity? Preliminary evidence suggests that early insulin therapy reduces
strain on the cell by correcting glucotoxicity and lipotoxicity. This -cell
rest may preserve function and structural integrity, which in turn can facilitate
durability of glycemic control (17).
2. Is early insulin therapy needed to reach glycemic targets for cardioprotection?
Epidemiological data suggest the need to fully normalize glucose control as CV
risk is already increased even in the upper normal range of the HbA1c levels or
in the pre-diabetes state (1820). If the ongoing interventional glucose control
outcome studies demonstrate a reduction in CV events with even lower HbA1c
levels, achievable only with early insulin supplementation in combination with
other glucose-lowering agents, the use of insulin will play an increasing role
in T2DM management (6). Currently, initiation of insulin therapy is generally
considered only if the HbA1c level remains >7% despite maximized oral combination therapy. However, the decision-making process for insulin initiation
may turn out to be even lower at >6.5% or perhaps >6% if the CV outcomes
of the interventional studies are positive, which will necessitate insulin therapy
in most patients with T2DM.
Early Insulin Therapy and -Cell Preservation

-Cell Dysfunction and -Cell Loss: Key Defects
in Type 2 Diabetes
There is strong evidence that -cell dysfunction is a fundamental underlying genetic abnormality in the pathogenesis of T2DM that cannot develop
solely because of insulin resistance. Early -Cell dysfunction the progression
from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT)
and finally to T2DM (21). Thereafter, deteriorating glycemic control results
from predominantly a progressive decline in pancreatic -cell function determines along with insulin insensitivity right resulting in increased hepatic
glucose production and impaired peripheral glucose uptake (7,22). As insulin
fails to suppress lipolysis, the increased concentrations of free fatty acids
(FFAs) combined with progressive hyperglycemia act negatively on pancreatic
cells and insulin-sensitive tissues to further inhibit both insulin secretion and
peripheral action (23).
74
Recent evidence has suggested that the progressive insulin deficiency in

T2DM is not only a functional defect of the cell but a decrease in -cell
mass (Ref) because of increased apoptosis. In a study of pancreatic tissue
from 124 autopsies, relative -cell volume, frequency of -cell apoptosis, cell replication, and the formation of new islets from exocrine ducts were
measured (24). Relative -cell volume was decreased by 63 and 44% in both
obese and lean persons with T2DM respectively, in comparison with healthy
age- and weight-matched non-diabetic controls. In addition, subjects with prediabetes also exhibited a 40% decreased relative -cell volume, suggesting this
is etiologically important in the development of T2DM due to a predominance
of -cell apoptosis, which was increased 10-fold in lean subjects and threefold
in obese subjects with T2DM. It appears that -cell loss is an early feature
of the pathogenesis of T2DM, and this finding is probably independent from
the rate of new islet formation. The implications for treating T2DM from this
perspective of -cell dysfunction and progressive -cell loss are that strategies
that limit glucotoxicity and lipotoxicity can potentially reduce the increased
rate of -cell apoptosis, and therefore, at least partial restoration of -cell
mass may be possible as islet neogenesis remains intact resulting in increased
functional -cell mass.
Indeed, insulin therapy in T2DM can improve peripheral insulin action
by correcting glucotoxicity and lipotoxicity and, by also inducing -cell
rest, can potentially enhance insulin secretion and thereby potentially reduce
-cell loss and/or preserve -cell integrity (Fig. 1). There is some preliminary
evidence, reviewed below, suggesting -cell preservation with early insulin
therapy, but long-term controlled studies, such as Outcome Reduction with
Initial Glargine Intervention (ORIGIN), will be needed to demonstrate that the
proposed strategy of very early insulin replacement for -cell preservation can
facilitate the maintenance of glycemic control (17).
The Timing of Insulin Initiation: A Window of Opportunity
The concept of the possible existence of a window of opportunity, such
that failure to improve glucose control early can result in long-term detrimental
effects on diabetes-related complications. Despite later restoration of glycemic
control because of metabolic or vascular imprinting. This is important to
consider in the context of early insulin intervention in T2DM. As reported in
the long-term follow-up of Diabetes Control and Complications Trial (DCCT)
in the Epidemiology of Diabetes Intervention and Complications (EDIC) study,
early improvement of glycemic control through intensive insulin treatment
intervention in patients with T1DM is associated with long-term reductions
in major diabetes-related complications, despite equivalent glycemic control
during the extended observation time (810). Whether the same phenomenon
75

Liver:
Glucose Output
Early Insulin
Replacement
?+
Pancreas:
Reduced Strain ?
Reduced Toxicity ?
Improved
Endogenous
Insulin Secretion
Muscle and Adipose Tissue:
Glucose Uptake
Insulin Resistance
Lipolysis
Fig. 1. Early insulin therapy in type 2 diabetes mellitus (T2DM)resting the cell
by replacing insulin. Early insulin therapy may contribute to improved insulin secretion
by pancreatic cells, which contributes to improved insulin-mediated suppression of
glucose production and peripheral tissue-mediated glucose uptake and clearance. (Modified
from 17).
applies in T2DM requires long-term follow up on the currently ongoing CV

outcome studies assessing the impact of glycemic control.
In addition, the concept of a window of opportunity may also apply to
the key contribution of the -cell dysfunction that goes undetected for several
years before the diagnosis of T2DM, as classically illustrated by the 6-year
follow-up data of the UK Prospective Diabetes Study (UKPDS). This report
demonstrated that by the time of diagnosis, patients may have already lost as
much as 50% of their -cell function with a subsequent inexorable decline in
-cell function (25).
Of interest is the UKPDS 57 report on a modified protocol for the last
eight UKPDS centers known as the Glucose Study 2 that tested whether
insulin therapy used alone from the time of diagnosis or as an early supplementation to oral agent therapy according to a specific FPG target could avoid
progressive deterioration of glycemic control. Insulin therapy was added to
sulfonylurea therapy if maximal doses did not maintain FPG levels <108 mg/dL
(6.0 mmol/L) (26). Most of the patients were initiated on insulin around
23 years after diagnosis, and over half of those newly diagnosed patients
treated with a sulfonylurea eventually required early insulin replacement that
achieved a median HbA1c level of 6.6% at 6 years. This study provided the first
proof of concept in newly diagnosed patients that prompt addition of insulin
76
replacement, when oral therapy is inadequate to reach glycemic targets, can

achieve sustain near-normoglycemic control in T2DM.
Conceivably, early insulin replacement can offer sustained improvements in
glycemic control. Preliminary support for the hypothesis of insulin-mediated
-cell rest is provided by the several studies, as reviewed below, in which
newly diagnosed patients with severe hyperglycemia treated only with shortterm intensive insulin therapy were subsequently able to maintain nearnormoglycemic control without any pharmacologic intervention for prolonged
periods of time.
The rationale for such an approach in T2DM came originally from short-term
intensive insulin therapy studies performed over the last 20 years that demonstrated improved insulin action and increased endogenous insulin secretion
probably induced by reversing glucotoxicity and lipotoxicity (2731). Further
preliminary support for this -cell rest hypothesis is provided by a small
uncontrolled Israeli study in newly diagnosed hyperglycemic patients with
T2DM subjected to a short, 2-week period of intensive insulin therapy, resulting
in near-normoglycemia.Once the intensive insulin therapy was stopped, most
of the patients continued with sustained adequate glycemic control for long
periods of time (9 to >50 months with a median of 26 months) without pharmacologic intervention to reduce blood glucose (32).
A similar principle was applied in a larger, but still uncontrolled 16-month
Korean trial in 92 patients with T2DM of longer duration disease (33). Overall,
34% of the patients went into remission that lasted an average of 14 months
after 54 39 days on intensive insulin therapy using an insulin pump. The
criteria for remission was sustained FPG of <108 mg/dL (6.0 mmol/L) and
postprandial glucose (PPG) of <180 mg/dL (10.0 mmol/L). It is important to
note that remission rates were higher when patients started intensive insulin
therapy with a shorter diabetes duration (3.3 3 years vs. 9.1 4 years for the
remission and non-remission groups, respectively; p < 0.001) and with lower
postprandial blood glucose levels and higher C-peptide responses, strongly
suggesting better -cell reserve.
Of interest, a small Scandinavian trial in newly diagnosed islet cell antibodynegative T2DM patients, randomized to either glyburide or two daily injections
of pre-mixed insulin, demonstrated similar significant reductions of HbA1c
levels during the first year in both groups, but, by the end of the second year,
HbA1c had deteriorated in the glyburide group but not in the insulin-treated
group (34). Of note, at 1 and 2 years, the glucagon-stimulated C-peptide
response was increased in the insulin-treated group, whereas it was decreased
in the sulfonylurea group. Fasting insulin levels after 2 years were higher
subsequent to treatment withdrawal in the insulin-treated group compared with
the sulfonylurea-treated group. It is conceivable that sulfonylurea treatment
77
might have had a deleterious effect on the cell or alternatively the early insulin
replacement protected and prolonged endogenous insulin secretion resulting in
better metabolic control.
Similarly, a recent Canadian study demonstrated that treating newly
diagnosed hyperglycemic patients with T2DM to a short (2- to 3-week) course
of intensive insulin therapy can successfully lay the foundation for prolonged
good glycemic control (35). The authors indicated that the ease with which
normoglycemia was achieved may predict those patients who can later succeed
in controlling glucose levels with attention to diet alone.
These intriguing findings, albeit with relatively few patients, suggest that
the earlier introduction of insulin treatment in T2DM might halt disease
progression and the increased endogenous insulin secretion may permit the
use of simpler insulin-replacement regimens alone or in combination with oral
agents for long-term maintenance of near-normoglycemic control and impact
on the prevention of costly complications.
Early Insulin Therapy and Cardioprotection

Sustained near-normoglycemia is the primary treatment goal in the
prevention of diabetes-related complications. Epidemiological analysis of the
UKPDS data showed a continuous association between the risk of CV complications and glycemia and showed that for each 1% decrease in HbA1c
there were significant reductions in major DM-related endpoints, that is, a
37% reduction in microvascular endpoints, a significant 43% reduction in
amputation or death from peripheral vascular disease, and a significant 14%
reduction in combined fatal and non-fatal myocardial infarction (5). Of note,
no glycemic threshold for these complications above normal glucose levels
was evident, suggesting that any improvement is beneficial, but these epidemiological data require full validation with interventional studies to define how
close to normal the HbA1c should be lowered.
Completed CV Outcome Trials in Type 2 Diabetes
Despite the importance of the health problems posed by T2DM and the
findings of the UKPDS, there is little definitive data on the effects of intensive
control of glycemia on CV event rates in patients with DM.
The Kumamoto study was a relatively small, long-term trial, not powered
for CV outcomes, but demonstrated a non-significant 44% reduction in CV
events, in addition to reduced microvascular complications in the intensive
insulin therapy group who achieved HbA1c levels of 7.1% compared with the
conventional insulin therapy who had an HbA1c 9.4% (3). In contrast, the VA
feasibility trial reported a non-significant 40% higher rate of CV events in the
78
intensive insulin plus combination oral agents group, who achieved an HbA1c
of 7.1% compared with the control group with an HbA1c of 9.3% (36).
The Steno-2 Study compared the effect of intensive, multifactorial intervention with that of conventional treatment on modifiable risk factors
for cardiovascular disease (CVD) in patients with T2DM and microalbuminuria (37). Eighty patients were randomly assigned to receive conventional treatment in accordance with national guidelines and 80 patients to
receive intensive treatment, which was characterized by a stepwise implementation of behaviour modification, followed by multiple drug therapy targeting
hyperglycemia, hypertension, dyslipidemia, and microalbuminuria, along with
secondary prevention of CVD with aspirin. The principal findings are shown
in Fig. 2.
These findings from the Steno-2 study offer important insights into the
value of a multi-targeted approach to DM management although the glycemic
targets were only reached by few patients, which emphasizes the need for
the important ongoing long-term outcome studies designed to provide more
answers to these important health care questions.
Ongoing CV Outcome Trials in Type 2 Diabetes
There are multiple ongoing trials testing different hypothesis with different
study designs and pharmacologic interventions attempting to demonstrate
benefits on hard CV event reductions (17,38). Among these three important
studies can potentially have a major impact to define the role of early insulin
Complication
Risk ratio (95% CI)
P value
1 Endpoint
0.47 (0.24 0.73)
0.008
53% risk reduction
Nephropathy
0.39 (0.17 0.87)
0.003
61% risk reduction
Retinopathy
0.42 (0.21 0.86)
0.02
58% risk reduction
0.37 (0.18 0.79)
0.002
63% risk reduction
1.09 (0.54 2.22)
0.66
Autonomic
neuropathy
Peripheral
neuropathy
0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

INTENSIVE better
CONVENTIONAL better
1 Endpoint: CVD death, nonfatal MI, CABG, PTCA, nonfatal stroke, amputation, any bypass
Fig. 2. Steno-2 Multifactorial Intervention Study. The relative risk of the development or
progression of nephropathy, retinopathy, and autonomic and peripheral neuropathy during
the average follow-up of 7.8 years in the intensive-therapy group compared with that in the
conventional-therapy group. (Reproduced from 37; 2003 Massachusetts Medical Society).
79
initiation in T2DM: the Veterans Affairs Diabetes Trial (VADT), the Action to
Control Cardiovascular Risk in Diabetes (ACCORD) study and the ORIGIN
trial (Table 1).
VADT is a 5 to 7 year, randomized, multicenter trial following 1792 older
patients with T2DM in the VA System in the USA (38). The study has been
designed to answer these specific questions: (i) in older VA patients with
established T2DM, what are the relative effects of conventional versus intensive
glycemic control on CV morbidity and mortality? (ii) in this population, what
is the risk-to-benefit ratio associated with intensive glycemic control? and
(iii) should treatment efforts be directed toward intensive glycemic control
or other areas (e.g., BP management, lipid therapy, supportive care)? The
primary outcome measures are major CV events (CV death, stroke, congestive
heart failure), amputation, CAD, and peripheral vascular disease. Secondary
outcome measures are angina, transient ischemic attack, critical limb ischemia,
total mortality, retinopathy, nephropathy, neuropathy, quality of life, cognitive
function, and cost-effectiveness.
ACCORD is a 5-year, randomized, multicenter, double 2 2 factorial design
trial following 10,000 patients with T2DM and high CVD risk. The study has
been designed to answer these specific questions: (i) does a strategy that targets
HbA1c to <6.0% reduce CVD events compared with HbA1c 7.07.9%? (ii) in
Table 1
Interventional Studies on Cardiovascular (CV) Outcomes
>Study
Participants (n)
Follow-Up
(years)
A1c Target
Intensive
VADT
ACCORD
1700
10,000
57
48
(average
5.6)
ORIGIN
12,500
48
<6%
<6%
Expected
Results
Standard
89%
7.07.9%
(expected
mean
7.5%)
FPG[<95
<7%A1C
mg/dL
(standard
(glargine)] care with
no insulin)
2007
2010
2008
Three ongoing, long-term clinical trials will help to define the role of early insulin initiation
in type 2 diabetes mellitus (T2DM): the Veterans Affairs Diabetes Trial (VADT), the Action to
Control Cardiovascular Risk in Diabetes (ACCORD) Study, and the Outcome Reduction with
Initial Glargine Intervention (ORIGIN) Trial.
80
the context of good glycemic control, does using a fibrate and a statin reduce
CVD events compared with statin treatment alone? (iii) in the context of good
glycemic control, does targeting systolic BP to <120 mm Hg reduce CVD events
compared with a systolic BP <140 mm Hg? The primary outcome measure is CVD
morbidity and mortality. Secondary outcome measures are other CV outcomes,
total mortality, microvascular outcomes, quality of life, and cost-effectiveness.
ORIGIN is a 5-year, randomized, open-label, multicenter, 2 2 factorial
design trial following approximately 12,500 patients 50 years of age with at
least one CVD risk factor (to state the risk factors) and pre-diabetes (IFG, IGT)
or early T2DM. The study has been designed to answer these specific questions:
(i) does early supplementation with insulin glargine targeting fasting plasma
glucose <95 mg/dL (5.3 mmol/L) reduce CV morbidity and/or mortality in
high-risk patients with pre-diabetes (IFG, IGT) or early T2DM? (ii) do omega-3
fatty acid supplements reduce CV mortality in patients with pre-diabetes (IFG,
IGT) or early T2DM? The primary outcome measures are CV morbidity and/or
mortality. Secondary outcome measures are myocardial infarction (MI), stroke,
death, coronary artery bypass and/or coronary angioplasty, hospitalization for
congestive heart failure, microvascular complications, and new T2DM.
These trials are designed to achieve glycemic targets very close to normal,
which are well below those levels reported in previous interventional clinical
trials. Clearly, the patients randomized to the intensive regimens in VADT and
ACCORD will be on multiple oral agents, but insulin will be required by most
to attain and sustain long-term near-normoglycemia. Positive outcomes demonstrating a reduction in the risk of CV events with these trials will determine
the new targets for glycemic control. Insulin will then possibly need to be
considered much earlier in the course of the disease if alternative glucoselowering strategies fail to achieve the new glycemic targets that could be set
as low as an HbA1c <6%. Furthermore, if the ORIGIN trial is also positive in
demonstrating a reduction in CV events, then considerations should be given
to basal insulin as a first line therapy to correct dysglycemia (FPG >95 mg/dL)
in early diabetes and/or pre-diabetes in patients with evidence of CV disease.
Clearly, any potential positive results will result in an overwhelming burden
to the health care system and potentially an increased risk of hypoglycemia,
which hopefully will be outweighed by a meaningful risk reduction of CV events.
WOULD THE NEW INSULINS OVERCOME COMPLEXITY

BARRIERS FOR EARLY INSULIN INITIATION?
Even if the rationale for earlier insulin initiation is correct and well validated,
the critical issues will firstly be acceptance by patients and secondly by physicians in general practice. The preceding evidence offers support to the concept
81
of insulin-mediated cessation of disease progression with early insulin intervention to preserve cells, especially if insulin is to be initiated much earlier
to achieve more stringent glycemic targets. The current treatment debate is
not about the introduction of intensive short-term insulin regimens as in the
pilot studies described above, but how to introduce simple insulin regimens,
dictated by clear algorithms and driven by blood glucose monitoring to achieve
long-term near-normoglycemia with minimal effort, but initiated and managed
in partnership with the patient early in the course of the disease. The concept
of early introduction of insulin in combination with oral agents should occur
as soon as the threshold target of HbA1c is exceeded; today, that target is 7%,
but in future that may well be 6% (39).
However, treatment inertia prevails in clinical practice, and the overall
glycemic burden to which patients are exposed reflects the delay in adjusting
therapy to meet the increasing requirements for intervention over time. On
average, patients accumulate 10 HbA1c -years of glycemic burden of more
than 7% before insulin is initiated (40). This clinical inertia, with a failure
to promptly advance treatment and dosages of the various oral agents and
insulin therapy, results in chronic hyperglycemia. The option of insulin therapy
has often emergest at an advanced stage of the disease (41,42). In addition,
the multiple barriers to insulin therapy will need to be addressed so that the
introduction of early insulin supplementation can become a feasible option for
the patient, in line with a physiological approach to supporting the endogenous
insulin deficit.
The postponement of insulin therapy in persons with T2DM is because
of many well-recognized barriers (12,43). The requirement for subcutaneous
insulin injections and the stigma of having to inject insulin cannot be underestimated, as the need for insulin is perceived by the patients and physician as a
personal failure and or seen as a terminal phase of the condition. The Diabetes
Attitude, Wishes and Needs (DAWN) study emphasized the need to consider
patients and health care providers attitudes and environment in addition to
therapy when attempting to improve the patients overall health status and well
being (44). The DAWN study clearly concluded that patient and provider
resistance to insulin is substantial and for providers it is part of a larger pattern
of reluctance to prescribe blood glucose-lowering medications. Interventions
to facilitate timely initiation of insulin therapy will need to address factors
associated with this resistance. The patients concerns are often compounded
by the physicians resistance to initiating insulin therapy and thereby very often
accept sub-optimal glycemic control for prolonged persists of time. Physicians
usual concerns include the complexity and limitations of current insulin preparations, the fear of hypoglycemia, weight gain, and the misconception that the
introduction of insulin can potentially increase insulin resistance and CV risk
82
as well as the time needed to educate the prevent above insulin administration
and self-maintaing of blood glucose. As discussed above, the evidence does
not support insulin therapy increasing insulin resistance (2731) or having an
unfavorable influence on other known CV risk factors; in fact, the opposite
may be turn out to be true.
Among all insulin barriers, the fear of hypoglycemia remains the main
barrier that explains why patients and physicians are both reluctant to its
initiation and also sub-optimally utilizing insulin in T2DM. Indeed, achieving
and maintaining euglycemia has been an elusive goal because of the pharmacokinetic imperfections of old human insulins and the resulting barrier of
hypoglycemia (45,46). The unpredictable kinetics of the previously available
long-acting insulin preparations, in particular NPH insulin, has been a key
component in the decision to delay insulin intervention (39). NPH is not an ideal
once-daily insulin, with a peak of activity 46 h after subcutaneous injection
an inadequate duration of action (1216 h) and variability in absorption due
to the need for resuspension prior to injection. The need for more complex
insulin treatment algorithms to account for the poor kinetic characteristics is a
major barrier to insulin initiation.
Progress has been made, however, with the introduction of more predictable
short- and long-acting insulin analogues, which have partially overcome some
of the insulin barriers by reducing the risk of hypoglycemia (47,48).
An additional, important barrier for physicians has been the hitherto complex
nature of insulin regimens and algorithms, which are difficult to implement
under the current limited time and logistical constraints of clinical practice.
Even if the reasons to start insulin earlier, as discussed above, are to be proven
correct, still any attempt to change the paradigm for earlier insulin replacement
will need to overcome the complexity barrier with simpler, safer, and more
effective strategies that are easy to implement in general practice. Initiation
with basal insulin by using long-acting insulin analogues or initiation with
prandial insulin by using short-acting insulin analogues or inhaled insulin will
be the focus of future discussions, and different comparative strategies will
require further study (39).
Overcoming Complexity BarriersStarting with Basal Insulin

The use of a basal insulin injection to supplement ongoing treatment with
oral agents has been demonstrated to offer a simple and practical approach
to overcome the complexities of introducing insulin therapy in persons with
type 2 diabetes. This strategy has the advantage that only once-daily insulin
injection is required and titration can be accomplished effectively in a relatively
safe and simple manner by the patient based on daily FPG monitoring (12).
83
Basal insulin replacement has gained considerable clinical research

experience and is increasingly being positioned as a first line insulin initiation approach in T2DM. New consensus guidelines (ADA/EASD) Nathan
et al. Proof of concept was initially demonstrated by the 24-week treat-totarget study that enrolled 756 insulin nave patients on oral agents with mean
HbA1c of 8.6% (entry values of 7.510%) and 89 years diabetes duration
(49). Patients continued to receive oral agents and were also treated with
either once-daily bedtime NPH insulin or insulin glargine, a long-acting insulin
analogue with a relatively flat action profile and up to 24-h duration of
action. The insulin dose was force-titrated weekly to an FPG target of100
mg/dL following a structured insulin titration algorithm according to FPG and
evidence of hypoglycemia. Similar reductions in HbA1c levels (6.96 versus
6.97%, respectively) were achieved by study end, and approximately 60%
of the patients achieved HbA1c values of 7% with both insulin regimens.
However, treatment with insulin glargine was associated with a significantly
lower incidence of nocturnal hypoglycemia. Similar results, in the same type
of patient population, have been achieved with insulin detemir, another longacting insulin analogue with a smooth, protracted time-action profile with a
duration of action of approximately 1416 h when compared with NPH (50)
when both insulins were given twice daily. Similar improvements of HbA1c
<7%, were seen but there was also a reduced risk of nocturnal hypoglycemia
and less weight gain with detemir compared with NPH.
A common consideration as therapy is escalated is the option of adding a
third oral agent, as opposed to initiating insulin (51). Important concerns with
three oral agents include the potential for an additive risk of adverse events,
dose adjustments that may become complex, and cost considerations. Recently,
the efficacy, safety, and cost of adding a third agent, a thiazolidinedione or
insulin glargine, were tested in T2DM patients who previously failed a regimen
of two oral agents, sulfonylurea and metformin (52). The average diabetes
duration was 89 years, and the baseline HbA1c of approximately 8.8% was
very similar to the treat-to-target study, but the insulin titration algorithm
was less stringent. Both strategies, add-on low-dose insulin glargine or addon maximum-dose rosiglitazone (RSG), resulted in similar HbA1c reductions
of 1.7 and 1.5%, respectively, with a final HbA1c of approximately 7.1%
(Fig. 3A). Greater improvements in HbA1c were seen with insulin glargine
when baseline HbA1c was 9.5% (Fig. 3B). Insulin glargine resulted in more
hypoglycemia but with less weight gain and no edema at a lower cost than
RSG. Perhaps, any of these triple agent strategies if used much earlier in the
course of the disease, at a lower baseline HbA1c level, just above 7%, and not
like in most studies with higher HbA1c 8.5%, then the chances of most patients
84

9.0
8.7 8.8%
Glargine
RSG
HbA1c (%)
8.5
8.0
7.5
7.0
7.1 7.2%
6.5
0
Change from baseline

in HbA1c (%)
7
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
7.5
8
12
16
Time (weeks)
20
24
*p = 0.5215 baseline vs study-end
p = 0.1446 glargine vs RSG
Baseline HbA1c (%)

8 8.5 9 9.5 10 10.5 11
RSG
Glargine
*
*p < 0.05 (least squares means), Glargine vs RSG
Fig. 3. Triple agent therapy in type 2 diabetes mellitus (T2DM). In a randomized

comparison of rosiglitazone (RSG) or insulin glargine as add-on therapy to sulfonylurea
and metformin, mean hemoglobin A1c (HbA1c ) levels from baseline to end point showed
a similar decrease for both insulin glargine (1.66%) and RSG (1.51%; p = 0.1446).
In the comparison of RSG or insulin glargine as add-on therapy, improvement in HbA1c
was significantly greater for insulin glargine-treated patients versus RSG-treated patients
if baseline HbA1c was >9.5%.
sustaining the HbA1c target of <7.0% would be considerably greater, but this
approach requires further long-term, controlled studies.
The original treat-to-target structured insulin algorithm is not only
effective but also simple to understand and implement and has been satisfactorily applied in multiple other studies (39). However, how widely effective
has it been when adopted in clinical practice remains controversial as patients
do not have the same level of support and interaction with the health care
providers as in the setting of clinical research studies. Often, patients are
sub-optimally titrated on these clinic-driven algorithms taking lower insulin
sub-optimal doses without achieving glycemic targets if they are not closely
supervised.
The LANMET study in patients with T2DM who were inadequately
controlled on oral agents (mean HbA1c 9.5%) took the treat-to-target concept
one step further in terms of simplicity to facilitate patient involvement
85
with self-titration of insulin (53). This study demonstrated the feasibility of

achieving tight glycemic control using a very simple forced-titration regimen
consisting of increments of 2 IU insulin dose every 3 days if FPG was
>100 mg/dL coupled with infrequent (3-monthly) physician contact. The study
design required patients to remain on metformin (2 g) and were randomized
to insulin glargine or NPH. Patients consistently self-monitored FPG levels
and also were empowered to self-adjust their insulin dose, which resulted in
significant in HbA1c of 2.4% reductions with a final HbA1c of 7.1% across
both groups but those patients receiving insulin glargine had a lower incidence
of hypoglycemia (Fig. 4).
Furthermore, the safety and efficacy of the two insulin glargine-forced
titration algorithms have been tested comparing the original algorithm from
the treat-to-target study, which was clinic-driven to direct weekly dose
escalations of 28 units according to different FPG values versus the selftitration algorithm from the LANMET study, which was patient-driven for
adjustments of 2 units every 3 days if the mean FPG was greater than 100
mg/dL (54). Interestingly, the patient-driven self-titration algorithm achieved
slightly better reductions in FPG and HbA1c levels and allowed titration to
higher insulin doses and with no difference in the frequency of hypoglycemia
between the two insulin regimens.
Results of these studies therefore clearly demonstrate that basal insulin
replacement can be easily implemented with long-acting insulin analogues to
HbA1c (%)
10
9
Treatment: Self-Titration 2U every 3 days to FPG < 100 mg/d

Hypoglycemia
Insulin Dose (units)
Weight Gain (kg)
events (/pt-yr)
100
+5
10
9.6 9.5
80
60
70 68
+44%
7.2 7.1
Preinsulin
+3.5
8.0
40
20
+2.6
1
5.5
.5
0
NPH insulin
2.4
7
Insulin glargine
Fig. 4. The LANMET Study. In this randomized, open-label trial, good glycemic control
was achieved with both insulin glargine and NPH insulin when using home glucose
monitoring. Insulin glargine was associated with reduced symptomatic hypoglycemia during
the first 12 weeks and dinner-time hyperglycemia compared with NPH insulin.
86
achieve FPG and HbA1c targets using forced titration algorithms that can be
driven by patients themselves, with no increase in the risk of hypoglycemia and
with the potential of reducing the burden on health care system utilization. The
novel strategy of empowering the patients to self-adjust their basal insulin dose
adds a further dimension to achieving normal fasting blood glucose targets as
an early strategy in this treatment paradigm ( fix fasting first) facilitated by the
use of long-acting insulin analogues with reduced risk of hypoglycemia.
However, if the target HbA1c level is not achieved after basal insulin is
effectively titrated to correct FPG levels to <100 mg/dL, then further benefit
can be attained by advancing the insulin regimen with progressive additions
of pre-meal short-acting insulin analogues or with inhaled insulin to control
postprandial glycemic peaks. Other options, not subject to this review, include
parenteral GLP-1 derivatives, pramlintide, or the oral agents such as the DPP-4
inhibitors.
Recent evidence provides some insight into the relative contributions of
fasting and postprandial hyperglycemia to the glycemic burden in patients
treated on oral agents without insulin (55). When the HbA1c is close to 7%,
the postprandial glucose excursions are the predominant factor in the glycemic
burden, and proper intervention with prandial insulin to escalate therapy can
further improve glycemic control when basal insulin therapy has already been
maximized. Coverage with basal insulin plus the stepwise introduction of
prandial inhaled insulin or short-acting insulin analogues at the main meal or
at the meal with the maximum glucose excursion first and then followed over
time with covering additional meals will be determined according to blood
glucose monitoring and the target HbA1c achieved.
Overcoming Complexity BarriersStarting with Prandial Insulin

Mealtime insulin supplementation to limit postprandial hyperglycemic
excursions in combination with oral agents is an attractive and physiologic
approach for the early initiation of insulin therapy. The administration of premeal doses of a short-acting insulin analogue (bolus) to control postprandial
hyperglycemic peaks has been successfully demonstrated in patients whose
HbA1c levels remain elevated despite the use of oral agents and the achievement
of normal fasting blood glucose (56,57). At the end of a 12-week study (57),
treatment with three injections of mealtime lispro insulin added to a sulfonylurea achieved lower HbA1c than sulfonylurea in combination with bedtime
NPH or with metformin. HbA1c improved with all therapies but was significantly lower for the lispro plus sulfonylurea compared with sulfonylurea combination with metformin or added bedtime NPH to the sulfonylurea (7.7, 8.3, and
8.5%, respectively). Clearly, still away from target values probably because of
inadequate titration, the increased complexity of this insulin regimen and the
87
need for multiple daily prandial insulin injections are major barriers for nonadherence, and the potential acceptance by the patients is understandably low.
However, now that inhaled insulin, Exubera , recently obtained FDA
approval, a prandial regimen using non-injectable pre-meal insulin replacement
may facilitate initiation of insulin therapy and has the potential to become a
valid option for first-line insulin intervention if on-going and future studies
demonstrate longer-term safety with sustained glycemic effects over time.
Currently, sustained efficacy and safety up to 4 years has been reported in
a small group of patients remaining from the original phase II studies who
were offered long-term inhaled insulin therapy after they completed the initial
12-week randomized, controlled trials (58).
The main efficacy and safety data on inhaled insulin in patients with T2DM
on oral agents come from a carefully controlled study that demonstrated
sustained glycemic effects, and the early small changes in pulmonary function
detected in FEV1 and DLco, did not lead to increased rates of lung function
loss over a 2-year period, and resolved upon discontinuation of therapy (59).
Similar findings were recently reported in T2DM patients on previous insulin
therapy, comparing prandial coverage with inhaled insulin versus a subcutaneous insulin. Treatment group differences in changes from baseline in FEV1
and DLco were small (<1.5% of mean baseline) and remained stable with no
progression for 2 years. Furthermore, HbA1c improved from 7.7 and 7.8% to
7.3 and 7.3% with inhaled and subcutaneous insulin, respectively, but inhaled
insulin resulted in greater FPG reductions from 151 to 136 mg/dL versus 148
to 147 mg/dL, respectively (60).
Regarding the potential for early initiation with inhaled insulin, the efficacy
of adding pre-prandial inhaled insulin to oral therapy was recently demonstrated
in a 3-month clinical trial (61). Patients with T2DM (n = 309) with mean
baseline HbA1c of 9.5% (entry criteria 811%) on combination oral therapy
with two agents (insulin secretagogue plus metformin or a thiazolidinedione)
were randomized to three different arms: (i) addition of prandial inhaled insulin
to the current doses of oral agents; (ii) discontinuation of oral agents and
initiation of prandial inhaled insulin as monotherapy; (iii) continuation of
oral agents with no changes (control group). The results were particularly
notable in that inhaled insulin added to oral agents showed a significant effect
on both the postprandial glucose increments and the FPG levels, with mean
decreases of 76 mg/dL in PPG and 53 mg/dL in FPG at 12 weeks (Fig. 5A).
The glycemic effects observed with inhaled human insulin extended beyond
the predicted pharmacokinetic activity by substantially improving FPG levels,
which probably contributes to the impressive reductions of HbA1c levels. The
largest decrease in HbA1c (1.9%) was demonstrated in the group receiving
combination oral agents plus supplementation with inhaled insulin whereas
88

INHa
Change in Fasting plasma

glucose (mg/dL)
10
INH + OAb
OA
0
10
20
30
40
50
60
INH OA adjusted difference at Week 12: 24 mg/dL; 95% CI [36, 11]

INH + OA OA adjusted difference at Week 12: 53 mg/dL; 95% CI [66, 41]
-
INHa
INH+OAb
OA
0
Change in 2-hour
postprandial plasma
glucose (mg/dL)
20
40
60
80
100
INH OA adjusted difference at Week 12: 62 mg/dL; 95% CI [79, 45]

INH + OA OA adjusted difference at Week 12: 76 mg/dL; 95% CI [93, 58]
11
Mean HbA1c (%)
10
9
a
7
6
Screening Baseline
12
Duration of treatment (weeks)

INH
INH + OA
OA
Week 12
(LOCF)
INH OA adjusted difference at Week 12 (LOCF): 1.18%; 95% CI [1.41, 0.95]

INH + OA OA adjusted difference at Week 12 (LOCF): 1.67%; 95% CI [1.90, 1.44]
Fig. 5. Inhaled insulin supplementation to oral agents. Adjusted mean change in fasting
plasma glucose concentration from baseline to study end after 12 weeks of inhaled insulin
treatment. Adjusted mean change in fasting plasma glucose concentration from baseline to
study end after 12 weeks of inhaled insulin treatment. Reductions in hemoglobin A1c level
were greatest with inhaled insulin. Adjusted treatment group differences for inhaled insulin
plus oral agents and inhaled insulin alone compared with continued oral agent therapy were
1.67 and 1.18%, respectively.
89
the group on inhaled insulin alone and the control group achieved a lesser
reduction in HbA1c of 1.4 and 0.2%, respectively (Fig. 5B).
Patient acceptance and preference will ultimately determine the future use
of inhaled insulin. Several studies have shown that patients receiving inhaled
insulin prefer this therapy and experience greater short- and longer-term satisfaction than patients taking subcutaneous insulin (62,63). The availability of
inhaled insulin could therefore have a major impact if physicians can convince
patients with T2DM to begin using insulin much earlier. It would be reasonable
to consider the option of starting insulin therapy at each meal, targeting premeal blood glucose levels, which can be basically considered late PPG levels,
as the first step in insulin therapy, challenging our current standard practice of
starting with a basal insulin replacement.
As we move to more stringent HbA1c targets (64,65), it is highly conceivable
that in the future we may consider, for those patients who are well controlled
with two or three oral agents but whose HbA1c are just above target 7%,
perhaps in the 7.17.5% range, the option of supplementing with inhaled
insulin. This strategy will be most appropriate and could facilitate initiation of
insulin at those mildly elevated HbA1c values that otherwise physicians and
patients have been very reluctant to start insulin. Perhaps, one dose of inhaled
Diet
OAD monotherapy
OAD combinations
OADs + Basal Insulin
HbA1c
or OADs + Inhaled Insulin ?
?
7%
OAD + Basal Insulin +

Inhaled Insulin
?
Evolving HbA1c Target
Duration of Diabetes
< 5 years
Fig. 6. The evolving management of type 2 diabetes mellitus (T2DM). The early, aggressive
approach to type 2 diabetes management avoids the risk of early treatment failure by
adopting an intensive therapeutic strategy immediately upon diagnosis. Early combinations
of agents with complementary modes of action targeting the dual defects underlying type 2
diabetes (insulin resistance and (-cell dysfunction) are most likely to support tight, long-term
glycemic control. Stringent hemoglobin A1c (HbA1c ) targets will determine the prompt
initiation and optimization of insulin replacement with either basal or inhaled insulin, and
eventually both, to supplement oral agents.
90
insulin before the main meal of the day, in combination with oral agents, may
suffice to achieve an HbA1c reduction of 0.40.5% that may be enough to
attain the HbA1c goal of <7%. It would be essential to start inhaled insulin
where an excessive glucose excursion is present [delta blood glucose >40
mg/dL (>2.2 mmol/L)]. Otherwise, if the initial HbA1c is considerably higher
or remains above 7% then further prandial coverage at each meal would be
advisable with insulin adjustments based on the PPG levels measured at the
following pre-meal time and/or based on the 2 h post pradical glucose level.
Eventually, patients may require supplementation of basal insulin if target
FPG and HbA1c are not achieved. Regardless of what insulin is initiated
first, it is likely that, eventually, a combination of basal and pradical insulin
increased on subentaneous will be required for long-term maintenance of nearnormoglycemic control (Fig. 6).
CONCLUSIONS
The evidence for improved glycemic control for preventing the onset and
progression of diabetes-related microvascular complications is overwhelming.
The concept of the possible existence of a window of opportunity for
improved glycemic control, because of a metabolic or vascular imprinting,
is gaining credence.
It may be that the early timing of physiologic insulin replacement within
a window of opportunity is critical for potential -cell preservation, which
may in turn can facilitate long-term maintenance of glycemic control.
Although the rationale is strong and the data clearly justify the early use of
insulin, the issues of implementation and overcoming perceive insulin barriers
remain critical. However, there has been a major change with respect to the
insulins available and how insulin can be delivered.
The advent of long-acting insulin analogues for early basal replacement
with inhaled insulin on rapid-acting insulin analogue, for progressive prandial
replacement provides the necessary tools for health care providers to empower
patients to take charge of their own diabetes control.
Ongoing trials, designed to achieve glycemic targets very close to normal,
may provide convincing evidence in terms of CV risk reductions, the task of
persuading physicians and patients of the need for early insulin replacement as
an expected strategy to achieve near-normoglycemic control will be lessened.
The advances outlined contribute greatly to addressing the multiple barriers
to insulin therapy so that the option of early insulin replacement can become
a feasible option for the patient, in line with a physiologic approach to
supplement and possibly sustain the remaining endogenous insulin secretion.
91
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Diabetic Retinopathy
Can it be Prevented?
Emily Y. Chew,
MD
CONTENTS
Introduction
Glycemic Control
Type 1 Diabetes
Type 2 Diabetes
Hypertension
Serum Lipids
Aspirin and Antiplatelet Treatments
Diabetes and Pregnancy
Conclusions
References
Summary
The intensive medical management of persons with diabetes, especially
both glycemic control as well as blood pressure control, has been proven
by randomized controlled clinical trials to be highly beneficial in reducing
both the development and progression of diabetic retinopathy in both types
1 and 2 diabetes. It is possible that aggressive therapy of dyslipidemia in
this population may also play an important role in the treatment of diabetic
retinopathy. This is to be proven in the randomized controlled trial called
Actions to Control Cardiovascular Risks in Diabetes (ACCORD) which is
designed to evaluate the role of treatment of intensive control of glycemia
and blood pressure and treatment of dyslipidemia. Other medical conditions
such as pregnancy may also have an effect on the progression of diabetic
retinopathy.
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Key Words: Diabetic retinopathy, glycemia, blood pressure, dyslipidemia aspirin use, pregnancy, diabetic macular edema
INTRODUCTION
Diabetic retinopathy is one of the leading causes of blindness in the USA
and in the developed world (1). In 2004, over 411 million persons were
estimated to have diabetic retinopathy with 899,000 affected with visionthreatening diabetic retinopathy (2). With the increase in the survival of the
aging population and the increase in the prevalence in diabetes, the number of
individual affected with diabetic retinopathy will increase as a major public
health disease. Any preventive measure may lessen the impact on the potential
toll this disease may take in terms of health care cost, personal loss in productivity, and societal cost and burden.
The two main causes of vision loss associated with diabetic retinopathy
are diabetic macular edema and proliferative diabetic retinopathy. The risk
factors known to be associated with the development and progression of sightthreatening diabetic retinopathy are varied and numerous (36). However, some
of these factors are not yet proven conclusively to be associated with the development and progression of retinopathy because there are either inconsistent
findings across various studies or the nature of the supportive data is only
observational. This chapter will explore some of these controversial factors
and will emphasize the potential approach to validating some of the results.
We will also emphasize the risk factors that are well known to be associated
with the development and progression of diabetic retinopathy.
GLYCEMIC CONTROL
Tight glycemic control has been proven to be an important factor the
progression of diabetic retinopathy. This risk factor, however, was considered
controversial when it was introduced by Dr. Elliot Joslin (7,8). He emphasized
the importance of intensive treatment to attain near-normal glucose control
in the treatment of diabetes for the prevention of diabetic complications in
his clinical practice in the 1950s and 1960s with great resistance from the
medical community of his times. In the late 1970s and throughout the 1980s,
the baseline hemoglobin A1C (HbA1C) level of the participants of Early
Treatment Diabetic Retinopathy was 9.8%, the Diabetes Control and Complications Trial (DCCT) was 9.1%, and the United Kingdom Prospective Diabetes
Trial (UKPDS) whose participants were recently diagnosed with diabetes, was
7.1%. The relatively higher HbA1C in the earlier studies reflect the tendency
of medical practice to have less intensive glycemic control in these earlier
years.
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Dr. Joslin was eventually proven to be correct a number of decades later

in the 1990s when the results of randomized controlled clinical trials showed
that tight or intensive glucose control compared with standard care prevented
progression or development of diabetic retinopathy and other microvascular
abnormalities. This was found for persons with type 1 or type 2 diabetes. The
results of these studies will be presented.
TYPE 1 DIABETES
In the DCCT, 1441 patients with type 1 diabetes were randomly assigned
to either conventional or intensive insulin treatment, and followed for a period
of 49 years (913). The DCCT demonstrated that intensive insulin treatment
is associated with a decreased risk of either the development of or progression
of diabetic retinopathy in patients with type 1 diabetes. In patients without any
visible retinopathy when enrolled in the DCCT, the 3-year risk of developing
retinopathy was reduced by 75% in the intensive insulin treatment group
compared with the standard treatment group. However, even in the intensively
treated group, retinopathy could not be completely prevented over the 9-year
course of the study. The benefit of the strict control was also evident in
patients with existing retinopathy (50% reduction in the rate of progression of
retinopathy compared with controls). At 6- and 12-month visits, a small adverse
affect of intensive treatment on retinopathy progression was seen, similar to
that described in other trials of glucose control. However, in eyes with little
or no retinopathy at that time of initiating intensive glucose control, this early
worsening of retinopathy is unlikely to threaten vision. When the DCCT results
were stratified by HbA1C levels, there was a 3540% reduction in the risk
of retinopathy progression for every 10% decrease in HbA1C (e.g., from 8 to
7%). This represented a fivefold increase in the risk for patients with HbA1C.
The beneficial effects of intensive therapy were evident after 3 years of
therapy on all different severities of retinopathy evaluated in the DCCT (9).
Intensive therapy reduced the risk of any retinopathy by 27% (p = 0.002). The
risk of developing retinopathy or progression to clinically significant degrees
was reduced by 3476% by intensive treatment of the glycemia. It was most
effective when initiated early in the course of the disease, and it had beneficial
effect over the entire range of retinopathy and in all patient subgroups. This
reduction in risk resulted in reduced need for laser treatment and saved sight.
After 6.5 years of follow-up, the DCCT ended, and all patients were
encouraged to maintain strict control of blood sugar. These patients are
followed in the Epidemiology of Diabetes Interventions and Complications
trial (EDIC), which includes 95% of DCCT subjects, half from each treatment
group. A total of 12941335 patients have been examined annually in the EDIC.
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Further progression of diabetic retinopathy during the first 4 years of the EDIC
was 6677% less in the former intensive treatment group than in the former
conventional treatment group (10). The benefit persists even at 7 years (11).
This benefit included an effect on severe diabetic retinopathy, including severe
nonproliferative diabetic retinopathy, proliferative diabetic retinopathy, clinically significant macular edema, and the need for focal or scatter laser therapy.
The decrease in the mean HbA1C from 9 to 8% did not drastically reduce the
progression of diabetic retinopathy in the former conventional treatment group
nor did the increase in HbA1c from 7 to 8% drastically accelerate diabetic
retinopathy in the former intensive treatment group. Thus, it takes time for
improvements in control to negate the long-lasting effects of prior prolonged
hyperglycemia, and once the biological effects of prolonged improved control
are manifest, the benefits are long lasting. Furthermore, the total glycemic
exposure of the patient (i.e., degree and duration) determines the degree of
retinopathy observed at any one time.
TYPE 2 DIABETES
Would similar results be seen in people with type 2 diabetes? The role of
intensive glucose control in type 2 diabetes was evaluated in a controlled,
randomized, controlled clinical trial, the United Kingdom Prospective Diabetes
Study (UKPDS). The effect of glycemic control on the incidence and
progression of diabetic retinopathy is similar in patients with type 2 diabetes,
as assessed in observational studies and randomized studies conducted in Japan
and the UK (1215). Findings in- a study of Japanese patients with type 2
diabetes have shown that multiple insulin-injection treatment reduced the onset
of retinopathy from 32 to 8% and reduced a two-step progression retinopathy
from 44 to 19% compared with people receiving conventional insulin treatments over 6 years (13). In the UKPDS, the largest and longest study of
4209 patients with type 2 diabetes followed for 15 years and there was a 25%
reduction in the risk of the any diabetes-related microvascular endpoint,
including the need for retinal photocoagulation in the intensive treatment group
compared with the conventional treatment group. After 6 years of followup, a smaller proportion of patients in the intensive treatment group than in
the conventional group had a two-step progression (worsening) in diabetic
retinopathy ( p < 0.01). Epidemiologic analysis of the UKPDS data showed
a continuous relationship between the risk of microvascular complications
and glycemia, such that for every percentage point decrease in HbA1C (e.g.,
98%), there was a 35% reduction in the risk of microvascular complications.
There is no longer a controversy regarding the importance of glycemic
control in the progression of diabetic retinopathy. The results of both the
DCCT and the UKPDS show that while intensive therapy of glucose reduces
99
the risk of the development and progression of diabetic retinopathy, it does not
prevent retinopathy completely. This still can be translated clinically to both
preservation of vision and reduction in therapy such as laser photocoagulation.
HYPERTENSION
The findings of observational studies assessing the importance of blood
pressure in the progression of nonproliferative diabetic retinopathy are inconsistent. However, in the UKPDS, a randomized comparison of more intensive
blood pressure control versus less intensive blood pressure control in persons
with type 2 diabetes demonstrated that intensive blood pressure control was
associated with a decreased risk of retinopathy progression (16). Of the 1148
hypertensive patients in the UKPDS, 758 were allocated to tight control of
blood pressure and 390 to less tight control with a median follow-up of 8.4
years. The target for the intensive treatment was a blood pressure <150/85
mm Hg versus a less tight blood pressure control goal of <180/105 mm Hg.
The outcome measures included the deterioration of diabetic retinopathy of two
or more steps along the modified Early Treatment Diabetic Retinopathy Study
(ETDRS) final scale, photocoagulation, vitreous hemorrhage, and cataract
extraction, and analysis of specific retinal lesions (microaneurysms, hard
exudates, and cotton-wool spots). Visual acuity was assessed at 3-year intervals.
Tight blood pressure control resulted in a 37% reduction in microvascular diseases, predominantly reduced risk of retinal photocoagulation, when
compared with less tight control. Retinal hard exudates increased from a
prevalence of 11.218.3% at 7.5 years after randomization with fewer lesions
found in the tight blood pressure (BP) control group [relative risk (RR), 0.53;
p < 0.001]. Cotton-wool spots increased in both groups but less so in the tight
BP control group which had fewer cotton-wool spots at 7.5 years (RR, 0.53;
p < 0.001). A two-step or more deterioration on the ETDRS scale was significantly different at 4.5 years with fewer people in the tight BP control group
progressing two steps or more (RR, 0.75; p = 0.02). Patients assigned to tight
BP control were less likely to undergo photocoagulation (RR, 0.65; p = 0.03).
This difference was mainly in photocoagulation for diabetic macular edema
(RR, 0.58; p = 0.02). There was a 50% reduction in the risk of moderate
vision loss as well with decrease in blindness or vision of 20/200 or worse.
The decreased vision of 20/200 or worse in one eye was found in 18 of 758
for the tight BP control group compared with 12 of 390 for less-tight BP
control group. The absolute risks of such poor vision was of 3.14.1 per 1000
patient-years, respectively (p = 0.046; RR, 0.76; 99% CI, 0.291.99).
A previously published study of blood pressure medication in diabetic
retinopathy suggested that there might be a specific benefit of angiotensinconverting enzyme (ACE) inhibition and blood pressure reduction, even in
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normo-tensive persons, on the progression of diabetic retinopathy (17).

The UKPDS included a randomized comparison of beta-blockers and ACE
inhibitors in the tight blood pressure control arm of that study. Benefits from
tight blood pressure control were present in both the beta-blocker and ACE
inhibitor treatment groups, with no statistically significant difference between
them. The results of the UKPDS suggest that the treatment effect is more likely
to be secondary to blood pressure reduction than to a specific effect of ACE
inhibitors (18).
SERUM LIPIDS
Although observational data suggest that serum lipids may be important in
the progression of diabetic retinopathy and development of diabetic macular
edema and retinal hard exudate, no clinical trial has proven the role of lowering
elevated serum cholesterol in the management of diabetic retinopathy. The
Wisconsin Epidemiologic Study of Diabetic Retinopathy, a population-based
study, and the ETDRS found that elevated levels of serum cholesterol were
associated with increased severity of retinal hard exudates (Fig. 1) (19,20).
A study of diabetic retinopathy in African Americans with type 1 diabetes
also showed the association of macular edema and retinal hard exudates
Fig. 1. The baseline data from the Early Treatment Diabetic Retinopathy Study (ETDRS)
demonstrate that serum total cholesterol is directly associated with the severity of retinal
hard exudate patients with diabetic retinopathy.
101
with elevated serum lipids (21). Patients with a total cholesterolhigh density
lipoprotein cholesterol (HDL-C) ratio of 4.5 or greater were almost twice as
likely to have retinal hard exudates compared with those with a ratio of < 4.5.
Higher quartile of total cholesterol or low-density lipoprotein cholesterol (LDLC) levels were 56 times more likely to have retinal hard exudates than those
in the lowest quartiles. In the ETDRS, elevated total cholesterol (240 mg/dL
or 6.21 mmol/L) was twice as likely to have retinal hard exudates at baseline
[odds ratio (OR): 2.00, 99% CI of 1.352.95). Similar results were found when
comparing elevated LDL levels (160 mg/dL or 1.14 mmol/L) with the lowest
level of LDL (130 mg/dL or 3.37 mmol/L) and the OR was 1.97, 99% CI of
1.32.96. Patients with elevated cholesterol and triglyceride levels were 50%
more likely to develop retinal hard exudates. Independent of the accompanying
macular edema, the severity of retinal hard exudates at baseline was associated
with decreased visual acuity in the ETDRS (Fig. 2). The severity of retinal
hard exudates was also a significant risk factor for moderate visual loss (15 or
more letter loss) during the course of the study. Patients with the most severe
level of retinal hard exudates had double the risk of experiencing moderate
visual loss.
Fig. 2. Multivariable logistic regression demonstrated that the risk of losing visual acuity
over five years of follow-up in the Early Treatment Diabetic Retinopathy Study (ETDRS)
was associated with both the presence and increasing severity of hard exudate at baseline,
adjusted for the presence and increasing severity of macular edema.
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Although the intensive treatment of hyperglycemia substantially reduced

the development and progression of diabetic retinopathy in the DCCT/EDIC
study, there was no statistically significant effect on macular edema. The
investigators evaluated the correlation of serum lipids and the incidence of
macular edema and retinal hard exudates in this cohort (22). Elevated LDL
was associated with an increased risk of macular edema. The comparison
of the highest quintile versus the lowest quintile of LDL resulted in an RR
of 1.95 (p for trend = 0.03). The total-to-HDL cholesterol ratio was also a
significant predictor for incident or new cases of clinically significant macular
edema with a RR of 3.84 (p for trend = 0.03). Similar findings were found for
association of serum lipids with the development of retinal hard exudates. After
adjusting for all known potential risk factors, the following were statistically
significant predictors of retinal hard exudates: total cholesterol: RR = 2.37, p
for trend = 0.001; LDL-C: 2.77, p for trend = 0.002; total-to-HDL cholesterol
ratio: 2.44, p for trend = 0.0004; and triglycerides: 3.20, p for trend = 0.006.
These findings were similar to those found in the ETDRS.
In a study of the risk factors associated with the development of subretinal
fibrosis in ETDRS patients with diabetic macular edema, the presence of severe
hard exudates was the strongest risk factor (23). Elevated serum triglyceride
levels were also associated with a greater risk of developing high-risk proliferative diabetic retinopathy in the ETDRS patients (6). In a study in Pittsburgh,
elevated triglycerides, as well as elevated LDL-C were found to be associated
with proliferative diabetic retinopathy (3).
These are all observational findings with compelling data. It is certainly
important to recommend lowering elevated serum lipids in patients with
diabetes to reduce the risk of cardiovascular disease (CVD). The risk of vision
loss, as seen in the observational studies, should be another motivating factor
for patients to lower elevated serum lipids. The effects of treating dyslipidemia
require further assessment. Currently, the hypothesis that treatment of dyslipidemia may be very important in the role of progression of diabetic retinopathy
is currently evaluated in the Actions to Control Cardiovascular Risk in Diabetes
(ACCORD) Eye Study. In brief, ACCORD is a randomized, controlled clinical
trial with three components, determining the effects of lowering blood glucose,
lowering blood pressure, and using fibrates to lower serum triglycerides and
raise serum HDL-C levels (on a background of statin treatment) on CVD in
patients with type 2 diabetes. A subset of participants with this study will
be evaluated with a standardized protocol for comprehensive eye exams and
fundus photography consisting of the seven stereoscopic fields. We hope this
study will yield data to help resolve the controversy of the role and will confirm
the results of the observational studies of dyslipidemia and diabetic retinopathy.
The ACCORD will also help to confirm the effects of tight glycemic and blood
pressure control on the development and progression of diabetic retinopathy.
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ASPIRIN AND ANTIPLATELET TREATMENTS

There was interest in the past to retard the development and progression
of diabetic retinopathy with antiplatelet treatment because of studies of
patients with rheumatoid arthritis. Three randomized controlled clinical trials
of antiplatelet treatments have been performed in patients with diabetic
retinopathy. None has demonstrated a clinical beneficial effect of treatment.
The Dipyridamole Aspirin Microangiopathy of Diabetes (DAMAD) study
(24) and Ticlopidine Microangiopathy of Diabetes Study (25) enrolled 475
and 435 patients, respectively. These two studies found similar results with
little difference in change in retinopathy severity as judged by visual acuity
measurements or ophthalmoscopy. There was a difference observed in counts
of microaneurysms on fluorescein angiograms, with the increase greater in the
placebo group, and less in the aspirin group, the aspirin plus dipyridamole
group, and the ticlopidine group. These small differences were of borderline
statistical significance and uncertain clinical importance.
In the ETDRS, all patients were randomly assigned to 650 mg of aspirin
per day or placebo, and one eye of each patient was randomly assigned to
immediate photocoagulation, while the other eye was assigned to deferral of
photocoagulation, i.e., careful follow-up and prompt scatter photocoagulation
if high risk retinopathy developed. The eyes assigned to deferral of laser
photocoagulation were assessed for the effects of aspirin on the progression
of diabetic retinopathy (26). Aspirin use did not affect the progression of
retinopathy, nor did it affect the risk of visual loss (27). Perhaps surprisingly,
aspirin use did not increase the risk of vitreous hemorrhage in patients with
AQ8 proliferative retinopathy (28). Aspirin use was associated with a 17%
reduction in the morbidity and mortality from CVD (29). Therefore, aspirin
should be considered for persons with diabetes, not because of any effect
on their diabetic retinopathy, but because of the benefits of aspirin that have
been demonstrated for persons at increased risk of CVD. The presence of
proliferative diabetic retinopathy should not be considered a contraindication
to aspirin use.
DIABETES AND PREGNANCY

The effects of pregnancy on the development and the rate of progression
of underlying diabetic retinopathy have been controversial. Although many
studies have suggested a worsening of retinopathy during pregnancy (3033),
others have not (34,35). Diabetic retinopathy can worsen during pregnancy
because of the pregnancy itself or the changes in metabolic control, usually a
marked improvement in glucose control.
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The DCCT is the largest prospective study to assess the effect of pregnancy
on the development and progression of diabetic retinopathy and other microvascular abnormalities (36). The women in the DCCT were generally younger and
had shorter duration of diabetes with fewer or less-severe diabetic complications than those previously reported in other studies. Women in the intensive
treatment group had HbA1C levels that were near normal for a mean of 3 years
before conception. When the analyses were stratified by the treatment group,
both the intensive and the conventional groups showed a short-term deterioration of retinopathy during pregnancy that persisted through the first year
post-partum. In the conventional treatment group, there was a 2.5-fold increase
in the risk of retinopathy progression when compared with nonpregnant women.
This was statistically significant and not affected by other risk factors. In the
intensive treatment group, the adjusted risks were not as great whereas the risk
of retinopathy progression was nominally statistically significant. However,
there were fewer events in the early treatment group.
There was a significant trend toward greater worsening of retinopathy with
greater reductions in HbA1C. This progression may be similar to that of the
early worsening that has been shown to be related to the magnitude of the
decrease of HbA1C with the intensive therapy of glycemia. However, when
the recent changes in retinopathy were compared between the pregnant and the
nonpregnant women, adjusted for the recent changes in HbA1C, the increased
worsening of retinopathy during pregnancy persisted. It would appear that both
the effects of pregnancy as well as the effects of intensive therapy are important
in the progression (worsening) of retinopathy. The follow-up examinations
showed that the effects of pregnancy on retinopathy continued to increase
over the first year following delivery of the baby. In addition, there were
no long-term consequences of this worsening of retinopathy as both pregnant
and nonpregnant women had similar severity of retinopathy at the end of
the study. Patients with diabetes who are planning to become pregnant are
encouraged to achieve as tight glucose control as possible to reduce the risk of
malformations and other genetic abnormalities. Patients with diabetes who are
planning to become pregnant are encouraged to have their eyes examined before
conception, to be counseled on the risk of development and/or progression of
diabetic retinopathy. During the first trimester, another eye examination should
be performed; subsequent follow-up will depend on the level of retinopathy
found; and post-partum examination may be also important.
CONCLUSIONS
Although diabetic retinopathy cannot be completely prevented, tight
glycemic and blood pressure control reduce both the rates of development
and the progression of diabetic retinopathy. Although observational data
105
are compelling for recommending aggressive treatment for dyslipidemia,

especially for prevention of CVD, there is no randomized controlled trial to
suggest that such treatment would be beneficial for preventing or retarding
the progression of diabetic retinopathy. The ACCORD study data will address
this issue in the future. Antiplatelet treatment has not been effective in the
treatment of diabetic retinopathy, but they can also be safely administered to
persons with diabetic retinopathy. No harmful effects were seen.
Pregnancy may increase the risk of progression of diabetic retinopathy
secondary to improvement in glycemic control and to the pregnancy itself.
Again, tight glycemic control, especially before conception, may decrease
many adverse side effects such as increased genetic abnormalities and malformations. Tight glucose control plays an important role in the prevention of
diabetic retinopathy progression in all clinical situations. Future research may
assess genetic associations in patients with diabetic retinopathy.
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18. Matthews DR, Stratton IM, Aldington SJ, Holman RR, Kohner EM; UK Prospective
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31. Klein BE, Moss SE, Klein R. Effect of pregnancy on progression of diabetic retinopathy.
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Diabetic Neuropathies
Evaluation, Management and Controversies
in Treatment Options
Aaron I. Vinik,
MD, PHD, FCP, FACP
CONTENTS
Introduction
Denition
Classication
Clinical Manifestations
Treatment
Conclusions
References
Summary
Diabetic neuropathies (DN) are a heterogeneous group of disorders that
include a wide range of abnormalities. They can be focal or diffuse, proximal
or distal, affecting both peripheral and autonomic nervous systems, causing
morbidity with significant impact on the quality of life of the person with
diabetes, resulting in early mortality. Distal symmetric polyneuropathy, the
most common form of DN, usually involves small and large nerve fibers.
Small nerve fiber neuropathy often presents with pain without objective
signs or electrophysiologic evidence of nerve damage. However, there are
now measures enabling early recognition of this type of neuropathy as a
component of the impaired glucose tolerance and metabolic syndromes. The
greatest risk of small fiber neuropathy is foot ulceration and subsequent
gangrene and amputation. Large nerve fiber neuropathies produce numbness,
ataxia and incoordination, impairing activities of daily living and causing
falls and fractures. A careful history and detailed physical examination is
109
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Vinik
essential for the diagnosis. Symptomatic therapy has become available, and
newer and better treatment modalities based on etiologic factors are being
explored with potential for significant impact on morbidity and mortality.
Preventive strategies and patient education still remain key factors in reducing
complication rates and mortality. A number of mechanical measures for the
treatment of neuropathy have been examined, and it is currently unclear
whether or not these have salutary effects over and above those of placebo,
and longer, well-controlled clinical trials are anticipated. In addition, there
is the suggestion that surgical unentrapment of nerves in DN may confer
symptomatic relief, but outside of clear applications in proven entrapments,
this form of intervention has not been endorsed universally. We now have
two drugs approved for the treatment of neuropathic pain in diabetes that is
a first, and it remains to be seen whether the evidence-based approach will
supersede the need for cost containment and the tried and tested approaches
to pain management in the clinic. Finally, the American Diabetes Association
have included somatic and autonomic guidelines in their 2006 issue of clinical
recommendations, which has come as a welcome relief to the Cinderella of
diabetic complications, DN.
Key Words: Diabetes mellitus; diabetic neuropathy; diabetic autonomic
neuropathy; treatment; pain.
INTRODUCTION
Diabetic neuropathies (DN) are amongst the most frequent complications of
diabetes mellitus (DM), affecting up to 50% of patients, leading to increased
morbidity and mortality, and economic burden. DN is the most common form
of neuropathy in developed countries and is responsible for 5075% of nontraumatic amputations. The major morbidity is foot ulceration, which can lead
to gangrene and ultimately to limb loss. Every year, 86,000 amputations are
performed on diabetic patients in the USA; yet, up to 75% of them are preventable
(1). DN also has a tremendous impact on patients quality of life (QOL) (2).
DN are a heterogeneous group of conditions that involve different components of the somatic and autonomic nervous systems. They can be focal
or diffuse, proximal or distal. Causative factors include persistent hyperglycemia, microvascular insufficiency, oxidative stress, nitrosative stress,
defective neurotrophism, and autoimmune-mediated nerve destruction (3).
The epidemiology and natural history of DN remains poorly defined, in part
because of variable criteria for the diagnosis, failure of many physicians to
recognize and diagnose the disease and lack of standardized methodologies
used for the evaluation of these patients(4). Nonetheless, it has been estimated
that 50% of patients with diabetes have DN, and 2.7 million have painful
111
neuropathy. DN is grossly underdiagnosed and untreated by endocrinologists

and non-endocrinologists alike (5).
Here we will focus on the clinical manifestations of DN and its symptomatic
treatment, with special emphasis on new therapies aimed at the underlying
pathogenesis and controversies in management.
DEFINITION
DN is the presence of symptoms and/or signs of peripheral nerve dysfunction
in people with diabetes after the exclusion of other causes. A careful clinical
examination is also needed for the diagnosis, because asymptomatic neuropathy
is common (4). A minimum of two abnormalities (symptoms, signs, nerve
conduction abnormalities, quantitative sensory tests, or quantitative autonomic
tests) are required for diagnosis and, for clinical studies, one of theses two
abnormalities should include quantitative tests or electrophysiology (4,6).
CLASSIFICATION
Table 1 describes the classification proposed by Thomas and modified by
us (7,8,9). It is important to note that different forms of DN often coexist in
the same patient (e.g., DPN and proximal neuropathy, or entrapments such as
carpal tunnel syndrome).
Table 1
Classification of Diabetic Neuropathies (8,9)
Somatic
Rapidly reversible
Focal and multifocal neuropathies
Generalized symmetrical PN
Autonomic
a
Hyperglycemic neuropathy
Cranial
Thoracolumbar radiculoneuropathy
Focal limb
Proximal motor (amyotrophy)
Coexisting CIDPa
Acute sensory
Chronic sensorimotor (DPN)
Small fiber neuropathy
Large fiber neuropathy
Cardiovascular, GI, Genitourinary,
papillary, metabolic
CIDP, chronic inflammatory demyelinating neuropathy.
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Vinik
CLINICAL MANIFESTATIONS
Somatic
Focal and Multifocal Neuropathies
Focal limb neuropathies are usually due to entrapment, and mononeuropathies must be distinguished from entrapment syndromes (9,10). Mononeuropathies often occur in the older population with an acute onset, associated
with pain, and a self-limiting course, resolving in 68 weeks. These can
involve the median (5.8% of all DN), ulnar (2.1%), radial (0.6%), and
common peroneal nerves (11). Cranial neuropathies in diabetic patients are
extremely rare (0.05%) and occur in older individuals with a long duration
of diabetes (12). Entrapment syndromes start slowly, progress and persist
without intervention. Carpal tunnel syndrome occurs three times as frequently
in diabetics compared with healthy populations (13) and is found in up
to one-third of patients with diabetes (10). The diagnosis is confirmed by
electrophysiological studies. Treatment consists of resting aided by placement
of wrist splint in a neutral position to avoid repetitive trauma. Antiinflammatory medications and steroid injections are sometimes useful. The role
of surgery is not clearly established for the different entrapments, for example,
good outcome with carpal tunnel syndrome and poor outcome with ulnar
entrapment but should be considered if weakness appears and medical treatment
fails (4,9).
Proximal Neuropathies
Typically occurs in older patients (5060 years) with type 2 diabetes and
presents with severe pain and uni- or bilateral muscle weakness and atrophy
in proximal thighs. Pathogenesis is still unclear, although immune-mediated
epineurial microvasculitis is the culprit in some cases. Controversy exists
as to whether or not immunosuppressive therapy should be recommended
because there are no double-blind placebo-controlled studies but using highdose steroids or intravenous immunoglobulin has proved successful in several
small studies(14).
Diabetic Truncal Radiculoneuropathy
Diabetic truncal radiculoneuropathy affects middle-aged to elderly patients,
especially males. Pain is the most important symptom, occurring in a girdlelike distribution over the lower thoracic or abdominal wall, uni- or bilaterally
distributed. Motor weakness is rare. Resolution generally occurs within 46
months. It is not clear that any form of intervention changes the natural history
of this condition.
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Chronic Inammatory Demyelinating Polyneuropathy

When an unusually severe, predominantly motor and progressive polyneuropathy develops in diabetic patients, chronic inflammatory demyelinating
polyneuropathy (CIDP) should be considered. Progressive motor deficit,
progressive sensory neuropathy despite optimal glycemic control together
with typical NCV findings and an unusually high CSF protein level suggest
the possibility of an underlying demyelinating neuropathy. The diagnosis is
often overlooked, although recognition is very important, because, unlike
DN, it is treatable. It occurs 11 times more frequently in the diabetic
than non-diabetic patient (15,16). Immunomodulatory therapy can produce
a relatively rapid and substantial improvement (17), but there are those
who believe that there is little to be gained over time and spontaneous
resolution.
Distal Polyneuropathies
Rapidly Reversible Hyperglycemic Neuropathy Reversible abnormalities of
nerve function with distal sensory symptoms may occur in patients with
recently diagnosed or poorly controlled diabetes. Recovery soon follows
restoration of euglycemia (4). However, it is also apparent that acute normalization of blood glucose with insulin or oral agents may actually accentuate
pain in this syndrome (see below).
Acute Sensory Neuropathy Acute painful sensory neuropathy (ASN) is a
distinctive variant of DPN and is characterized by severe pain, cachexia,
weight loss, depression, and, in males, erectile dysfunction (7). Patients report
unremitting burning, deep pain, and hyperesthesia especially in the feet. Other
symptoms include sharp stabbing or electric shock-like sensations in the
lower limbs that appear more frequently during the night. Signs are usually
absent with a relatively normal clinical examination, except for allodynia and,
occasionally, absent or reduced ankle reflexes.
ASN is usually associated with poor glycemic control but may also appear
after rapid improvement of hyperglycemia (18). It has been hypothesized
that changes in blood glucose flux produces alterations in epineurial blood
flow, leading to ischemia (19). Other authors propose an immune-mediated
mechanism (20).
The key to the management of this syndrome is achieving blood glucose
stability. Most patients also require medication for neuropathic pain. The
natural history of this disease is resolution of symptoms within 6 months to
1 year (18). There are insufficient information on trials of immunotherapy to
define its role here.
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Vinik
Distal Symmetric Polyneuropathy

Clinical Presentation Distal symmetric polyneuropathy (DPN) is probably
the most common form of DN (4,20). It is seen in both type 1 and type
2 DM with similar frequency, and it may be already present at the time of
diagnosis of type 2 DM (18). A population survey reported that 30% of type
1 and 3640% of type 2 diabetic patients experienced neuropathic symptoms
(21) but an American Diabetes Association Omnibus survey of 8119 patients
reported symptoms compatible with neuropathy in 75% of patients illustrating
the need for specificity with regard to symptom attribution to neuropathy.
Several studies have suggested that impaired glucose tolerance (IGT), and the
metabolic syndrome may account for 3050% of idiopathic neuropathies
(22,25).
Sensory symptoms are more prominent than motor and usually involve the
lower limbs. These include pain, paresthesiae, and hyperaesthesia, deep aching,
burning, and sharp stabbing sensations. In addition, patients may experience
negative symptoms such as numbness in feet and legs leading in time to painless
foot ulcers and subsequent amputations, if the neuropathy is not promptly
recognized and treated. Unsteadiness frequently occurs because of abnormal
proprioception and muscle sensory function (26,27). Some patients may be
completely asymptomatic and signs may be only discovered by a detailed
neurological examination.
On physical examination, there is usually a symmetrical stocking-like distribution of sensory abnormalities in both lower limbs. In severe cases, the
hands may be involved. All sensory modalities can be affected, particularly loss of vibration, touch, and position perception (large A / fiber
damage); and abnormal heat and cold temperature perception (small A
and unmyelinated C fiber damage). Ankle and knee reflexes may be absent
or reduced. Mild muscle wasting may be observed, but severe weakness
is rare and, if present, should raise the question of a possible non- DN
(4,20,28). DPN is frequently accompanied by autonomic neuropathy (AN).
All patients with DPN are at increased risk of foot ulceration and Charcots
neuroarthropathy.
Diagnosis of DPNs
History and Physical Examination. Symptoms of neuropathy are personal
experiences and vary markedly from one patient to another. Symptom questionnaires with similar scoring systems have been developed. These are useful
to assess responses to treatment. The Neurologic Symptom Score (NSS) (29)
115
has 38 items that capture symptoms of muscle weakness, sensory disturbances,

and autonomic dysfunction.
A comprehensive clinical examination is key to the diagnosis of DPN. Feet
must be examined in detail to detect ulcers, calluses, and deformities, and
footwear inspected at every visit. The American Diabetes Association (ADA)
recommends that all type 2 diabetic patients should be screened for DN at
diagnosis, and all type 1 diabetic patients 5 years after diagnosis. Thereafter,
screening should be repeated annually and must include sensory examination
of the feet and ankle reflexes (8). One or more of the following can be used
to assess sensory function: pinprick, temperature, vibration perception (using
128-Hz tuning fork), and 10-G monofilament pressure perception at the distal
halluces. Combinations of more than one test have more than 87% sensitivity
in detecting DPN (8,30). Longitudinal studies have shown that these simple
tests are good predictors of foot ulcer risk (31). Numerous composite scores
to evaluate clinical signs of DN such as the nerve impairment score (NIS) are
useful in documenting and monitoring neuropathic deficits (32).
Quantitative Sensory Testing. Quantitative Sensory Testing (QST) may be of
value in the detection of subclinical neuropathy, assessment of progression, and
the prediction of risk for foot ulceration (30,33). These standardized measures
of vibration and thermal thresholds also play an important role in multicenter
clinical trials as primary efficacy endpoints as discussed below (2).
Nerve Conduction Studies. The use of electrophysiologic measures (NCV) in
both clinical practice and multicenter clinical trials is recommended (34,35),
but their global use in the clinical arena is not universally agreed on. There
are however specific situations where NCS may be of particular help. In
type 2 diabetes patients (36), NCV abnormalities in the lower limbs increased
from 8% at baseline to 42% after 10 years of disease. A slow progression
of NCV abnormalities in type 1 diabetes was observed in the Diabetes
Control and Complication Trial (DCCT) (37). The sural and peroneal nerve
conduction velocities diminished by 2.8 and 2.7 m/s, respectively, over a 5year period. Patients who were free of neuropathy at baseline had a 40%
incidence of abnormal NCV in the conventionally treated group versus 16%
in the intensive therapy treated group after 5 years. Small, unmyelinated
nerve fibers are affected early in DM and are not reflected in NCV studies.
Other methods that do not depend on conduction such as QST or skin
biopsy with quantification of IENF are necessary to identify these patients
(20). Nevertheless, NCV plays a key role in ruling out other causes of
neuropathy and is essential for the identification of focal and multifocal
neuropathies (4,10).
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Vinik
DIABETES
Genes/Height, Environment
Smoking/Alcohol
AUTOIMMUNITY
METABOLIC
Hyperglycemia, Hypoinsulinemia,
GF Abnormalities, Dyslipidemia
Nonenzymatic
Glycosylation
AGE
Ab to GFs,
NGF & receptors,
Insulin, IGF-1,
IGF-II, P75TRK
C fixing
Ab/glycolipids
Cell death/apoptosis
MICROVASCULAR
INSUFFICIENCY
Aldose Reductase Activity

Polyols, Myoinositol
Na/K ATPase
DAG & 2
PKC Activity
Oxidative/Nitrosative Stress
ROS, NF B activity
Cytokines/integrins
Endothelial
Dysfunction
PGI2 / NO, ET,
A11, EDHF
Delivery of GFs (NGF,
NT3,IGF-I, IGF-II, Insulin)
NERVE DYSFUNCTION
Antigenic Leakage
ORGANIC/STRUCTURAL NERVE DAMAGE

Axonopathy (atrophy, loss)
Demyelinatin (segmental, progressive)
Laminin 2 , IGF-I, IGF-II, NGF, NT3, Insulin
NERVE REGENERATION
RESTORATION OF NERVE FUNCTION
Fig. 1. Modified pathogenesis of diabetic neuropathies from Vinik et al. (95,96)
Skin Biopsy and Quantification of Intraepidermal Nerve Fibers. The

importance of the skin biopsy as a diagnostic tool for DPN is increasingly
being recognized (38,39,40). This technique quantitates small epidermal nerve
fibers through antibody staining of the pan axonal marker protein gene product
9.5 (PGP 9.5). Although minimally invasive (3-mm diameter punch biopsies),
it enables a direct study of small fibers, which cannot be evaluated by NCV
studies (Fig. 1).
Quality of Life in DN. It is widely recognized that neuropathy per se can
affect the QOL of the diabetic patient. The Norfolk QOL questionnaire for DN
is a validated tool addressing specific symptoms and impact of large, small,
and autonomic nerve fiber functions. The tool has been used in clinical trials
and is available in several validated language versions (2). The NeuroQoL
(41) measures patients perceptions of the impact of neuropathy and foot
ulcers.
The diagnosis of DPN is mainly clinical, aided by specific diagnostic tests
according to the type and severity of the neuropathy. However, non-diabetic
causes of neuropathy must always be excluded, depending on the clinical
findings (Fig. 2).
117
Conceptualization of the Generation of

Neuropathic Pain
Normal
C - fiber
sensitization
C - fiber loss
Nociceptor
sensitization
Central
disinhibition
Cold hyperalgesia
Sympat
+
_
NA
C A
C A / A
C A
C
C A
D
Fig. 2. Schematic representation of the generation of pain. (A) Central terminals

of c-afferents project into the dorsal horn and make contact with secondary painsignaling neurons. Mechanoreceptive A afferents project without synaptic transmission
into the dorsal columns (not shown) and also contact secondary afferent dorsal horn
neurons. (B) Spontaneous activity in peripheral nociceptors (peripheral sensitization,
black stars) induces changes in the central sensory processing, leading to spinal cord
hyperexcitability (central sensitization, white star) that causes input from mechanoreceptive A (light touch) and A fibers (punctuate stimuli) to be perceived as pain
(allodynia). (C) C-nociceptor degeneration and novel synaptic contacts of A fibers with
free central nociceptive neurons, causing dynamic mechanical allodynia. (D) Selective
damage of cold-sensitive A fibers that leads to central disinhibition, resulting in cold
hyperalgesia (9).
Autonomic Neuropathy
Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes but remains among the least recognized and understood. It
has a significant negative impact on survival and QOL. Furthermore, cardiovascular autonomic neuropathy (CAN) increases risk of mortality. A metaanalysis, evaluating 15 clinical studies, found a relative risk for mortality of
3.45 (95% CI 2.664.47; p < 0.001) in studies that used two or more measures
to define CAN (42). The reported prevalence of DAN varies widely depending
on the cohort studied and the methods used for the diagnosis (7.790%) (43,44).
The most common clinical features, diagnostic methods, and treatment options
are presented in Table 2 Management of hyperglycemia, lipids, blood pressure,
Diarrhea (often nocturnal alternating with

constipation)
Endoscopy
Constipation
Frequent small meals, prokinetic

agents (metoclopramide, domperidone,
erythromycin)
Antibiotics, antiemetics, bulking agents,
tricyclic antidepressants, pyloric botox,
gastric pacing
High-fiber diet, and bulking agents,
osmotic laxatives, lubricating agents
Soluble fiber, gluten, and lactose
restriction, anticholinergic agents,
cholestyramine, antibiotics, somatostatin,
pancreatic enzyme supplements
Gastric emptying study, barium

study
Endoscopy, manometry,
electrogastrogram
Graded supervised exercise, ACE

inhibitors, -Blockers
Mechanical measures, clonidine,
midodrine, octreotide, erythropoietin
Treatments
HRV, MUGA thallium scan,

MIBG scan
HRV, supine and standing BP,
catecholamines
Tests
Abdominal pain, early satiety, nausea,

vomiting, bloating, belching
Postural hypotension, dizziness,

weakness, fatigue, syncope
Gastrointestinal
Gastroparesis, erratic glucose control
Cardiac
Resting tachycardia, exercise intolerance
Symptoms
Table 2
Clinical Features, Diagnosis and Treatment of DAN (44)
Emollients and skin lubricants,

scopolamine, glycopyrrolate, botulinum
toxin, vasodilators
Quantitative sudomotor axon

reflex, sweat test, skin blood
flow
Recognition of unusual presentation of

MI, control of risk factors, control of
plasma glucose levels
Care with driving at night
Bethanechol, intermittent catheterization
Cystometrogram, postvoiding
sonography
Pupillometry, HRV
Sex therapy, psychological counseling,

5-phosphodiesterase inhibitors, PG E1
injections, devices or prostheses
Vaginal lubricants
H&P, HRV, penile-brachial

pressure index, nocturnal penile
tumes
HRV, heart rate variability; MUGA, multigated angiography; MIBG, metaiodobenzlyguanidine; H & P, history and physical examination; MI,
myocardial infarction.
Pupillomotor and visceral dysfunction

Visual blurring, impaired adaptation to
ambient light, Argyll- Robertson pupil
Impaired visceral sensation: silent MI,
hypoglycemia unawareness
Vaginal dryness
Bladder dysfunction
Frequency, urgency, nocturia, urinary
retention, incontinence
Sudomotor dysfunction
Anhidrosis, heat intolerance, dry skin,
hyperhidrosis
Sexual dysfunction
Erectile dysfunction
120
Vinik
and use of antioxidants (45) and ACE inhibitors (46) reduce the odds ratio for
AN to 0.32 (47).
TREATMENT
Treatment of DN should be targeted toward a number of different aspects:
1. Treatment of specific underlying pathogenic mechanisms.
2. Treatment of symptoms and improvement in QOL.
3. Prevention of progression and treatment of complications of neuropathy.
Treatment of Specific Underlying Pathogenic Mechanisms

Glycemic and Metabolic Control
Numerous studies have shown a relationship between hyperglycemia and
the development and severity of DN. The DCCT research group reported
that clinical and electrophysiological evidence of neuropathy was reduced by
50% in those treated intensively with insulin (48). In the UK Prospective
Diabetes Study (UKPDS), control of blood glucose was associated with
improvement in vibration perception (49,50). The Steno trial using multifactorial intervention (51) reported a reduction in the odds ratio to 0.32 for the
development of AN. Furthermore, the EURODIAB, a prospective study that
included 3250 patients across Europe (52) has shown that the incidence of
neuropathy is also associated with potentially modifiable cardiovascular risk
factors, including a raised triglyceride level, body mass index, smoking, and
hypertension. Therefore, treatment of neuropathy should include measures to
reduce macrovascular risk factors, including hyperglycemia, blood pressure,
and lipid control and lifestyle modifications including exercise and weight
reduction, smoking cessation, a diet rich in omega-3 fatty acids and avoidance
of excess alcohol consumption (51).
Oxidative Stress
A number of studies have shown that hyperglycemia causes oxidative stress
in tissues that are susceptible to complications of diabetes, including peripheral
nerves. Figure 1 presents our current understanding of the mechanisms and
potential therapeutic pathways for oxidative stress-induced nerve damage.
Studies show that hyperglycemia induces an increased presence of markers of
oxidative stress, such as superoxide and peroxynitrite ions, and that antioxidant
defense moieties are reduced in patients with diabetic peripheral neuropathy
(53). Therefore, therapies known to reduce oxidative stress are recommended
but do not have evidence-based support of large-scale clinical trials but rather
meta-analysis of several smaller trials.(54).
121
Investigational therapies include Aldose Reductase inhibitors (ARIs), alpha

lipoic acid, gamma linolenic acid, benfotiamine, and protein kinase C
inhibitors. ARIs reduce the flux of glucose through the polyol pathway,
inhibiting tissue accumulation of sorbitol and fructose. Newer ARIs are
currently being explored (55), but it is becoming clear that these agents may
be insufficient per se and combinations of treatments may be needed (9).
Gamma-Linolenic acid has been reported to cause significant improvement
in clinical and electrophysiological tests for neuropathy (56), but there are no
large-scale clinical trials to support its use alone or in combination in patients
with neuropathy.
Alpha-Lipoic acid or Thioctic acid has been used for its antioxidant
properties and for its thiol replenishing redox-modulating properties. A number
of studies show its favorable influence on microcirculation and reversal of
some symptoms of neuropathy (57). While there appears to be some skepticism
with regard to the strengths of the meta-analysis ongoing studies will examine
its long-term effects on electrophysiology and clinical assessments.
Protein Kinase C Beta (PKC-b) Inhibition
PKC activation is a critical step in the pathway to diabetic microvascular complications (58). It is activated by both hyperglycemia and disordered fatty acid metabolism resulting in increased production of vasoconstrictive, angiogenic, and chemotactic cytokines including transforming growth
factor-, vascular endothelial growth factor (VEGF), endothelin (ET-1), and
intercellular adhesion molecules (ICAMs). Preliminary results of a multinational, randomized, phase-2, double-blind, placebo-controlled trial with ruboxistaurin (a PKC- inhibitor) failed to achieve the endpoints. Nevertheless, it
showed a statistically significant improvement in symptoms in the ruboxistaurin (RBX)-treated neuropathy groups with a sural nerve action potential
(SNAP) greater than 0.5 V at baseline, (59) as compared with placebo (60).
The change from baseline for vibratory detection threshold (VDT) was statistically significantly improved in the treated groups. While one phase-3 study
failed to meet the endpoint of reduction in symptoms, phase-3 studies are
currently taking place, which include objective measures of neuropathy that
may confirm or refute the above findings.
Neurotrophic Factors
There is increasing evidence that there is a deficiency of nerve growth
factor (NGF) in diabetes, as well as the dependent neuropeptides substance
P (SP) and calcitonin gene-related peptide (CGRP) and that this contributes
to the clinical perturbations in small fiber function (61). Clinical trials with
NGF have not been successful but are subject to certain caveats with regard to
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Vinik
design (see below), and NGF may still hold promise for sensory and autonomic
neuropathies (62). The pathogenesis of DN includes loss of vasa nervorum, so
it is likely that appropriate application of VEGF would reverse the dysfunction.
Introduction of VEGF gene into muscle of DM animal models improved nerve
function (63). There are ongoing VEGF gene studies in humans.
Immune Therapy
Several different autoantibodies in human sera have been reported that can
react with epitopes in neuronal cells and have been associated with DN. We
have reported a 12% incidence of apredominantly motor form of neuropathy
in patients with diabetes associated with monosialoganglioside antibodies (64).
Perhaps the clearest link between autoimmunity and neuropathy has been
the demonstration of an 11-fold increase likelihood of CIDP, multiple motor
polyneuropathy (MMP), vasculitis, and monoclonal gammopathies in diabetes
(15). However, new data support a predictive role of the presence of antineuronal antibodies on the later development of neuropathy (65), which may not
be innocent bystanders but neurotoxins (66). There may be selected cases,
particularly those with AN and antineuronal autoimmunity, and CIDP, that
benefit from IVIg (67).
Treatment of Symptoms and Improvement in Quality of Life

Control of pain is one of the most difficult management issues in DN. It
often involves different classes of drugs and requires combination therapies.
In any painful syndrome, special attention to the underlying condition is
essential for the overall management and for differentiation from other conditions that may coexist in patients with diabetes (i.e., claudication, Charcots
neuroarthropathy, fasciitis, osteoarthritis, radiculopathy, Mortons neuroma,
tarsal tunnel syndrome). A careful history of the nature of pain, its exact
location, and detailed examination of the lower limbs is mandatory to
ascertain alternate causes of pain. Pain can be caused by dysfunction of
different types of nerve fibers (A- vs. C fiber) that are modulated by
sympathetic input with spontaneous firing of different neurotransmitters to
the dorsal root ganglia (DRG), spinal cord and cerebral cortex. Figure 2
describes the pathophysiological basis for the generation of neuropathic
pain. Different types of pain respond to different types of therapies (9).
Figure 3 describes the different nerve fibers affected and possible targeted
treatments.
C-Fiber Pain
Small unmyelinated C fiber damage gives rise to burning or lancinating pain
often accompanied by hyperalgesia and dysesthesia. Peripheral sympathetic
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Pain Targets
Descending fibres
TCAs / SSRIs / SNRIs

? 2 antag / Tramadol
Duloxetine
DRG
Pregabalin
5HT
Opioid
2
Dextro methorphan
Substance P
Ca channels
C-fiber
Glutamate
Glutamate
Substantia
gelatinosa
Capsaicin
Clonidine
A fiber
GABA
Na channels
Topiramate
Carbamazepine
TCAs / Insulin
NMDA
AMPA
mGlur
GABAA
GABAB
Interneuron
Topiramate
Gabapentin
Fig. 3. Different mechanisms of pain and possible treatments: C fibers are modulated by
sympathetic input with spontaneous firing of different neurotransmitters to the DRG, spinal
cord and cerebral cortex. Sympathetic blockers (clonidine) and depletion of axonal SP
used by C-fibers as their neurotransmitter (capsaicin) may improve pain. In contrast, A
fibers utilize NA+ channels for their conduction and agents that inhibit Na+ exchange such
as antiepileptic drugs, tricyclic antidepressants and insulin may ameliorate this form of
pain. Anticonvulsants (Carbamazepine, gabapentin, topiramate) potentiate GABA activity,
inhibit Na+ and Ca++ channels and inhibit NMDA and AMPA receptors. Pregabalin binds
to the 2 1 subunit of the Ca++ channel and modifies Ca++ uptake. Dextromethorphan
blocks NMDA receptors in the spinal cord. TCA, SSRIs, and SNRIs inhibit serotonin
and norepinephrine reuptake, enhancing their effect in endogenous pain-inhibitory systems
in the brain. Tramadol is a central opioid analgesic Abbreviations: SP: substance P,
TCA: tricyclic antidepressants, SSRIs: selective serotonin reuptake inhibitors, SNRIs:
serotonin and norepinephrine reuptake inhibitors, NMDA: N-methyl-D-aspartate, AMPA:
-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, GABA: gamma-aminobutyric
acid (9,96).
fibers are C-fibers, too, and spontaneous firing or activation exacerbates the
pain, which can be blocked with systemic administration of the 2 -adrenergic
agonist Clonidine. These nerve fibers are peptidergic carrying substance P
as the neurotransmitter. Depletion of substance P with local application of
capsaicin abolishes transmission of painful stimuli to higher centers (68).
Targeting higher levels of pain transmission also helps with C fiber pain
(69,70).
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A-Delta Fiber Pain

Pain from A-delta fibers is deep-seated, dull, and aching. It responds to
nerve blocks, Tramadol or dextromethorphan, antidepressants and tricyclic
agents. Insulin infusion at a rate of 0.81 units/h without lowering blood
glucose helps in resolution of pain in about 48 h (71). N-methyl-d-aspartate
(NMDA) receptor antagonist like dextromethorphan exert an analgesic effect
in hyperalgesia and allodynia while centrally acting opioids such as Tramadol
achieve symptomatic relief (72).
Antidepressants in Neuropathy
These drugs inhibit reuptake of norepinephrine and/or serotonin. Anticholinergic effects, orthostatic hypotension, and sexual side effects limit their
use. They remain first line agents in many centers, but consideration of
their safety and tolerability is important in avoiding adverse effects, a
common result of treatment of neuropathic pain. Dosages must be titrated
based on positive responses, treatment adherence, and adverse events (73).
Among the norepinephrine reuptake inhibitors, desipramine, amitryptylline,
and imipramine have been shown to be of benefit. Selective serotonin reuptake
inhibitors (SSRIs) that have been used for neuropathic pain are paroxetine,
fluoxetine, sertraline, and citalopram. Fluoxetine appears to provide some pain
relief (74). Duloxetine has recently been approved for neuropathic pain in the
USA. It is a selective, balanced, and potent inhibitor of serotonin (5-HT) and
noradrenalin reuptake (SNRIs) in the brain and spinal cord leading to increase
neuronal activity in efferent inhibitory pathways. Physicians must be alert to
suicidal ideation, exacerbation of autonomic symptoms, as well as aggravation
of depression, and should stop the drug immediately (69).
Anticonvulsants in DN
Anticonvulsants have stood the test of time in treatment of DN. Principal
mechanisms of action include sodium channel blockade, potentiation of
gamma-amino butyric (GABA) activity, calcium channel blockade, antagonism
of glutamate at NMDAreceptors or -amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid (AMPA) receptors (3).
Carbamazepine is useful for patients with shooting or electric, shock-like
pain. In a placebo-controlled trial, gabapentin-treated patients had significantly
lower mean daily pain scores and improvement of all secondary efficacy
parameters (75). Gabapentin has the additional benefit of improving sleep (75),
which is often compromised in patients with chronic pain (73). In the long
term, it is known to produce weight gain, which may complicate diabetes
management, and it has not been successful in all trials (76).
125
Pregabalin produced significant improvements on pain scores within 1 week

of treatment (p < 0.01), which persisted for the 8 weeks (p < 0.01). For the
patient global impression of change (PGIC), there was a 67% improvement
versus 39% in patients given placebo (p = 0.001). Furthermore, 40% of patients
receiving Pregabalin reported a 50% reduction in pain, compared with 14.5%
with placebo (p = 0.001) (70).
In trials with topiramate, a fructose analog, 50% of patients on topiramate
versus 34% on placebo responded to treatment, defined as a >30% reduction in
pain score (p < 0.004). Topiramate also reduced pain intensity versus placebo
(p < 0.003) as well as sleep disruption scores (p < 0.02) (77). This drug
also lowers blood pressure, has a favorable impact on lipids, decreases insulin
resistance, and causes growth of intraepidermal nerve fibers (77,78).
As mentioned previously, pain symptoms in neuropathy significantly impact
QOL. Neuropathic pain therapy is challenging, and selection of pain medication
and dosages must be individualized, with attention to potential side effects and
drug interactions.
Adjunctive Management and Treatment of Complications

While small fiber neuropathy presents as different forms of pain, large
fiber neuropathy is manifested by reduced vibration perception and position
sense, weakness, muscle wasting, and depressed deep tendon reflexes. Diabetic
patients with large fiber neuropathies are uncoordinated and ataxic and are
17 times more likely to fall than their non-neuropathic counterparts (79).
Therefore, it is important to improve strength and balance in patients with large
fiber neuropathy. Patients can benefit from high intensity strength training
by increasing muscle strength, improving coordination and balance, and thus
reducing fall and fracture risks (80). Low impact activities, which emphasize
muscular strength and coordination, and challenge the vestibular system, such
as Pilates, yoga, and Tai Chi, may also be particularly helpful. In addition,
options to prevent and correct foot deformities are available, for example,
orthotics, surgery, and reconstruction.
Basic management of small fiber neuropathies by the patient should be
encouraged. These are foot protection and ulcer prevention by wearing padded
socks; regular foot inspection using a mirror to examine the soles of the
feet daily; selection of proper footwear; scrutiny of shoes for the presence of
foreign objects; avoidance of sun-heated surfaces; hot bathwater or sleeping
with feet in front of fireplaces or heaters. Patient education should reinforce
these strategies and, additionally, discourage soaking feet in water. Education
will also promote foot care by encouraging emollient creams to help skin retain
moisture and prevent cracking and infection.
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Mechanical Measures
Transcutaneous Nerve Stimulation (Electrotherapy),
Magnetic Field Therapy, Infrared Light, and Electrical
Cord Stimulation
Transcutaneous nerve stimulation (electrotherapy) occasionally may be
helpful and certainly represents one of the more benign therapies for painful
neuropathy (81,82). Care should be taken to move the electrodes around to
identify sensitive areas and obtain maximal relief.
Static magnetic field therapy (83) has been reported to be of benefit, but
it was difficult to blind such studies. More recently, Bosi and colleagues
used frequency-modulated electromagnetic neural stimulation (FREMS) in 31
patients with painful DN using an ingenious method of 10 applications of
placebo versus active treatment using a switch on the device. FREMS induces
a significant reduction in daytime and nighttime pain, in addition a significant
increase in tactile threshold detected using SMW and lowering of the VDT
using a biosthesiometer, improved motor nerve conduction velocity. A significant persistent of the effect was observed after 4 months, and there was an
additional benefit in measures of QOL using the SF 36 in terms of general
health, physical, and social functioning (84).This finding suggest that FREMS
may be an active safe method to improve symptoms of neuropathy with the
added possibility of enhancing neurological function.
Similarly the use of infrared light has reportedly had benefit, but this remains
to be proven. Leonard and colleagues examined 27 patients; 9 of whom were
sensitive to a 6.65 g Semmes Weinstein monofilament (SWM) and 18 who were
insensate. Extremities were treated for 2 weeks with sham or active infrared,
and there was reportedly a reduction in the number of 5.07 g SWM insensate
sites in patients with mild neuropathy but not in those with greater sensory
loss and reportedly improved balance, which was not quantified objectively.
Clearly these observations need to be extended for longer periods and more
objective measure applied to evaluating the responsiveness.
A case series of patients with severe painful neuropathy unresponsive to
conventional therapy suggested efficacy of using an implanted spinal cord
stimulator (85). However, this cannot be generally recommended except in
very resistant cases as it is invasive, expensive, and unproven in controlled
studies.
The presence of certain kinds of subclinical noise has been shown to enhance
sensitivity in various situations, and sensory neurons exposed to low-level noise
have enhanced neurotransmission. Khaodhiar and colleagues (86) examined the
acute effects of vibration of the sole of the foot below the individuals threshold
for 3060 s in 20 subjects with mild neuropathy and determined the impact
127
on vibration detection and Semmes Weinstein monofilament thresholds. They

found that VDT threshold improved, and the ability to detect MF application
to the sole of the foot but not the big toe was enhanced. This ability to amplify
signals from the neuropathic foot may have relevance to protecting feet from
injury and possibly even enhancing postural stability. These studies need to be
expanded to longer term to determine the durability of their effects and that
hopefully there will be no tachyphyllaxis.
Surgery for the Treatment of Neuropathy

Controversy exists as to the role tarsal tunnel release has in the management
of the diabetic patient with a painful foot syndrome. The major problem is
the application of tarsal tunnel release to DPN and not specifically for those
patients with tarsal tunnel entrapment syndrome (TTS). Because of the intrinsic
swelling of peripheral nerves in the diabetic (endoneurial edema secondary to
increased sorbitol levels within the peripheral nerve), an increased incidence
of compression neuropathy has been well documented. The double crush
syndrome as described by Upton and McComas (87) may be applied to the
diabetic patient. This hypothesis states that when multiple sub-clinical nerve
compressions exist in series; they may be additive and give rise to symptoms
even though each compression, by itself, would not. The first crush would
be the peripheral neuropathy of diabetes and the second crush compression
of the tibial nerve at the tarsal tunnel. TTS (88) is a painful lower limb
entrapment. Passing through the tarsal tunnel, the tibial nerve innervates only
muscles of the sole and clinical signs are mostly sensory. Foot pain may be
severe, burning, worse on standing and walking; Tinel sign on underside of
medial malleolus, with atrophy of the sole muscles is typical. Weakness is
rare, because most of the small foot muscles (flexor hallucis longus) are not
damaged in TTS. Pain on the inside of the foot must be distinguished from
other causes of pain for example: a Mortons neuroma, plantar fasciitis, heel
spurs, arthritis or bone spurs, early Charcots neuroarthropathy. An MRI of the
foot can be very helpful to identify neuromas and shows edema of bones in
the midfoot with Charcots, which presents as a hot foot with increased blood
flow (89). It may also be a manifestation of systemic disease (90). Once these
are excluded, NCV can be informative in the case of a normal plantar response
from one leg and abnormal one from the symptomatic one in unilateral TTS.
TTS is not difficult to diagnose clinically when DSPN is not severe and NCV
is moderately abnormal. Mild symmetric peroneal and tibial NCV abnormality
with intact ankle jerks and sensation of the dorsal aspect of the foot with the
abovementioned clinical signs are the most important diagnostic features of
TTS. When the neuropathy is severe, then diagnosis may be impossible. A
positive Tinel sign, tapping just below the medial malleolus maybe helpful but
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Vinik
unfortunately may also simply reflect nerve damage in peripheral neuropathy,

a negative sign suggesting that nerve damage predicts a poor outcome of
surgery.
If patients are carefully selected, release of the tibial nerve through the tarsal
tunnel in the diabetic may improve plantar sensibility and help prevent plantar
ulceration and ultimate lower extremity amputation. Several recent studies lend
credence to this notion, although study design flaws need to be rectified before
universal acceptance of this principle is achieved. Caffee et al. (91) presented
data on 36 patients collected over a 9-year period from 19891997 reviewed
retrospectively. The mean follow up was 32 months, and these were patients
who had severe disease with foot ulcers in 11 patients and painful paresthesias
in 28 cases. Fifty-eight decompressions were done in 36 patients followed for
784 months. In these studies, the Semmes Weinstein monofilaments were
used to monitor responses. Twenty-four of twenty-eight had complete relief
of pain some on the operating table still under anesthetic and 13 of 24 had
improved subjective sensation. He concluded that there is some room for
optimism but had no objective data of recovery, the only record of change
being that reported on by the patients. The failure in 50% of cases is attributed
to the advanced status of their disease and that objective testing of sensation is
an oxymoron despite the reports by Wiemann and Patel (92) and Dellon (93)
of improved two point discrimination after surgical decompression.
In the Wiemann and Patel (92) report on 33 limbs in 26 patients, 32 had
a positive Tinel sign yet 19 of 26 responded and 7 with positive Tinel signs
did not. Thus, as Dellon (93) showed there may be an 80% response in Tinel
positive people but failure in 20% would be in agreement with the Wiemann
and Patel (92) study, suggesting that the sign is not a good predictor of response.
Unfortunately, in the Wiemann and Patel (92) study, neither foot pressures nor
ED showed any changes in the operated patients and only symptoms of pain
improved. The objective measures of two point discrimination fell equivalently
from15.1 4 to 11.1 3.5 in responders and from 13.7 3 to 11.1 2.5 in
non-responders pointing out the lack of validity of this as a test of response
to decompression. Thus, these studies have not clearly established the role of
decompression in entrapment syndromes, left us floundering with regard to the
value of a positive Tinel sign over the ankle and created some consternation
amongst those people who are concerned that this is being advocated as a
procedure for common or garden DN in the absence of entrapment even when
there is no evidence of recoverable nerve function. Indeed, as Carneiro (94)
pointed out, there is a need to grade the severity of the entrapments using
measures of sensory deficits with validated tests, the presence of a Tinel sign,
the time taken for Phalens test to become positive and the presence of motor
features and atrophy to identify the best candidates for surgery. We would go
129
further than that and add that a conduction block must be present at the site,
that there should not be such severe DN to preclude distinction of this from
entrapment, and that controlled sham operations have to be compared with
unentrapment for relief of symptoms if this is the only measurement.
CONCLUSIONS
Somatic and autonomic neuropathies (DPN) are amongst the most common
long-term complications of diabetes and its precursors, IGT, and the metabolic
syndrome. DPN is associated with considerable morbidity and mortality and
significant impact on QOL. It is highly prevalent in diabetic populations although
often not recognized by physicians. A thorough history and detailed physical
examination is essential for the diagnosis. A number of simple tests that can
be done in the clinic are useful for detection of DPN and prediction of complications, such as foot ulcers and gangrene. Standardized and validated quantitative measures of disease progression are now available and allow better interpretation of responses to different treatments and study results. Management
of the disease is complex and the key to success depends, in part, on discovering the underlying pathological processes in each particular clinical presentation. Studies on new agents that target the pathophysiological mechanisms
have lead to a better understanding of the pathogenesis of DPN as well as the
pain mechanisms for the different types of pain syndromes. Two drugs have
recently been approved in the USA for the treatment of neuropathic pain of
diabetes. Two decades ago, physicians could only diagnose DPN and commiserate with the patient. This has changed in the last few years with increasing
available therapies as the knowledge of the condition continues to grow.
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Pract Endocrinol Metab.
Endpoints in Clinical Research Studies
Aaron I. Vinik,
MD, PHD, FCP, FACP
CONTENTS
Introduction
Symptoms of Neuropathy as an Endpoint
in Clinical Studies
Quality of Life in Diabetic Neuropathy
Neurovascular Function
Identication of Candidates for
Participation in Research Studies
Conclusions
References
Summary
Clinical trials of agents for the treatment of diabetic neuropathy have
been confronted with a lack of agreement on appropriate endpoints and
have generated controversy on why ample demonstration of efficacy of
an agent in animal studies has not been readily translated into success in
human clinical trials. There has been a failure to recognize that the relief of
symptoms does not equate to change in the underlying biological disorder
and great disagreement on indices, which can reliably measure changes in
nerve function which translate into changes in the quality of life, activities of
daily living, and health of the individual. Here, one will focus on the various
measures that have been used for the evaluation of symptoms and those that
quantify nerve function and compare and contrast the reasons for failure
of different measures neurological deficits, prevention of degeneration of
specific small fiber, large fiber and autonomic nerve deficits and those that
have potential for reversal of these deficits.
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Key Words: Intensive care unit; intensive insulin therapy; hyperglycemia; hypoglycemia
INTRODUCTION
Among the challenges for studies of diabetic neuropathy is the selection of
the measures that can be used to determine the efficacy of the agents. Common
endpoints include (i) questionnaires that allow for quantification of any changes
in the signs or symptoms of diabetic neuropathy, or the quality of life (QOL) of
the patient, (ii) Objective evaluation of the physical impact of neuropathy, (iii)
quantitative tests of sensory, motor, and autonomic modalities that allow more
precise measures of nerve function, (iv) electrophysiologic evaluation of nerve
conduction, (v) skin biopsy that allows direct observation of the morphology of
sensory nerve fibers, and (vi) combinations of these tests that add to the power
of being able to detect the impact of any prospective agent for the treatment
of neuropathy.
SYMPTOMS OF NEUROPATHY AS AN ENDPOINT

IN CLINICAL STUDIES
Systematic questioning regarding family history of nondiabetic neuropathies
should be addressed first. If any other causes for peripheral neuropathy are
discovered in the family history then other therapeutic approaches should
be used. The diagnosis of diabetic neuropathy requires a careful history for
which many questionnaires have been developed (15). Symptoms are scored
according to the Neurologic Symptom Score (NSS). This inventory, modified
over time in the Norfolk clinical research center from the original by Dyck (2),
captures symptoms of muscle weakness, sensory disturbances, and autonomic
function as simply present or absent according to the patients prompted report.
On the basis of patient responses, neuropathy symptoms are scored as follows:
0 = no symptoms; 1 = symptoms present. The NSS is a 38-item inventory
of symptoms scored as yes or no and modified by severity with three
levels. These individual points are summed for a final symptom score. We
have provided the modified inventory in the appendix.
An ad hoc panel on endpoints for diabetic neuropathy trials suggested
that symptoms could be a satisfactory endpoint for epidemiologic studies
and controlled trials in diabetic peripheral neuropathy (DPN) (6). Sensory
symptoms of neuropathy can be classified into negative (i.e., with a decrease
or absent sensory fibers, receptors or central mechanism) or positive (from
hyperfunction of the systems). Negative symptoms relate to the patients
reports of decreased ability to feel tactile stimuli, mechanical displacement
or movement of hair, skin or other anatomical parts and decreased cognitive
function (e.g., recognition of temperature changes or differences in cooling
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and warming and cold and heat pain or other noxious stimuli). Sensory loss
includes imbalance ataxia inability to perform skilled movements. Notably,
these are reported quite differently in different ethnic groups and in different
countries. For example, in Japan patients will report on unusual sensations
in their legs, and in the USA, patients talk of inability to discern different
textures, for example, when crossing the floor from a tiled surface to a carpet
in going from the bathroom to the bedroom. Loss of position awareness is
often very distressing and has a marked impact on QOL and activities of daily
living (ADLs), compromising the ability to play sports. In contrast, positive
symptoms are sensory experiences that arise spontaneously. Patients describe
small fiber symptoms as superficial, prickling, tingling, and burning sensations,
such as a fire or bee stinging. This may be accompanied by misinterpretation for
nonpainful stimuli as painful, referred to as allodynia, and clinically, this may
correspond with hyperesthesia or hyperalgesia. On the contrary, patients with
predominantly large fiber disease will report such feelings as: a dog gnawing at
the bones of the feet; a toothache in the foot; the feet feel like they are encased
in concrete; they feel like cardboard or cotton bunched up in the shoe; they
always have a sock on or feel squeezed; and constriction with aching, boring,
or throbbing deep-seated pain. A third of pain symptoms are a spontaneous
burst of pain such as lightning, which comes and goes and may last but a few
minutes. These are regarded as neuropathic pain, and may have an electrical
lancinating quality, are short lived, and tend to occur in clusters and in the
same anatomical region. Restless leg pain usually is a deep, aching pain, and
occurs with inactivity and often responds to mobilization. Pain is often cyclical
and usually worse at night. One surprising observation is that when the patient
talks of numbness it may not mean a deficit in pain perception, but rather that
the patient feels that the limb has gone to sleep or as if they have been given
an anesthetic. It is a positive symptom. Perhaps the most distressing symptom
relates to the apparent or real perception of weakness. Pain produces anxiety,
and weakness causes depression! In diabetes, the small fiber, large fiber, motor
and sensory symptoms tend to occur together simultaneously, although there
are many instances in which they may be distinct. The hot foot syndrome is one
in which pure small fiber symptoms are present with normal strength, reflexes
and electrophysiology, and there may be no objective features to confirm
neuropathic origin. The advent of skin biopsies has established loss of intraepidermal nerve fibers (IENF) as being the root cause (see below), and these small
fiber functions are not measured by electrophysiological tests. For this reason,
tools that quantify these symptoms have become critical as endpoints in studies
of DPN. Several tools have now been developed which are reproducible,
standardized, and valid measurements that address the positive and negative
symptoms and provide measurements of the constancy, severity, distributions,
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and frequency of the symptoms. In the Total Symptom Score, the severity
(mild, moderate, or severe) and frequency (infrequent, frequent, and constant)
are scored (4). The nerve symptom change (NSC), the positive and negative
symptoms are characterized as absent, mild, moderate and severe by anatomical
location are quantitated by number, severity and change by comparison with a
previous examination (7). For pain, discussed elsewhere in this book, different
pain questionnaires or visual analog scales are used, and the questions address
the most severe pain in the last 24 h as a single days recall or a weeks recall
(8,9). The newest tool that had been used successfully in clinical trial is the
Neuropathy Total symptom Score-6 (NTSS-6) (10,11). The NTSS-6 questionnaire was developed conceptually to evaluate the frequency and intensity
of individual neuropathy sensory symptoms identified frequently in patients
with DPN (numbness and/or insensitivity, prickling and/or tingling sensation,
aching pain, burning pain, lancinating pain, and allodynia and/or hyperalgesia).
The NTSS-6 was administered eight times over a 1-year period to 205 DPN
patients. The NTSS-6 reliability (determined by internal consistency and test
retest reproducibility), construct (convergent) validity, clinical responsiveness,
clinical relevance (interpretability) and minimally clinically important differences (MCID) were determined. Internal consistency was demonstrated at
all eight visits (Cronbachs p > 0.7). Testretest reproducibility (intraclass
correlation coefficient >0.9) was observed during the baseline period and at
endpoint. Construct validity was demonstrated by a statistically significant
correlation between the NTSS-6 score and the Neuropathy Symptoms and
Change (NSC) score (p < 0.01). Clinical responsiveness was demonstrated by
significant correlations between change in the NTSS-6 and (i) change in the
NSC score ( p < 0.01); (ii) change in the Neuropathy Impairment Score of the
Lower Limbs; and (iii) composite nerve function scores ( p < 0.007). Clinical
relevance was demonstrated by a statistically significant association between
the change in the NTSS-6 score and the Clinical Global Impression (r = 0.402,
p < 0.01). The within- and between-groups MCID for the total NTSS-6 scores
were 1.26 and 0.97, respectively. The authors conclude that the NTSS-6 is
a valid and reliable instrument for assessing clinically meaningful changes in
neuropathic sensory symptoms in DPN patients.
Distinction of neuropathic pain from various other causes is important in
study design. Failure to do so was the cause of failure of three studies of
topiramate in DPN, whereas the successful trial (12) specified the origin of the
pain, so that it was not confused with entrapment, fasciitis, or gout arthritis
to name a few. Four criteria help to define this: (i) Several symptoms occur
together, for example, numbness and pain with weakness; (ii) They occur in
the known distribution of DPN; (iii) They conform to the anatomy of the
peripheral nervous system; and (iv) They conform to the areas found on clinical
139
examination to have nerve damage, although this may be very misleading.

Whatever the case, a physical examination remains mandatory to define the
nature of the underlying pathology.
For therapeutic trials, the distinction between symptomatic therapy and
therapy addressing the basic biology of the disease must be made. For example,
a simple analgesic does not alter nerve function. It must also be shown that
the agent used does not relieve the symptoms by damaging the nerves. For
this reason, the agency insists that electrophysiological studies are done and
the days of the 28-day pain trial are over and 36 months trial are now
required. To demonstrate that the agent does not hurt the nervous system
requires demonstration of no deleterious effects on nerve physiology, and to
show that there is indeed a biologic effect, the changes must outlast the period
of treatment or go beyond the pharmacological action of the drug. With this in
mind, the studies need to be powered adequately on these endpoints, and the
design power and execution of the study must be adequate. Thus, the following
requirements should be met:
1. The symptom must improve to a significant degree.
2. The improvement must not be due to worsening of neuropathy.
3. The change, if possible, should correlate with evidence of improved nerve
function (electrophysiology, IENF, Quantitative sensory testing [QST] and
QAFT).
4. The change should be biologically relevant (e.g., if the scale is three intervals,
mild, moderate or severe, or infrequent, frequent or constant, then a 1.667
on one of the three scales would be biologically relevant. If more than one
descriptor is used for the symptom, then this can be reduced to 0.834 points.),
based on the view that this is what patients interpret as clinically meaningful (6).
5. The drug being evaluated should have a low number needed to treat (NNT) to
achieve response in a single patient, i.e., a high responder rate and a very low
number needed to harm (NNH) (13).
6. The effects are greater than those of placebo. Assuming placebo effects can
yield a 30% improvement in 30% of patients, a 50% improvement in 50% of
patients seems ideal.
7. Adequate masking should have been achieved. For example, NGF caused local
site pain when administered, which is difficult to conceal and clouds judgment.
Certain ARI pills had a bitter taste not matched by placebo.
Neurological Examination
The neurological examination is carried out in a standardized manner by a
trained neurologist or diabetologist who has undergone specialized instruction
on the degree of precision required to obtain reproducible results and to use
judgment for the size and strength of the individual. Results are scored on
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a 5-point Likert scale using the Neurologic Impairment Score (NIS) tool, a
37-item inventory that measures motor and sensory function bilaterally on a 04
or 02 scale as judged by the clinician in the neurological exam. The motor
neurological examination measures cranial nerve weakness, pupillary reflexes,
muscle weakness, muscle wasting, and reflexes. The sensory neurological evaluation measures sensation in the right and left index and little fingers and great
and little toes to touch, prickling pain, vibration, joint position, and pressure
(using 1- and 10-g monofilaments). The NIS tool for lower limbs (NIS-LL)
reflects only abnormalities in the lower limbs. The total neuropathy score (TNS)
reflects a summation of the symptoms, sensory, and motor scores. A score
of =1 is no neuropathy, 29 mild, 1019 moderate, and >20 severe neuropathy.
All the signs and symptoms of neuropathy can be scored and recorded
allowing changes in response to treatment to be monitored longitudinally.
In addition, there have been similar forms developed for quantitation of the
disabilities related to nerve dysfunction and even forms for quantitation of
the impact on the patients QOL. Unfortunately, such questionnaires are quite
subjective and may not be sensitive enough to discern small changes in nerve
fiber functions in a small test group over a short period of time. Unless a study
includes a large number of subjects and a sufficient period of time, significant
changes may not be detectable, particularly in the short time periods that most
efficacy trials are designed for.
Quantitative Sensory Tests

QST is performed to assess somatosensory function using established,
validated methods and algorithms for measuring both large and small fiber
somatosensory function. These include vibration thresholds, light touch
(Semmes-Weinstein monofilaments), cold and warm thermal sensation, and
cold- and heat-induced pain thresholds at the dominant great toe (14).
Generally, for each of these non-noxious sensations, we use the method of
limits, six ascending trials with an inter-stimulus interval randomly varying
from 4 to 20 s using the Medoc TSA 2001/VSA 3000 (Medoc Advanced
Medical, Minneapolis, MN, USA) or the Case IV device (15), although there
are others in use. The thresholds are calculated as the mean stimulus intensity
level over all six responses.
QUALITY OF LIFE IN DIABETIC NEUROPATHY

In previous studies, patients perceptions of the effects of DPN have been
assessed using generic instruments (1618) or a symptom checklist (19). These
instruments do not capture the entire spectrum of unique aspects of DPN,
particularly those related to specific somatic and autonomic nerve fibers. We
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previously reported data on health-related QOL and ADL in relation to specific

nerve fiber function (20). Subsequently, the NeuroQol (21), which measures
patients perceptions of the impact of neuropathy and foot ulcers, has been
published. While focusing on peripheral neuropathy outcomes, specifically
foot ulcers, it does not cover the full scope of neuropathy related to large
fiber, small fiber, and autonomic neuropathy function. In contrast, we have
developed a comprehensive questionnaire that captures the entire spectrum
of DPN, including the concentration of symptoms in the extremities, subtle
loss of function such as fine motor impairments and slight sensory changes,
unique problems with proprioception and balance, and autonomic symptoms
that are not captured in existing instruments. This instrument has the ability
to discriminate the presence of neuropathy as well as the different levels of
neuropathy and the specific nerve fibers involved (20). It can be used to
monitor disease progression as well as evaluate treatment modalities (22,23).
Since its development and preliminary validation, the tool has been used in
clinical trials providing further validation opportunities as well as psychometric
evaluation (22).
A caveat is our findings that the Norfolk QOL-DN identifies symptoms in
patients with diabetes who do not have established neuropathy. The symptom
complex of diabetes in patients with diabetes without neuropathy characterized
by highly variable blood sugar levels together with the effects of other factors
of the metabolic syndrome such as high blood pressure, insulin resistance,
and dyslipidemia appears to manifest health-related problems not entirely
dissimilar to their neuropathic counterparts. Further research is necessary to
fully understand these contributions to patients perception of QOL. As such,
future modifications to these items in the Norfolk QOL-DN may be necessary.
We believe that QOL is an important tool for measuring patients perception
of the impact of diabetes and neuropathy on their physical and psychosocial
functioning and may act as a guide in decision-making toward altering apparent
health and functional status.
Quantitative Electrophysiology
Nerve conduction studies (NCS) are the most reproducible, reliable, and
objective measure of peripheral neuropathy available currently to document
peripheral neuropathy. NCS in DPN has demonstrated small changes in nerve
function (conduction velocity) with treatment in well-controlled studies (24,
25). The translation of small changes in NCS into clinical relevance has raised
doubts (26). The natural progression of DPN is a decline of peroneal motor
conduction velocity of only 0.20.4 m/s per year (27). A clinically meaningful
improvement of 1.5 m/s therefore generally requires about 3 years. Most
recently, this has been achieved in the study of an ARI in which the participants
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were carefully selected to have positive sural sensory nerve action potentials
(SNAPs) (28). There is a strong correlation between myelinated fiber density
and SNAP and a loss of 1 v in SNAP correlates with a loss of about 150 nerve
fibers/mm2 . There is about a 5% loss per year in SNAP, supporting the notion
that selection of patients for entry into studies who have mild neuropathy or
those of relatively short duration with the greatest likelihood of responding.
Alternatively, a 50% prevention of the expected deterioration in a given time
interval has been considered evidence of positive efficacy (27).
F waves detect any abnormality in the antidromic conduction of the
compound neural wave generated by electrical stimulation distally reaching the
spinal cord, activating a subpopulation of spinal cord motor neurons, followed
by the orthodromic conduction of the newly established wave and postsynaptic
activation of muscle fibers in the appropriate distribution. The long loop of
this measure increases the likelihood of identifying an abnormality at any of
several sites, and it has been shown to be the most reproducible measure in
NCS of diabetic neuropathy (29). NCS of course does not measure small fibers
and for this reason alone cannot be the sole endpoint in clinical studies.
A key role for electrophysiological assessment is to rule out other causes
of neuropathy or to identify neuropathies superimposed on DPN. Unilateral
conditions, such as entrapments, are far more common in the patients with
diabetes (30). The principal factors that influence the speed of NCV are (i) the
integrity and degree of myelination of the largest diameter fibers, (ii) the
mean cross-sectional diameter of the responding axons, (iii) the representative
internodal distance in the segment under study, and (iv) the micro-environment
at the nodes, including the distribution of ion channels. Thus, small unmyelinated fibers and the changes cannot be evaluated using NCS and must rely on
measures such as skin biopsies and QST! Furthermore, demyelinating conditions affect conduction velocities, whereas diabetes primarily reduces amplitudes, thus the finding of a profound reduction in conduction velocity strongly
supports the occurrence in a diabetic patient of an alternative condition. Indeed,
the odds of occurrence of CIDP were 11 times higher among diabetic than
nondiabetic patients (31). With the recognition of the limitations of NCS
for the evaluation of neuropathy in diabetes, it remains a robust measure in
clinical trials and serves to exclude entrapments, demyelinating conditions, and
responsiveness to interventions can be based on the identification of potential
responders with mild neuropathy based on the presence of sural nerve responses.
Quantitative Sensory Tests

Because diabetic neuropathy virtually always exhibits compromise of
sensory nerve function and often includes autonomic dysfunction, quantitative
143
sensory and autonomic measures are an attractive alternative to the questionnaire scoring approach. Over the past 1520 years, there has been progressive
development of protocols and devices for quantitatively measuring thermal
sensation, vibration, and pressure detection. In 2002, an international group
of experts in diabetic neuropathy held a consensus meeting to develop guidelines for the management of DPN by the practicing clinician using quantitative
function tests (32). Combined, these tests cover a range of sensory modalities, including vibratory, proprioceptive, tactile, pain, thermal, and autonomic
function. These measurements are geared for evaluation of sensory functions at
specific points on the body with relative accuracy and precision. The strengths
of QST are well documented (33), but the investigator must also be aware
of the limitations of QST. No matter what the instrument or procedure used,
QST can be considered only a semi-objective measure, because the results
are affected by the subjects attention, motivation, and cooperation, as well as
by anthropometric variables such as age, gender, body mass, and history of
smoking and alcohol consumption. Expectancy and subject bias are additional
factors that can exert a powerful influence on QST findings. In addition, QST
is sensitive to changes in structure or function along the entire neuro-axis from
nerve to cortex; it is not a specific measure of peripheral nerve function (33).
The American Academy of Neurology reported that QST could be used as an
ancillary measure for clinical and research purposes (34) but were not sufficiently robust for routine clinical use. Nevertheless, quantitative sensory and
autonomic testing, under the right conditions, provides a means for evaluation
of the efficacy of treatments for diabetic neuropathy. QST is a psychophysical
measure of polyneuropathy but is much more variable and unpredictable than
NCS in the diabetic neuropathy population.
The most reliable QST is quantitative vibration perception threshold by
various techniques (35). QST of vibration (vibration detection threshold
[VDT]) is particularly useful as a sensitive and specific measure of large
fiber function because it can be done quickly, is noninvasive, simple, painless,
and reproducible (14). VDT reflects the activation of mechanoreceptors and
conduction in large fiber nerves that are important for proprioception, position,
ataxia, balance, and gait as well as muscle strength. VDT correlated with
the neuropathy disability score (36), lack of reflex in the lower extremities,
and symptoms of DPN (37,38) and nerve conduction changes (39). A strong
correlation was noted between VDT and a number of microvessel abnormalities (40). Loss of vibration perception predisposes individuals with diabetes
to instability, falling, and decreased QOL (41,42). Prospective studies have
established impaired vibration sensation as a positive predictor of long-term
complications such as ulcers and amputations (4345).
The improvement found in VDT in the recently reported ruboxystaurin
study (11) is unique in that it demonstrates that directly the drug impacts the
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Vinik
pathophysiology of the peripheral nerve rather than acting centrally to reduce

pain through analgesic pathways. Thus, there are many reasons to believe
that QST particularly of VDT can be used in the evaluation of responses to
intervention in clinical trials.
However, patients followed in research trials frequently have more abnormality of small fiber function, (46), and the variability of small fiber QST
testing is even greater than that of large fiber QST testing in the clinic setting
and has not proven useful save for possibly the cooling detection threshold in
the NGF study (47).
Quantitative Autonomic Function Tests

Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes (48). Major clinical manifestations of DAN include
resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, gastroparesis, erectile dysfunction, sudomotor dysfunction, impaired
neurovascular function, brittle diabetes, and hypoglycemic autonomic failure.
DAN may affect many organ systems throughout the body (e.g., gastrointestinal, genitourinary, and cardiovascular). Gastrointestinal disturbances
(e.g., esophageal enteropathy, gastroparesis, constipation, diarrhea, and fecal
incontinence) are common, and any section of the gastrointestinal tract may
be affected. Gastroparesis should be suspected in individuals with erratic
glucose control. Upper gastrointestinal symptoms should lead to consideration
of all possible causes including autonomic dysfunction. Although a radiographic gastric emptying study can definitively establish the diagnosis of
gastroparesis, a reasonable approach is to exclude autonomic dysfunction and
other known causes of these upper GI symptoms. Constipation is the most
common lower gastrointestinal symptom but can alternate with episodes of
diarrhea. Diagnostic approaches should rule out autonomic dysfunction and
the well-known causes such as neoplasia. Occasionally, anorectal manometry
and other specialized tests typically performed by the gastroenterologist may
be helpful.
DAN is also associated with genitourinary tract disturbances including
bladder and/or sexual dysfunction. Evaluation of bladder dysfunction should
be performed for individuals with diabetes who have recurrent urinary tract
infections, pyelonephritis, incontinence, or a palpable bladder. Specialized
assessment of bladder dysfunction typically is performed by an urologist.
In men, DAN may cause loss of penile erection and/or retrograde ejaculation. A complete work-up for impotence in men should include history
(medical and sexual), psychological evaluation, hormone levels, measurement
of nocturnal penile tumescence, tests to assess penile, pelvic, and spinal
nerve function, cardiovascular autonomic function tests, and measurement of
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penile and brachial blood pressure. Neurovascular dysfunction resulting from

DAN contributes to a wide spectrum of clinical disorders, including erectile
dysfunction, loss of skin integrity, and abnormal vascular reflexes. Disruption
of microvascular skin flow and sudomotor function may occur as among
the earliest results of DAN and lead to dry skin, loss of sweating and the
development of fissures and cracks that allow microorganisms to enter. These
changes ultimately contribute to the development of ulcers, gangrene, and
limb loss. Various aspects of neurovascular function can be evaluated with
specialized tests, but generally these have not been well standardized and have
limited clinical utility.
Cardiovascular autonomic neuropathy (CAN) is the most studied and clinically important form of DAN. Meta-analyses of published data demonstrate
that reduced cardiovascular autonomic function as measured by heart rate
variability (HRV) is strongly (i.e., relative risk is doubled) associated with
increased risk of silent myocardial ischemia and mortality. The determination
of the presence of CAN is usually based on a battery of autonomic function tests
rather than just on one test. Proceedings from a consensus conference in 1992
and re-affirmed in ref. 13 recommended that three tests (R-R variation, Valsalva
maneuver, and postural blood pressure testing) be used for longitudinal testing
of the cardiovascular autonomic system. Other forms of autonomic neuropathy
can be evaluated with specialized tests, but these are less standardized and
less available than commonly used tests of cardiovascular autonomic function,
which quantify loss of HRV. Interpretability of serial HRV testing requires
accurate, precise, and reproducible procedures that employ established physiologic maneuvers. The battery of three recommended tests for assessing CAN
is readily performed in the average clinic, hospital, or diagnostic center with
the use of available technology. Measurement of HRV at time of diagnosis of
type 2 diabetes and within 5 years after diagnosis of type 1 diabetes (unless an
individual has symptoms suggestive of autonomic dysfunction earlier) serves
to establish a baseline, with which 1-year interval tests can be compared.
Regular HRV testing provides early detection and thereby promotes timely
diagnostic and therapeutic interventions. HRV testing may also facilitate differential diagnosis and the attribution of symptoms (e.g., erectile dysfunction,
dyspepsia, and dizziness) to autonomic dysfunction. Finally, knowledge
of early autonomic dysfunction can encourage patient and physician to
improve metabolic control and to use therapies such as angiotensin-converting
enzyme inhibitors and beta-blockers proven to be effective for patients
with CAN.
Low and colleagues examined 231 patients with diabetes (type 1, n = 83;
type 2, n = 148) and 245 healthy subjects using a self-report instrument
(Autonomic Symptom Profile [49]) and evaluated the severity and distribution
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of autonomic deficits (cardiovagal, sudomotor, and adrenergic) with the

objective laboratory-based composite autonomic severity score (CASS). CASS
is a screening carried out in the Mayo Autonomic Laboratory that evaluates
the severity and distribution of post-ganglionic autonomic nerve fiber function.
Using the CASS, Philip Low (50) made the statement that autonomic
symptoms and deficits are common in diabetes; yet, mild in severity, the
correlation between symptoms and deficits is overall weak, emphasizing
the need to separately identify autonomic symptoms. In our factor analysis,
three autonomic features were identified as constituting the autonomic factor.
These features included orthostasis, diarrhea, sudomotor, adrenergic, and
cardiovagal functions. Sympathetic postganglionic cholinergic function is
assessed using the quantitative sudomotor axon-reflex test at the forearm
and three lower extremity sites. Sympathetic adrenergic function is carried
out by the measurement of the beat-to-beat blood pressure and heart rate
responses to head up tilt and the Valsalva maneuver. Cardiovagal function
is evaluated by heart rate response to deep breathing and the Valsalva
maneuver. Results are compared to a normative database of 557 normal
subjects. On the basis of the results of the screen, a 10-point composite
score can be derived (CASS) that corrects for the compounding effects of
age and sex. The 10-point scale is divided into three subscales: adrenergic
(range 04), sudomotor (range 03), and cardiovagal (range 03). The ASP
includes orthostasis, secretomotor, urinary, diarrhea, constipation, sleep, pupillomotor, male sexual function, vasomotor, upper gastrointestinal, and syncope
as symptoms. Although symptoms were frequent and there appeared to be a
difference in patients with type 1 and type 2 diabetes, Spearman rank correlations showed no relationships between the CASS and the ASP in patients with
type 2 diabetes. The authors concluded that autonomic symptoms and deficits
are common in diabetes, but mild in severity, and the correlation between
symptom scores and overall deficits is weak in mild diabetic neuropathy,
emphasizing the need to separately evaluate autonomic symptoms.
Vinik et al. have reported on the use of their NSS, which contains 11
questions pertinent to the same areas of dysfunction that the ASP covers
(51). In 350 patients with mild (Dyck Stage 1) neuropathy, symptoms were
present, but there were significant floor effects, so that the autonomic domain
of the Norfolk QOL-DN tool did not identify this as a major factor. However,
in a German population with advance neuropathy and a history of present
of foot ulcers or an amputation, autonomic symptoms were clearly present
and related to autonomic function. These were orthostasis, constipation, and
vomiting. In the mild population, these are not features. However, they appear
in patients with more advanced neuropathy. Clearly, further studies are needed
to determine what the optimum tool is for the evaluation of responses of
autonomic symptoms and objective measures to intervention will be.
147
NEUROVASCULAR FUNCTION
There is now widespread recognition that type 2 diabetes is one
manifestation of a constellation comprising insulin resistance, dyslipidemia,
obesity, hypertension, and hypercoagulability referred to as the dysmetabolic
syndrome (5254). Recently, yet another component has been added: altered
blood flow in various organs including skin, muscle, gut, pancreas, corpora
cavernosa, and so on. There is even the suggestion that disturbed blood flow
may be a major contributor to apparent resistance to the action of insulin
(5258). Recently, there has been more direct evidence that disturbed blood
flow in skin precedes the development of diabetes and is part of an inflammatory syndrome, but the precise mechanisms of disturbance in blood flow
has escaped resolution (59).
We have previously demonstrated several neurovascular abnormalities that
occur in diabetes (60,61). There is both impaired peripheral vasoconstriction
and vasodilatation in cutaneous vessels that strongly resembles an enhancement
of normal aging effects seen in peripheral vasculature (60). There is a correlation between the reduction in blood flow and reduced C-fiber function in the
toes. The abnormalities in blood flow in the fingers was found in the absence
of disordered sensory perception, suggesting that it may be a more sensitive
measure of neurovascular function and does not reflect permanent structural
damage to neurons. We devised a simple stimulus for vessel distension that
relies on the effects of local heating and purely on the hydrostatic gradient
imposed by elevation and lowering of the upper limb, that is, reflecting the degree
of microvascular distensibility (61,62). In hairy skin (the hand dorsum), there
is an active vasodilative mechanism that is dependent on C-fiber nociceptors
that accounts for 75% of vascular dilative capacity when heated. There were,
in addition, significant inverse correlations between systolic blood pressure
and hyperemic response to ischemia (r = 0.76, p < 0.01) and the heated arm
lowering (r = 0.52, p < 0.05). There were also significant correlations between
blood flow at 35C and the LDL cholesterol (r = 0.62, p < 0.001), C-peptide
(r = 0.65, p < 0.05), and triglycerides (r = 0.47, p < 0.05). Thus, there
is a disorder of the whole neurovascular unit in type 2 diabetes that co-segregates
with elements of the metabolic syndrome particularly insulin resistance.
We have shown that the neurovascular response can be used as an endpoint
in studies of topiramate (63,64), and the tests are now being used in studies of
other agents that are prospective candidates for the treatment and prevention
of neuropathy.
Skin Biopsy for the Evaluation of Nerve Fiber Morphology

Another potential endpoint for diabetic neuropathy treatment studies is skin
biopsy for the evaluation of peripheral nerve fibers in the affected areas.
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In common practice, a small punch biopsy is collected from affected sites

and subsequent immunochemical staining with antibody to PGP 9.5; a panneuronal marker reveals the epidermal nerve fibers. Good results have been
obtained with both light microscopy and confocal microscopy for evaluation
of the density, length, and integrity of IENF. These techniques have been
used to describe a loss of nerve fiber density and fiber length in diabetic
neuropathy (6567). Our own data shows that there is a decrease in IENF
length in patients with metabolic syndrome, considered a pre-diabetic state
(68). However, evaluation may be complicated by an apparent increase in fiber
density in the years immediately surrounding the diagnosis of diabetes (67).
Although further work needs to be done to verify this observation in a larger
population, it is possible that this represents an initial attempt to maintain
sensory system function in the face of nerves that are failing physiologically.
Demonstrating how quickly changes in epidermal nerve fibers can be
detected by the skin biopsy technique, it has been used to observe the loss of
fiber density just 2 weeks after topical exposure to capsaicin, a noxious agent
that depletes substance P from C fibers (69,70). Subsequent recovery of fiber
density over a similarly short period of time after removal of capsaicin has also
been demonstrated by skin biopsy (71). Their studies of IENF embrace the use
of capsaicin-induced fiber loss and measurement of the rate of regeneration in a
study of 31 healthy controls and 20 subjects with diabetes. Although the rate of
regeneration in diabetes was highly variable, it was correlated with the baseline
IENF density but not age, gender, or epidermal thickness. They report that the
normal rate of regeneration is 0.177 0.075 fibers/mm/day after adjusting for
initial fiber density, in diabetes was reduced to 0.1 0.07 fibers/mm/day, and
that concomitant neuropathy reduced this further to 0.04 0.03 fibers/mm/day
and was independent of diabetes type, control, or duration. They suggest that
their results have significant implications for study design with the ability to
measure regenerative capacity over a few months and that this would reduce
the length of trials as well as identify suitable candidates for entry into trials.
Our data, in contrast, show that, in as few as 20 patients treated with the
antiepileptic agent Topiramate, spontaneous nerve fiber regeneration can be
quantified within 18 weeks (63). Our technique uses confocal microscopy,
but it is not certain yet that the two approaches would yield very different
results. Thus, it appears that, as this technique becomes more widespread, it
will provide another means for examining the effects of various therapies on
sensory fibers that are compromised in diabetic neuropathy.
Combined Measures of Nerve Function

The NIS-LL is a quantitative method of scoring the abnormalities of
neurologic examination. This scale is quantitative, validated, and reproducible
149
although not reaching the standards of other objective measures. The NIS-LL
is a direct evaluation of the clinical deficits present in neuropathy, which lead
to the severe end-stage complications of the diabetic foot such as recurrent foot
ulceration, gangrene, and amputation. Dycks scale has been utilized in small
clinical trials (e.g., phase II nerve growth factor study) and has shown positive
clinical change in response to treatment. A change in the scale is considered a
significant alteration in polyneuropathy as the scale is designed to document
relatively large changes.
The NIS-LL is a scoring system graduated from 0 points (the normal finding)
to a maximum of 88 points (the absence of all motor, sensory, and reflex activity
in the lower extremities). The scale is additive of all deficits (64 potential points
for muscle strength, 8 points for reflexes, and 16 points for sensory function)
in the lower extremities. Combining the scale with other measures ensures that
other important features of neuropathy (which may predispose to other complications) are not overlooked. For example, autonomic dysfunction that causes
early mortality in all patients and impotence in males should not be overlooked.
Chronic painful symptoms can be disabling in a subset of diabetic neuropathy
patients and need to be addressed as well. Patients problems in diabetic polyneuropathy are not restricted to foot ulceration, gangrene, and amputation.
IDENTIFICATION OF CANDIDATES FOR PARTICIPATION

IN RESEARCH STUDIES
Accurate diagnosis and staging of DPN and exclusion of conditions that
mimic DPN are critical prerequisites of clinical trials designed to evaluate an
intervention (72). However, what appears to be just as critical is the need to
evaluate the level of impairment because dead nerves are unlikely to respond
to any form of intervention. Patients with less severe impairment because
of DPN may be the most responsive to a therapeutic intervention (7375)
designed to reverse or slow the progression (7376). Thus, early identification
of neuropathy disease-state impairment may help identify a population of
patients who are most amenable to intervention with experimental therapies
beyond glycemic control.
Traditionally, VDT has been recognized as a sensitive tool for the detection
of neuropathy. Nonetheless, VDT for the prediction of responsiveness in
clinical trials has not proven to be infallible. When vibration impairment
is observed, other markers of less severe DPN need to be identified. The
medial plantar SNAP has been suggested as a sensitive indicator of diabetic
neuropathy; however, it is absent at a younger age in diabetes (mean 43.7 1.2
years of age), and therefore, this nerve cannot be tested in many patients with
diabetes and vibration loss (77). Reflexes are often used as an early marker of
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DPN; however, changes in reflexes are not as sensitive as nerve-fiber function

(45). On the basis of several studies, what has emerged is that the presence or
absence of a sural SNAP may serve as a valid marker of less severe DPN with
vibratory impairment (7882).
Because the presence or absence of a sural SNAP had not been adequately
evaluated as a marker of less severe DPN responsiveness to therapeutic intervention in large multinational clinical trials (8387), we assessed the presence
of sural SNAPs as a marker of vibratory impairment in less severe DPN in
patients enrolled in a multinational, placebo-controlled, randomized clinical
trial, where the effects of ruboxistaurin (a specific inhibitor of the beta isoform
of protein kinase C) were measured (1088). We have recently reported (28)
that, in patients with impaired VDT of 97 percentile, preserved sural SNAPs
identified a subset of patients with less severe DPN who were ideal candidates to select for clinical trials who could be predicted to respond to intervention. Identifying patients with DPN amenable to therapy is a challenge.
To determine whether the amplitude of the sural SNAP reflects the severity
of DPN, an analysis was performed in 205 patients with DPN, identified by
an abnormal VDT, who were enrolled in a multinational clinical trial investigating ruboxistaurin mesylate (28). Nerve conduction velocity and response
amplitude and latency were measured and compared. VDT was significantly
lower in those with preserved sural SNAPs (n = 128) than in those in whom
they were absent (n = 77; 21.5 vs. 22.7 JND units, p = 0.002). Thus, preserved
sural SNAP denoted less severe DPN. Logistic regression analyses evaluating
baseline characteristics, HbA1c, and baseline symptom scores identified only
DPN duration as a factor that might contribute to the presence of sural SNAP
( p = 0.004; odds ratio = 0.896). We concluded that, in patients with abnormal
VDT, preserved sural SNAP identifies a patient population with less severe
DPN who may respond to therapeutic intervention in clinical trials.
The following summarizes our view of prospective endpoints in Diabetic
Neuropathy Trials:
1. Symptoms: include Nerve Symptom Score, NSC, Total Symptom Score,
Visual Analogue Scale for pain, Brief Pain Inventory, McGill pain questionnaire, Weekly Pain Inventories, Nerve Total Symptom Score 6, Clinical
global Impression: subjective but proven measures in clinical trials on pain
relieving drugs.
2. Quantitative neurologic exam focusing on distal sensorimotor function
(sensation, strength, and reflexes): semi-objective.
3. Neurophysiology (velocity, amplitude, F-wave, multiple nerve, both sensory
and motor): objective.
4. QST (vibration, thermal, and pain): semi-objective.
5. Morphology: (skin biopsy density, branching pattern) objective.
151
6. Neurovascular function: objective.

7. Autonomic testing: objective.
8. QOL: subjective.
CONCLUSIONS
There are now a large range of tools that have been developed for the evaluation of novel treatments for both the symptoms and the underlying disorders
of diabetic neuropathies. Evaluation of pain and its relief appears to have come
of age with the approval of two drugs specifically for diabetic neuropathic pain
despite using different endpoints but nonetheless well-designed and executed
trials. It has nonetheless become clear that using symptoms as an endpoint
in longer-term studies with drugs that have the potential for changing the
biology of the disease is fraught with danger because the natural history of
diabetic neuropathy is changing for reasons that are not clear but may relate to
improved general well-being, attention to the reduction of multiple risk factors
for the development of neuropathy, healthier lifestyles and regular exercise
and improved nutrition apart from the use of statins and ACEs and ARBs
almost universally in the diabetic population that may impact neuropathy.
Furthermore, the regression to the mean is also relevant to the evaluation of
symptoms because the condition is self-liming, and there is a huge placebo
effect. Indeed one of the best things one can do with patients in pain is to enter
them into a trial, at least 30% will have a 30% improvement even if they only
receive placebo.
Progression is being made with trials that are using harder endpoints for
the evaluation of large fiber, small fiber, and autonomic nerve function.
Recent trials of Aldose Reductase inhibitors have shown changes in electrophysiology and vibration perception; PKC inhibition has been associated
with reduction symptoms and improved vibration and alpha lipoic acid with
improved autonomic function. More recently, there is evidence that topiramate
can induce small fiber regeneration of IENFs. It thus seems that advances are
being made, so that it will not be the trials that fail but rather that the drugs
that fail, and hopefully, we will have a new cadre of agents that address the
underlying biological disturbance in diabetic neuropathy that can be shown to
pass muster in clinical trials with appropriate endpoints.
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Intensive Insulin Therapy

for the Critically Ill Patient
Ilse Vanhorebeek, PHD
and Greet Van den Berghe,
MD, PHD
CONTENTS
Introduction
Clinical Complications Associated with CI
Hyperglycemia in CI
Blood Glucose Control with Intensive
Insulin Therapy in CI
Intensive Insulin Therapy and the Risk
of Hypoglycemia
Mechanism by Which Intensive Insulin
Therapy Achieves Blood Glucose Control
Mechanisms Explaining the Improved Outcome
with Intensive Insulin Therapy
Conclusions
Acknowledgments
References
Summary
More and more evidence argues against the concept that the characteristic dysregulation of glucose homeostasis in critical illness or diabetes
of injury is an adaptive, benefical response in the modern intensive care
era. Stress hyperglycemia has been linked to poor outcome of the patients
in several studies. Proof of a causal relationship has been provided by a
large, prospective, randomized, controlled study where strict blood glucose
control to normoglycemia with intensive insulin therapy strongly reduced
157
158
Vanhorebeek and Van den Berghe
mortality and morbidity of surgical intensive care patients. These results

were recently confirmed in a medical intensive care patient population. Most
of the clinical benefits of intensive insulin therapy appear to be related to the
blood glucose control, but also non-glycemic metabolic and non-metabolic
actions of insulin contribute. Although substantial progress has been made
in the understanding of the pathways involved, more studies are needed to
improve our knowledge on their relative importance and that of those yet to
be unravelled.
Key Words: Critical illness, hyperglycemia, insulin, mortality, morbidity
INTRODUCTION
With the discovery of insulin in 1922, Banting and Best were the pioneers
of a revolutionary break-through in medicine. Whereas type 1 diabetes used
to be a lethal condition because of the development of ketoacidosis, patients
with this disorder nowadays can be treated with insulin, and this approach
has dramatically improved outcome. Already in the late nineteenth century,
dysregulated glucose homeostasis also appeared to be a hallmark of critical
illness (CI). Indeed, hyperglycemia commonly develops during several types
of CI, irrespective of previously diagnosed diabetes, and has long been
considered an adaptive and beneficial stress response. However, it is becoming
increasingly clear that the development of hyperglycemia is detrimental to
the critically ill patient. Moreover, a recent large prospective randomized trial
clearly demonstrated a plethora of clinical benefits of strict blood glucose
control with intensive insulin therapy with, most strikingly, an almost 50%
reduction in mortality (1). The importance of this observation is illustrated
by the lack of any intervention with such a pronounced beneficial effect on
overall intensive care survival since the introduction of mechanical ventilation
in the 1950s.
CLINICAL COMPLICATIONS ASSOCIATED WITH CI

The progress in intensive care medicine starting with the introduction of
mechanical ventilation in the 1950s has largely increased the chances of shortterm survival of patients suffering from previously lethal, acute insults. Consequently, patients now frequently enter a chronic phase of CI, during which
they remain dependent on vital organ support for a more or less extended
time period. As this condition resulted from artificial interference by humans,
with sophisticated mechanical devices, a wide array of drugs, and high-tech
monitoring systems, nature has not been able to select survival mechanisms to
Intensive Insulin Therapy for the Critically Ill Patient
159
overcome this challenge. As such, mortality has remained high among these
prolonged critically ill patients, mostly because of non-resolving multiple organ
failure and regardless of the initial disease requiring intensive care unit (ICU)
admission.
Unlike in diabetic nephropathy, mainly affecting the glomerulus,
CI-associated kidney failure mostly results from acute tubular necrosis. Extracorporeal hemofiltration or dialysis is the only therapeutic option that can be
applied to bridge the time to spontaneous recovery (2). Taking measures to
prevent deterioration of renal function in these patients, such as maintaining
or optimizing renal perfusion and diligence with monitoring of nephrotoxic
therapies, is therefore of crucial importance.
Prolonged critically ill patients often suffer from a diffuse axonal polyneuropathy (3). CI polyneuropathy clinically presents as a tetraparesis with muscle
atrophy. However, confirmation by using electromyography is required. The
course of this complication usually is self-limited and good recovery is
expected once the underlying disease is overcome. Nevertheless, it severely
delays weaning from the ventilator and mobilization of the patient (4). Specific
prevention or treatment of CI polyneuropathy is hampered by the poor understanding of the exact pathogenesis (5), although several factors have been
implicated in the etiology of this condition, such as sepsis and the accompanying release of cytokines, use of high-dose corticosteroids, and use of
neuromuscular blocking agents.
Increased susceptibility to and insufficient control of severe infections
because of suppressed innate immunity, referred to as immunoparalysis,
renders the patients vulnerable for infectious complications (6). Although at
first sight paradoxical, the patients are also at high risk of excessive systemic
inflammation, associated with cellular injury and coagulation abnormalities,
thus contributing to multiple organ failure (7). The development of anemia
is another common clinical problem in critically ill patients and is associated
with substantial red blood cell transfusion requirements (8).
Within hours and during the first days following an acute severe insult, a
hyperactive anterior pituitary gland evokes a hypercatabolic response (911).
Clinical manifestations, including fever, tachypnea, and tachycardia, are
accompanied by hyperglycemia, lipid abnormalities, and accelerated proteolysis. Its main purpose is the provision of endogenous substrates to wounded
tissues and reparative cells, for healing at a time when caloric intake is limited.
However, the sustained hypercatabolic response during prolonged CI induces
profound erosion of lean body mass by ongoing proteolysis, despite artificial
feeding and relative preservation of adipose tissue, referred to as the wasting
syndrome of CI. Patients can lose 10% or even more of their muscle mass in
a week (12,13), but also other organs are affected, including liver, kidney, and
160
heart, leading to impaired function. Prolonged mechanical ventilatory support

is often required because of extreme muscle weakness and fatigue. Prolonged
CI is invariably associated with neuroendocrine changes, which are related to
the hypercatabolism (911). More specifically, relatively suppressed function
of the anterior pituitary gland is now responsible for suppressed function of its
peripheral target organs.
All the described changes are thought to contribute to multiple organ failure,
or the lack of recovery hereof, and to prolonged need of intensive care and
high risk of death.
HYPERGLYCEMIA IN CI
In normal individuals, blood glucose levels are tightly regulated within the
narrow range of 60140 mg/dl. However, glucose levels usually rise during
CI, labeled stress diabetes or diabetes of injury (14,15). Until recently, it
was considered state of the art to tolerate blood glucose levels up to 220 mg/dl
in fed critically ill patients (16), and only excessive hyperglycemia exceeding
this value was treated. Reasons to treat hyperglycemia above this threshold
included the occurrence of hyperglycemia-induced osmotic diuresis and fluid
shifts at these high levels and the knowledge from the diabetes literature
that uncontrolled and pronounced hyperglycemia predisposes to infectious
complications (15,17). Arguments to tolerate glucose levels up to 220 mg/dl
were the classic dogma that moderate hyperglycemia in critically ill patients is
beneficial for organs that largely rely on glucose for their energy supply but do
not require insulin for glucose uptake, such as the brain and blood cells, and
the fear for occasional hypoglycemia and consequent brain injury with tight
glucose management.
Development of Hyperglycemia in CI Patients

In the acute phase of CI, an upregulation of both gluconeogenesis and
glycogenolysis enhances hepatic glucose production. After a transient fall in
insulin levels hyperinsulinemia develops. Such high insulin levels normally
suppress both pathways but in CI are unable to maintain normoglycemia.
Increased levels of glucagon, cortisol, growth hormone, catecholamines,
and cytokines all play a role (1823). How the hyperglycemic response is
maintained during prolonged CI remains relatively unclear. In comparison
with the acute phase, cortisol, growth hormone, catecholamine, and cytokine
levels usually decrease in the chronic phase of CI, whereas glucagon levels
are not well documented. In addition to the stimulation of glucose production,
impaired glucose uptake contributes to the development of hyperglycemia.
161
The important exercise-stimulated glucose uptake in skeletal muscle is likely

abolished in view of the immobilization of the patient. Insulin-stimulated
glucose uptake by glucose transporter-4 (GLUT-4) is compromised (24,25).
Nevertheless, whole body glucose uptake is increased, accounted for by tissues
that are not dependent on insulin for glucose uptake, such as brain and blood
cells (15,26). The combined picture of higher levels of insulin, elevated hepatic
glucose production and impaired peripheral glucose uptake, reflects the development of peripheral insulin resistance during CI.
Hyperglycemia and Outcome of CI Patients

Several recent studies clearly identify the development of hyperglycemia as
an important risk factor for mortality and morbidity of critically ill patients.
Elevated glucose levels predicted increased mortality and length of ICU
and hospital stay of trauma patients and were associated with infectious
morbidity and prolonged need of mechanical ventilation (2730). Apart from
the predictive value of hyperglycemia for worse survival of patients suffering
from severe brain injury, a significant relationship was found between high
blood glucose levels and worse neurologic status, impaired pupil reactivity,
intracranial hypertension, and longer hospital length of stay (31,32). Similarly,
hyperglycemia predicted a higher risk of death after stroke and a poor functional
recovery in those patients who survived (33). In addition, a strong link has been
described between increased blood glucose levels and the risk of CI polyneuropathy in sepsis and the systemic inflammatory response syndrome (34). A
meta-analysis on myocardial infarction also revealed an association between
stress hyperglycemia and increased risk of in-hospital mortality and congestive
heart failure or cardiogenic shock (35) and even mild elevations in fasting
glucose levels in patients with coronary artery disease undergoing percutaneous coronary intervention have been associated with a substantial mortality
risk (36). Furthermore, the glucose level of patients undergoing coronary artery
bypass grafting appeared to be an important predictor of delayed extubation
(37). Retrospective analysis of a heterogeneous population of critically ill
patients revealed that even a modest degree of hyperglycemia was associated
with a substantially increased hospital mortality (38). A study on the occurrence of hyperglycemia among critically ill children with widely varying
pathology showed a correlation with higher in-hospital mortality and longer
length of stay (39). Peak blood glucose levels and duration of hyperglycemia
appeared independently associated with mortality of critically ill children (40).
In severely burned children, mortality, incidence of bacteremia and fungemia,
and number of skin-grafting procedures were higher in hyperglycemic than in
normoglycemic patients (41).
162
BLOOD GLUCOSE CONTROL WITH INTENSIVE INSULIN

THERAPY IN CI
First strong evidence against the traditional concept of tolerating glucose
levels up to as high as 200 mg/dl came from the landmark prospective,
randomized, controlled study on intensive insulin therapy in surgical critically ill patients (1). This study of a large group of patients admitted to
the ICU predominantly after extensive, complicated surgery or trauma indeed
revealed major clinical benefits of strict glycemic control with insulin. In the
conventional approach, patients received insulin only if glucose concentrations
exceeded 215 mg/dl with the aim of keeping concentrations between 180 and
200 mg/dl, resulting in mean blood glucose levels of 150160 mg/dl (hyperglycemia). Insulin was administered to the patients in the intensive insulin
therapy group to maintain blood glucose levels between 80 and 110 mg/dl,
which resulted in mean blood glucose levels of 90100 mg/dl (normoglycemia).
Tight blood glucose control with insulin strikingly lowered ICU mortality from
8.0 to 4.6% (43% reduction). The benefit was particularly attributed to the
group of patients who required intensive care for more than 5 days with a
48% mortality reduction from 20.2 to 10.6%. Besides saving lives, intensive
insulin therapy largely prevented several CI-associated complications. The
incidence of CI polyneuropathy was reduced by 44%, the development of blood
stream infections by 46%, and acute renal failure requiring dialysis or hemofiltration by 41%. The number of patients who acquired liver dysfunction with
hyperbilirubinemia was lowered by 16%. Furthermore, anemia less frequently
developed as illustrated by the 50% reduction in the median number of red
blood cell transfusions needed. Finally, patients were also less dependent on
prolonged mechanical ventilation and intensive care. A large number of patients
were included in the study after complicated cardiac surgery. Nevertheless, the
clinical benefits of this therapy were equally present in most other diagnostic
subgroups. Particularly in the group of patients with isolated brain injury,
intensive insulin therapy was able to protect the central and peripheral nervous
system from secondary insults and improved long-term rehabilitation (42).
An important confirmation of the clinical benefits of intensive insulin
therapy was recently obtained with the demonstration, by a large randomized
controlled trial, that the Leuven protocol of glycemic control with insulin in
adult surgical critically ill patients (1) was similarly effective in a strictly
medical ICU patient population (43). Indeed, hospital mortality was reduced
from 40.0 to 37.3% in the intention-to-treat population (not significant) and
from 52.5 to 43.0% in the target group of long-stay patients needing at least
a third day of intensive care, for which the study had been powered based
on the results of the surgical study. Intensive insulin therapy significantly
163
reduced morbidity in the intention-to-treat group, with lower occurence of

new development of kidney injury and hyperbilirubinemia, earlier weaning
from mechanical ventilation and earlier discharge from the ICU and from
the hospital. The reduction in morbidity was even more striking in the target
group of patients remaining in ICU for at least a third day. These patients
were discharged from the hospital alive on average 10 days earlier than on
conventional insulin therapy. The number of long-stay patients with hyperinflammation was also reduced. In real life intensive care of a heterogeneous medical/surgical patient population, an observational study (44) had
evaluated the impact of implementing a tight glucose management protocol by
comparison with historical controls as a reference and also largely confirmed
the clinical benefits (1). In this study, intravenous insulin was only administered
if glucose levels exceeded 200 mg/dl on two successive measurements and
aimed to lower glycemia below 140 mg/dl. Hence, blood glucose control was
somewhat less strict and resulted in mean glucose levels of 131 mg/dl in the
protocol period, compared with 152 mg/dl in the baseline period. In comparison
with the historical control group, patients did clinically better after the implementation of the glucose control protocol, with a 29% decrease in hospital
mortality, length of ICU stay decreased by 11%, 75% less patients developed
new renal failure, and 19% less patients required red blood cell transfusion. No
effect was seen with regard to prevention of severe infections, but the incidence
of this complication was already low in the baseline period. In a predominantly
general surgical patient population, however, another prospective, randomized,
controlled study, albeit a small one, confirmed the findings of a decreased
incidence of total nosocomial infections (including intravascular device, blood
stream, intravascular device-related blood stream, and surgical site infections)
with intensive insulin therapy targeting glucose levels between 80 and 120
mg/dl (45). This intervention resulted in mean daily glucose levels of 125
versus 179 mg/dl in the standard glycemic control group. In an observational
study of patients with diabetes mellitus undergoing cardiac surgery, intravenous
insulin infusion to eliminate hyperglycemia also lowered in-hospital mortality
compared with the historical control group, with fewer deep sternal wound
infections and shorter length of hospital stay (46).
INTENSIVE INSULIN THERAPY AND THE RISK

OF HYPOGLYCEMIA
The risk of hypoglycemia is a major concern when intensive insulin therapy
is administered to critically ill patients. Severe hypoglycemia (<30 mg/dl) or
prolonged hypoglycemia can lead to convulsions, coma, and irreversible brain
damage and also cardiac arrhythmias can be induced (47). Patients who have
164
an altered mental status, who are intubated, or who are severely ill may be
unable to recognize or communicate hypoglycemic symptoms (16). Moreover,
clinical symptoms of the autonomic response (sweating, tachycardia, tremor)
and central nervous symptoms such as dizziness, blurred vision, altered mental
acuity, confusion, and eventually convulsions may be masked by concomitant
diseases and by inherent intensive care treatments such as sedation, analgesia,
and mechanical ventilation.
The hazard of hypoglycemia clearly warrants adequate training of the
nursing and medical staff, at least initially making use of a strict and detailed
insulin titration protocol. The best way to achieve blood glucose control during
intensive care is by continuous insulin infusion, and the use of oral anti-diabetic
agents in the patients with previously diagnosed diabetes should be discontinued (16). This way of administration is quite obvious for several reasons.
First, feeding of the ICU patients is usually a continuous process, whether
this occurs by enteral or total parenteral nutrition or with a combination of
both. Continuous intravenous administration of insulin is more reliable and
consistent than subcutaneous injections. Furthermore, insulin need in this way
can be more easily and precisely titrated in response to the actual blood glucose
levels and, discontinuing or reducing the insulin infusion allows rapid cessation
of insulin action in case the patient develops hypoglycemia, as intravenous
insulin has a short half-life.
Specific measures to prevent hypoglycemia include the concomitant administration of insulin and carbohydrates (intravenous dextrose or tube feeds) and
close monitoring of blood glucose levels (16). Within the first 1224 h after
admission of the patients in the large surgical ICU study (1), glucose levels
were measured every 12 h. The frequency of the measurements was scaled
down to every 4 h once the targeted blood glucose level was reached with a
stable insulin dose. However, one has to remain alert after stable glucose levels
are obtained. Indeed, although the incidence of hypoglycemia in the study was
relatively low (1), many of the cases where it did develop were attributed to
inadequate insulin dose reduction during interruption of enteral feeding.
MECHANISM BY WHICH INTENSIVE INSULIN THERAPY

ACHIEVES BLOOD GLUCOSE CONTROL
Data from the studies performed by our group suggest that mainly stimulation of glucose uptake by skeletal muscle explains how intensive insulin
therapy lowers circulating glucose levels in critically ill patients, rather than
an effect of insulin on hepatic glucose handling (Fig. 1) (48,49). This is illustrated by improved responsiveness of insulin-regulated genes in skeletal muscle,
whereas it appeared that insulin resistance in the liver is not overcome by
165

amino acids
IGFBP-1
glucose
glucose
GK
PEPCK
GLUT-4
HXK-II
glycogen
Fig. 1. Lowering of blood glucose levels by intensive insulin therapy in critical illness.
Data from previous studies performed by our group suggest that insulin lowers blood
glucose levels predominantly through increased skeletal muscle glucose uptake, rather
than through an effect on hepatic glucose handling (48,49). Improved responsiveness of
insulin-regulated genes in patients from the intensive insulin therapy group is indicated in
green, whereas refractoriness to insulin is indicated in red. GLUT-4: glucose transporter-4,
HXK-II: hexokinase-II, GK: glucokinase, PEPCK: phosphoenolpyruvate carboxykinase,
IGFBP-1: insulin-like growth factor-binding protein-1.
intensive insulin therapy. In muscle, GLUT-4 controls insulin-stimulated glucose

uptake, whereas hexokinase-II is the rate-limiting enzyme in intracellular insulinstimulated glucose metabolism. mRNA expression of both genes in postmortem
skeletal muscle biopsies of critically ill patients was increased by intensive
insulin therapy (48). In contrast, mRNA expression of glucokinase, the ratelimiting enzyme for insulin-mediated glucose uptake and glycogen synthesis
in liver, was not affected by insulin therapy in postmortem liver biopsies of
the patients (48). Repression of gluconeogenesis by insulin was not enhanced,
as shown by comparable transcript levels of its rate-limiting enzyme phosphoenolpyruvate carboxy-kinase in both conventional and intensive insulin therapy
groups (49). Likewise, intensive insulin therapy was not able to counteract
the increase in insulin-like growth factor-binding protein-1 (another protein
transcriptionally regulated by insulin and shown to correlate with mortality),
neither at the mRNA level nor at the protein level in the circulation (49).
In contrast to our results for prolonged critically ill patients, whole-body
glucose disposal was not affected in a small study on only 6 severely traumatized patients in the acute phase of illness, whereas endogenous glucose
production appeared to be reduced (50). It has to be emphasized, however, that
acute and prolonged critically ill patients may have very different neuroendocrine characteristics (911). Furthermore, whole-body glucose disposal
was studied without distinguishing between insulin-dependent and insulinindependent glucose uptake, which are oppositely affected by insulin and thus
may explain the absence of an effect on this parameter.
166
MECHANISMS EXPLAINING THE IMPROVED OUTCOME

WITH INTENSIVE INSULIN THERAPY
Both hyperglycemia and the administration of a high dose of insulin were
associated with a high risk of death in surgical critically ill patients, as revealed
by multivariate logistic regression analysis (1,51). This indicates that it was the
blood glucose control and/or other metabolic effects of insulin that accompany
tight blood glucose control, and not the insulin dose administered per se, that
contributed to the improved survival with intensive insulin therapy. Other data
also suggest that the mortality benefits can be attributed to glycemic control
rather than the absolute insulin doses administered (38,52). The observed
association between high insulin dose and mortality is likely explained by more
severe insulin resistance in the sicker patients, who have a high risk of death.
Glycemic control accounted for most morbidity effects, including the reduced
incidence of CI polyneuropathy and bacteremia (51). Both glucose control and
insulin dose contributed to the reduced inflammation, albeit with a superior
effect of lowering glucose levels.
In this study, the risk of death appeared to be linearly correlated with the degree
of hyperglycemia, with no clear cut-off level below which there was no further
benefit (51). Indeed, the patients who received conventional insulin therapy and
who developed only moderate hyperglycemia (110150 mg/dl) had a lower risk of
death than those with severe hyperglycemia (150200 mg/dl), whereas they were
at higher risk of death than patients whose blood glucose levels were controlled
below 110 mg/dl with intensive insulin therapy (Fig. 2). Tight glycemic control
below 110 mg/dl similarly appeared to be of crucial importance for the prevention
of CI polyneuropathy, bacteremia, anemia, and acute renal failure (Fig. 2) (51).
In particular, a positive linear correlation was observed between glycemia and
the risk of developing CI polyneuropathy, where multivariate logistic regression
analysis also confirmed the crucial role of preventing glucose toxicity to protect
the neurons (42).
Mechanisms of Glucose Toxicity in CI and Effects

of Intensive Insulin Therapy
If indeed avoiding even a moderate degree of hyperglycemia is crucial, it
is striking that by doing so only during the relatively short period the patients
needed intensive care, this strategy prevented the most feared complications
of CI. Normal cells respond to moderate hyperglycemia by downregulation
of glucose transporters to protect themselves from deleterious effects (53).
In diabetic patients, chronic hyperglycemia also causes severe complications,
but in a time frame which is several orders of magnitude longer than the
time it took to prevent life-threatening complications with intensive insulin
167

45
P = 0.0009
P < 0.0001
CI polyneuropathy
P < 0.05
bacteremia
NS
inflammation
P < 0.05
>2 red cell transfusions
P < 0.05
acute renal failure
Cumulative Hazard (%) (in hospital death)
P < 0.01
death in ICU
40
35
30
25
P = 0.026
20
15
10
5
0
0 10 20 30 40 50 60 70 80
Risk (%)
50
100
150
200
250
Days after inclusion
Fig. 2. Stratification of risk of death and morbidity factors for mean blood glucose levels.
Left panel: Post-hoc analysis of the percentage of risk of death in intensive care unit (ICU),
development of critical illness (CI), polyneuropathy, bacteremia, inflammation [C-reactive
protein (CRP) higher than 150 mg/l for more than 3 days], need for more than two red
cell transfusions, and acute renal failure requiring hemofiltration/dialysis among long-stay
(more than 5 days) patients stratified for mean blood glucose levels. Filled bars represent
patients with a mean blood glucose level lower than 110 mg/dl, shaded bars represent
patients with a mean blood glucose level between 110 and 150 mg/dl, and unfilled bars
represent patients with a mean blood glucose level higher than 150 mg/dl. The indicated
p-values were obtained using the 2 -test. Reproduced with permission from (51). Right
panel: KaplanMeier cumulative risk of in-hospital death among long-stay patients with a
mean blood glucose level lower than 110 mg/dl (), between 110 and 150 mg/dl () and
higher than 150 mg/dl (). The p-value of 0.0009, obtained with MantelCox log-rank
test, indicates the significance level of the overall difference in risk of death among the
groups, and the p-value of 0.026 indicates the significance level of the difference between
the <110 mg/dl and 110150 mg/dl groups. Reproduced with permission from (51).
therapy in CI. Therefore, the obvious question is why hyperglycemia would

be more acutely toxic in critically ill patients than in healthy individuals or
diabetic patients.
Glucose uptake independent of insulin, mediated by the facilitative glucose
transporters, GLUT-1, GLUT-2, or GLUT-3, may play a role. Indeed, several
factors induced in CI have been shown to upregulate the expression and membrane
localization of GLUT-1 and GLUT-3 in different cell types. These include
cytokines, angiotensin II, endothelin-1, vascular endothelial growth factor, and
transforming growth factor- but also hypoxia appears to be a regulatory factor
(5458). In this way, the normal downregulatory protective response against
hyperglycemia may be overruled. Furthermore, GLUT-2 and GLUT-3 allow
168
glucose to enter cells directly proportional to the extracellular glucose level

over the range of glycemia present in CI (Km 9 mmol/l for GLUT-3 and
much higher for GLUT-2) (59). Hence, cellular glucose overload may develop
in the central and peripheral nervous system, endothelial, epithelial and immune
cells, as well as hepatocytes, renal tubules, pancreatic cells and gastrointestinal
mucosa. In contrast, cellular systems and tissues that predominantly rely on
insulin-dependent glucose transport through GLUT-4, such as skeletal muscle
and myocardium, may be relatively protected against hyperglycemia-induced
cellular glucose overload and toxicity.
Recent data on mitochondrial ultrastructure and function in tissues from
surgical critically ill patients are consistent with this concept (60). We showed
that prevention of hyperglycemia with intensive insulin therapy is protective
to the hepatocytic mitochondrial compartment of critically ill patients (60).
In hepatocytes of patients in the conventional treatment group, hypertrophic
mitochondria were observed with an increased number of abnormal and
irregular cristae as well as reduced electron density of the matrix (Fig. 3).
However, these severe ultrastructural abnormalities were virtually absent in
patients with blood glucose levels tightly controlled to normoglycemia. At
the functional level, this was associated with higher activities of respiratory
chain complex I and complex IV in the patients who received intensive insulin
therapy. In contrast to liver, no morphological abnormalities were detected
in skeletal muscle, nor were any of the respiratory chain enzyme complexes
affected by insulin therapy. This is in line with a direct effect of avoiding
glucose toxicity on the hepatocytic mitochondrial compartment by strict blood
glucose control rather than of insulinization. Mitochondrial dysfunction and
the associated bioenergetic failure have been regarded as factors contributing
to multiple organ failure, the most common cause of death in sepsis and
prolonged CI, and have indeed been related to lethal outcome in patients and
in a resuscitated long-term rat model of sepsis (61,62). As such, prevention of
hyperglycemia-induced mitochondrial damage to cellular systems with passive
glucose uptake in addition to liver could theoretically explain some of the
protective effects of intensive insulin therapy in severe illness.
There is substantial evidence that links diabetes and hyperglycemia to
the development of increased oxidative stress. This is in part accounted for
by enhanced mitochondrial superoxide production (63), but also, transition
metal-catalyzed glucose oxidation and activation of NADPH oxidase take part,
amongst other mechanisms (64,65). In turn, high levels of reactive oxygen
radicals have been shown to inhibit the glycolytic enzyme glyceraldehyde3-phosphate dehydrogenase. Consequently, glycolysis is blocked and glucose
is shuttled into toxic pathways, contributing to vascular damage to tissues
and organs (63). Moreover, nitric oxide levels are increased in CI
169

A
Fig. 3. Mitochondrial ultrastructure in liver and skeletal muscle of critically ill patients.
Electron micrographs show greatly enlarged mitochondria with an increased number of
disarrayed cristae and reduced electron density of the matrix in hepatocytes adjacent to
normal mitochondria (A and B), contrasting with normal mitochondrial morphology in
skeletal muscle (C) of conventionally treated patients. In most of the intensively treated
patients, hepatocytic mitochondrial ultrastructure was normal [D (c: canaliculus), E], as
in all muscle biopsy samples from these patients (F). Original magnification: 23,000
[reprinted with permission from Elsevier (60)].
because of cytokine-induced activation of nitric oxide synthesis, whereas

hypoxia-reperfusion in the patients aggravates superoxide production. In this
way, the formation of the reactive nitrogen species peroxynitrite is promoted,
able to induce tyrosine nitration of proteins, and thus affect their normal
function (66). Mitochondrial complex I is just one example of an activity
suppressed by tyrosine nitration (67).
High glucose levels also affect all major components of innate immunity
(68). Polymorphonuclear neutrophil function and intracellular bactericidal and
opsonic activity are compromised by hyperglycemia (6972). This may play a
role in the increased risk of infections observed for patients who are exposed
to such high glucose levels (17,73). Tight glycemic control has been shown to
ameliorate the leukocyte oxidative burst and phagocytotic activity in patients
with diabetes (69,72) . Importantly, intensive insulin therapy largely prevented
severe nosocomial infections and lethal sepsis also in non-diabetic surgical
170
ICU patients (1). In an animal model of prolonged CI (74), glucose control with
insulin beneficially affected innate immunity by preservation of phagocytosis
and oxidative burst function of monocytes (75).
Non-Glycemic Metabolic Effects of Intensive Insulin Therapy

The serum lipid profile is severely disturbed in critically ill patients. Most
characteristically, levels of triglycerides are elevated (due to an increase
in very-low-density lipoprotein), whereas levels of high-density lipoprotein
(HDL)- and low-density lipoprotein (LDL)-cholesterol are very low (7678).
Intensive insulin therapy prevented the rise in serum triglycerides during full
nutritional support and substantially increased circulating HDL and LDL and
the level of cholesterol associated with these lipoproteins (48). Insulin treatment
also decreased serum triglycerides and free fatty acids in burned children (79).
Given the important role of triglycerides in energy provision and of lipoproteins
in transportation of lipid components (cholesterol, triglycerides, phospholipids,
lipid-soluble vitamins) and endotoxin scavenging (8082), a contribution of the
(partial) correction of the lipid profile to improved outcome may be expected.
Multivariate logistic regression analysis indeed revealed that improvement
of the dyslipidemia with insulin therapy explained a significant part of the
reduced mortality and organ failure (48). Surprisingly, these effects surpassed
those of glycemic control. Furthermore, when the model was controlled for all
metabolic effects of insulin, including the lipid effect, the risk associated with
high-dose insulin administration disappeared (48,52). As such, this important
finding argues in favor of titrating insulin to doses required to achieve its
metabolic effects.
Insulin has a well-recognized anabolic effect, which comprises both stimulation of muscle protein synthesis and attenuation of protein breakdown (8385).
Therefore, its administration has been put forward as an intervention to attenuate
the catabolic syndrome of prolonged CI (86). In surgical critically ill patients
who received intensive insulin therapy (1), this anabolic effect of insulin
was not obvious from clinical observation. However, intensive insulin therapy
resulted in a higher protein content in postmortem skeletal muscle biopsies of
the patients (60) and prevented weight loss in a rabbit model of prolonged
CI (75). Altered regulation at the level of the somatotropic axis appeared
not to be involved in the anabolic effect of insulin, unlike expectations (87).
Non-Metabolic Effects of Intensive Insulin Therapy

Independent of its preventive effect on infection, intensive insulin therapy
was able to preclude excessive inflammation in critically ill patients, as
illustrated by lower serum C-reactive protein (CRP) and mannose-binding
171
lectin levels compared with conventional insulin therapy (88). In multivariate

analysis, the effect on CRP significantly contributed to the observed outcome
benefit (48). However, it was no longer independently related to the outcome
benefit when the changes in lipid metabolism were taken into account (48).
In that way, a link may be put forward between the anti-inflammatory effect
of intensive insulin therapy and its amelioration of the lipid profile, but a
mechanistic explanation for the dominant effect of serum lipid correction still
needs to be delineated. Attenuation of the CRP response by insulin therapy
was also confirmed in a rabbit model of prolonged CI (75). We recently investigated the effect of intensive insulin therapy on an extensive series of proand anti-inflammatory cytokines in surgical critically ill patients, but found no
major effect (89). In burned children, however, the administration of insulin
resulted in lower pro-inflammatory cytokines and proteins, whereas the antiinflammatory cascade was stimulated, although these effects were largely seen
only late after the insult (79). Similar results were obtained from endotoxemic
rats and thermally injured rats (90,91). Also, in an endotoxin-induced porcine
model of CI, hyperinsulinemia was shown to lower pro-inflammatory cytokines
(92). Although anti-inflammatory effects of insulin therapy may be direct,
prevention of hyperglycemia may be crucial as well.
Insulin has also shown to improve myocardial function and to protect the
myocardium during acute myocardial infarction, open-heart surgery, endotoxic
shock, and other critical conditions (93,94). Direct anti-apoptotic properties of
insulin independent of glucose uptake and involving insulin signaling play a
role (93,95,96). However, insulins cardioprotective action may at least partly
be due to lowering of glucose levels (93), which likely explains the disappointing results in the absence of adequate glucose control obtained in the
recent large, randomized CREATE-ECLA trial on glucose-insulin-potassium
(GIK) infusion in patients with acute myocardial infarction (97) and the
DIGAMI-2 trial in patients with diabetes and myocardial infarction (98).
Finally, as in patients with diabetes, prevention of endothelial dysfunction
and hypercoagulation may contribute to the protective effects of insulin therapy
in CI (99). We indeed demonstrated that maintenance of normoglycemia
with intensive insulin therapy protected the endothelium, which contributed to
prevention of organ failure and death with this intervention (89). The therapy
reduced endothelial activation, reflected in lower levels of adhesion molecules.
The mechanism likely involves inhibition of excessive inducible nitric oxide
synthase (iNOS)-induced NO release. Moreover, intensive insulin therapy
reduced the levels of asymmetric dimethylarginine (100), an endogenous
inhibitor of nitric oxide synthase activity, which competes with cellular
transport of its substrate arginine and thus interferes with nitric oxide
production. The modulation of this arginine derivative by insulin was associated
172
with a better outcome, most likely mediated by reducing the inhibition of the
constitutively expressed endothelial nitric oxide synthase (101), contributing
to preservation of organ blood flow.
CONCLUSIONS
The development of hyperglycemia is detrimental for the outcome of critically ill patients. However, the simple metabolic intervention of maintaining
normoglycemia with intensive insulin therapy to a large extent improves
survival of critically ill patients and reduces morbidity. In the last few years,
substantial progress has been made in the understanding of the mechanisms
underlying these clinical benefits, and it appears that both strict glycemic
control and other metabolic and non-metabolic effects of the insulin administered contribute. However, more studies are needed to further elucidate the exact
pathways involved, as well as the relative contribution of prevention of glucose
toxicity and direct non-glycemic effects of insulin. This knowledge will open
new perspectives for developing strategies to further improve outcome of CI.
ACKNOWLEDGMENTS
The work was supported by research grants from the Catholic University of
Leuven (OT/03/56) and the FWO Flanders Belgium (G.0278.03, G.0533.06).
I. Vanhorebeek is a Post-doctoral Fellow of the FWO Flanders Belgium. G.
Van den Berghe holds an unrestrictive Catholic University of Leuven Novo
Nordisk Chair of Research.
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diabetic cardiac surgery patients. Anesth Analg 1999; 88:10111016.
70. Nielson CP, Hindson DA. Inhibition of polymorphonuclear leukocyte respiratory burst
by elevated glucose concentrations in vitro. Diabetes 1989; 38:10311035.
71. Perner A, Nielsen SE, Rask-Madsen J. High glucose impairs superoxide production from
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73. Furnary AP, Zerr KJ, Grunkemeier GL, Starr A. Continuous intravenous insulin infusion
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74. Weekers F, Van Herck E, Coopmans W, et al. A novel in vivo rabbit model of hypercatabolic critical illness reveals a bi-phasic neuroendocrine stress response. Endocrinology
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82. Harris HW, Grunfeld C, Feingold KR, et al. Chylomicrons alter the fate of endotoxin,
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84. Agus MSD, Javid PJ, Ryan DP, Jaksic T. Intravenous insulin decreases protein breakdown
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10
Childhood Diabetes Explosion

Michael S. Stalvey, MD,
and Desmond A. Schatz,
MD
CONTENTS
Introduction
What Has Led to Both Childhood Type 1
and Type 2 Diabetes Reaching Epidemic
Levels?
Tackling the Problems
Conclusion
Acknowledgments
References
Summary
A century ago, the incidence of both Type 1 (T1D) and Type 2 (T2D)
was very low. Worldwide epidemics of both T1D and T2D have placed
tremendous burdens on both affected individuals and society. Disproportionate resources are spent on complications of the diseases. Although
multiple etiologies have been promulgated, for T1D, causative factors and
the precise mechanisms leading to the disease remain elusive. In contrast,
the rising incidence of T2D in children is closely associated with the obesity
explosion which is strongly linked to an increased food supply and decreased
physical activity. The rising incidence of obesity has reached pandemic
proportions with more than a billion people affected worldwide. Focus needs
to be directed to understanding the complex interaction between genes, the
environment, and the immune system culminating in T1D and tackling the
obesity epidemic. This chapter will discuss the emergence of the diabetes
explosion, the proposed pathogenic mechanisms, and potential interventions.
179
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Stalvey and Schatz
Key Words: Type 1 diabetes, type 2 diabetes, autoimmunity, obesity,

insulin resistance
INTRODUCTION
An explosion inevitably conjures images of destruction, chaos, anxiety,
fear, and panic. The twenty-first century confronts the world with new health
challenges, if not explosions, at least alarming epidemics not only of childhood
type 2 diabetes (T2D) but also, and perhaps less well recognized, of type 1
diabetes (T1D) (Table 1; Figs 1 and 2). At the beginning of the twentieth
century, when hunger was rampant even in industrialized nations, no one would
have envisioned that both childhood and adult obesities and its comorbidities
including T2D would become one of our greatest healthcare problems.
A hundred years ago, the worldwide incidence of both T1D and T2D was
very low. Because insulin had yet to be discovered, children or adults who
developed T1D had a short life expectancy. With the advent of insulin therapy
Table 1
Comparison of Type 1 and Type 2 Diabetes
T1D
T2D
Usual clinical course
Insulin-dependent
Non-insulin-dependent
(initially)
Usual age of onset
<18 y LADA recognized

in 5-15% of adults with
T2D
Lean
Acute-onset
Yes
>40 y but increasing,

especially among obese
teen minorities
Obesity 80-90%
Subtle
No
Family history
15% with affected

first-degree relative
Common
Ethnicity
Predominantly Caucasian
Islet autoantibodies
(GADA, ICA,
IA-2A, IAA)
Present at onset
More common in people

of Asian, African, Latino,
Native American origin
Absent
HLA-DR3,DR4,
DQB1*0201, *0302
Increased frequency
No increased frequency
Body weight
Clinical presentation
Ketosis-prone
181
Fig. 1. Increasing incidence of type 1 diabetes in children in Norway from 1950 to present.
Reproduced from Gale, EA (1) with permission.
and the subsequent refinements in insulin synthesis and delivery, the survival of
individuals with T1D has permitted normal reproductive lives. The explosion
of T1D cannot, however, be attributed to increased numbers of genetically
susceptible offspring of people with T1D. The dramatic increase in T1D around
Fig. 2. Annual incidence of type 2 diabetes and prevalence of obesity among Japanese
school children. Reproduced from Alberti et al (2) with permission.
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the mid-twentieth century can only be explained by environmental factors.

Although the dramatic rise in T1D slowed in the late twentieth century and
the beginning of the twenty-first century, the incidence continues to increase.
The contemporary availability of high caloric density, low cost, convenient, and heavily promoted foods, together with environmental impediments
to physical activity, has led to accelerating rates of obesity and rapidly rising
numbers of T2D in both the adult and more recently the adolescent populations.
The frequency of T2D has far exceeded T1D for many decades and targets
all population groups. Edwin Gale (3) aptly describes T2D as targeting the
rich in poor countries and the poor in rich countries. T2DM, which 2025
years ago, accounted for less than 3% of all cases of new-onset diabetes in
children and adolescents, today accounts for up to 45% of new-onset cases
among adolescents (4).
In 1987, the Center for Disease Control and Prevention estimated that
diabetes affected 6.8 million individuals in the USA (5). By 2002, reports
indicated that diabetes affected over 18 million individuals, with T2D
accounting for approximately 9095% of all cases (6). The number of persons
worldwide with diabetes is predicted to reach 300 million by the year 2025.
King et al. (7) predict a 42% increase in developed countries and a 170%
increase in developing countries.
The burden of diabetes is great on both the individual and the society.
Despite improvements in therapy, a disproportionate amount of resources is
spent on patients with macro- and microvascular complications of diabetes.
In the USA alone, the direct cost of diabetes more than doubled from 1997
to 2002 ($44 billion to $92 billion). The projected direct costs for diabetes
healthcare in the USA are $138 billion in the year 2020 (8).
WHAT HAS LED TO BOTH CHILDHOOD TYPE 1

AND TYPE 2 DIABETES REACHING EPIDEMIC LEVELS?
Type 1 Diabetes
At the start of the twentieth century, childhood diabetes was considered
to be rare and rapidly fatal. By the end of the century, 34 children per
1000 in Western countries were developing T1D by age of 20 years, and a
steady rise in incidence had been reported from other parts of the world (7).
In 1890, the reported death rate from diabetes of children less than 15 years
of age in the USA was 1.3/100,000/year (1) rising to 27/100,000/year over
the years 19001920 (1). Although the reliability of these data is uncertain
because of variable access to medical care and absence of validation of
diagnosis, physician surveys and other clinical/hospital records do not suggest
a substantial increase in incidence during the era of 19201950 (1). In the
183
second half of the twentieth century, multiple studies from Europe (Norway,
Denmark, Sardinia, and UK) and the USA reported a dramatic increase in the
incidence of T1D. The incidence appears to be increasing in linear fashion (1).
These findings are most prominent in countries known for high prevalence rates
of diabetes. In Finland, in the 1950s, incidence rates were 1012/100,000/year
and are now (4550/100,000/year. Almost 1 of 160 Finnish children develop
T1D by age 16 years. Although increases in T1D frequency have been observed
in almost every country where it has been monitored, the rates are still smaller
than those noted for T2D. Extrapolation of current trends suggests that the
global incidence of T1D will increase by 40% over the period 19982010 (9).
Worldwide, Finland and Sardinia have the highest T1D incidence
(4550/100,000/year) (10,11). The USA has an annual incidence of approximately 15/100,000 children or more than 12,000 new cases per year. The
peak incidence occurs at adolescence, however a more modest peak is noted
in preschool age children. There is evidence that the increasing worldwide
incidence of T1D is especially noted in young children (9,1214). Not included
in these incidence data are the increasing number of adult patients initially
diagnosed with T2D who have latent autoimmune diabetes of adults (LADA),
a slowly progressive form of T1D (1523). Between 4 and 17% of T2D
patients have LADA based on the presence of islet autoantibodies, with the
highest percentages being in young patients. Among 25- to 34-year-old T2D
patients in the United Kingdom Prospective Diabetes Study, 34% had one
or more diabetes-specific autoantibodies and 47% of Swedish 1534 yearold T2D patients were positive. LADA could affect as many individuals as
classic, acute-onset T1D. The etiology of the increase in incidence is not
well understood. The change in incidence within genetically stable populations
indicates an effect of changes in the environment. The presence of disparate
geographic differences in addition to the rising worldwide incidence as well as
an approximate 5066% discordance rate in identical twins further indicates
that environmental agents must be operative (24). Islet-specific autoantibodies
can frequently be detected within the first few years of life (2527), implying
environmental encounters affecting islet cells very early in development.
As there is invariably a latent period between the appearance of autoantibodies and onset of disease, additional environmental factorsinteracting with
genetic predisposition further appear to modulate the rate of disease (28).
Many attempts have been made to explain the rising incidence of diabetes
over the past 30 years. Early nutrition and infection have been the most
frequently advanced hypotheses with exposure to cows milk (29) or to rubella
or enterovirus infection (30) most often proposed. There is, however, no direct
evidence that either plays a major role in causation.
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There is indirect evidence that in utero exposure may account for at least a
portion of cases. Congenital rubella infection can cause -cell autoimmunity
in 70% and diabetes in up to 40% of children infected in utero, but not in
those infected postnatally (3136). The incubation period of T1D in congenital
rubella patients is 520 years, and persistent rubella virus infection of the
pancreas has been demonstrated. The infection can also trigger autoimmune
thyroiditis. Development of T1D in these patients is associated with the
HLA-DR3 and four alleles (32). A molecular mimicry has been reported
between a rubella virus protein and a 52-kDa pancreatic islet -cell autoantigen
(36).Disappearance of the syndrome and the small but associated number of
T1D cases following universal rubella vaccination have proven that T1D can
be prevented by modification of environmental factors.
A relationship between islet autoimmunity and enteroviral infection
exposure in utero has also been proposed (3739). Studies from both Finland
and Sweden indicate that maternal enterovirus infection increases the likelihood
of subsequent diabetes in the offspring (37,38). In the Finnish study, significant
increases in IgM antibodies to CBV5 and CBV5 procapsid enterovirus
antigens were noted in the sera of pregnant mothers whose offspring subsequently developed T1D. In the Swedish studies, case mothers had significantly greater frequency of insulin CBV3 IgM antibodies than those whose
offspring did not develop T1D. Molecular mimicry between the P2-C protein
of Coxsackie virus and the glutamic acid decarboxylase (GAD) protein (40)
has been proposed to account for the -cell autoimmunity. The presence
of antibodies against enteroviruses in people with autoimmunity does not,
however, prove a causal relationship. It should also be noted that the number
of women not exposed during pregnancy is increasing and that infection
in early childhood has become less common in the course of the century
(41). These considerations do not exclude arguments based on changing
antigenicity of viruses (or other environmental toxins or foods) or timing
of exposure to them. People with autoimmunity may also be more prone
to enteroviral infection, may have a stronger humoral response to infection
because of their particular HLA genetic susceptibility, or may be in a
non-specific hyperimmune state following exposure to various exogenous
antigens (41). Islet-related autoantibodies have also been detected after
mumps, rubella, measles, chickenpox, Coxsackie, and ECHO4 and rotavirus
infections (4245).
The hypothesis that there is an association between a protective effect
of breastfeeding and early exposure to cows milk on the incidence of
autoimmunity and T1D is controversial (1517, 4648). Gersons extensive
meta-analysis demonstrated a weak but significant association between T1D
and both a shortened period of breast-feeding and cows milk exposure
185
before 34 months of age (18). In both the Bio Breeding (BB) rat and NonObese Diabetic (NOD) mouse (animal models of T1D), diet plays an important
role in the development of T1D. Casein is the major protein fraction of cows
milk. Feeding semi-purified diets with simple sugars replacing complex carbohydrates and hydrolyzed casein as the protein source routinely retards the
development of diabetes (19,20). Karjalainen et al. (48) showed that antibodies
to bovine serum albumin (BSA) (immunologically distinct from human serum
albumin) were present in 100% of Finnish children with new-onset T1D,
but were absent in controls. The majority of these antibodies were directed
against a 17 amino acid fragment of BSA (ABBOS), to which peripheral
blood lymphocytes from T1D patients were subsequently shown to respond
by proliferation. Structural similarities between this ABBOS peptide and an
islet autoantigen protein ICA69 invoked the appealing pathogenic concept
of molecular mimicry, by which the early introduction of cows milk would
allow absorption of the intact protein before gut maturation, thus immunizing
the infant and directing an immune response to the islets through its ICA69
mimic (21). There is evidence countervailing each argument for the cows milk
hypothesis (17). The Diabetes Autoimmunity Study in the Young (DAISY)
has found no association between early exposure to cows milk and -cell
autoimmunity in young siblings and offspring of diabetes patients or when the
analyses were restricted to those with the highest risk HLA genotypes (16).
The accuracy and relevance of the dietary recall information from the higher
risk population may reflect bias (22).
Breast-feeding patterns do not reflect changes in the incidence of childhood
diabetes (23). There is little to suggest that this is, in any way, related to
changes in the incidence of childhood diabetes. Cows milk consumption (per
person per year) has been shown to be correlated with T1D incidence in some
countries but not in others. In Sardinia, with the second highest incidence rate
in Europe (after Finland), and where the incidence of T1D continues to rise,
cows milk consumption is less than half that in Finland (49). Most studies
examining infant feeding practices have looked at the first 36 months of life
and not at other later nutritional practices. Other studies have suggested an
association between an increased risk of diabetes and weaning foods, as well
as milk and dairy product consumption, and the ingestion of foods containing
nitrosamine in the 12 months before diagnosis. Atkinson et al. (15) were
unable to show any link between the presence of antibodies to BSA and
disease. Other studies in both childhood and adult-onset T1D patients have not
supported the utility of measuring BSA antibodies as a marker of the disease
either at diagnosis or in disease prediction (50). ICA69 are found in several
other organs besides pancreatic cells and are seemingly not exclusive to T1D.
The anticipated cross-reactivity of these antibodies with BSA has not been
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Stalvey and Schatz
confirmed. In the animal models, there is little or no effect of the feeding of

increased quantities of BSA or skim milk powder on diabetes frequencies.
That ingestion of nutrient-containing elements of plants such as soy and
wheat may have an effect on the development of diabetes is suggested by
studies of non-obese diabetic mice (51). In humans, two recent studies
DAISY and the German study of offspring of T1D parentsprovided evidence
that susceptibility to T1D is associated with the timing of exposure to cereal and
gluten (52,53). In DAISY, initial exposure to cereal between birth and 3 months
of age and after 7 months of age imparted risk of autoimmunity. In the German
study of offspring of T1D parents, Zeigler and colleagues (53) demonstrated
an increased risk for autoimmunity in infants initially exposed to gluten before
3 months of age and found no increased risk in infants whose initial exposure
was after 6 months of age. Although both studies provided interesting findings,
their conclusions are in some ways contradictory and demonstrate the need for
larger collaborative investigations to determine appropriately how early dietary
exposures affect risk for autoimmunity.
As previously noted, the highest incidence of T1D worldwide occurs in
Finland (now almost 50/100,000/year), which is more than three times that
in the USA. The incidence of the disease is related to distance north of the
equator. Sun exposure in northern Finland is extremely limited, and low serum
concentrations of vitamin D are common. Hypponen et al. (54) suggest that
ensuring adequate vitamin D supplementation for infants could help to reverse
the trend of increasing incidence of T1D. The investigators conducted a birth
cohort study of almost 11,000 infants in northern Finland who were followed
to age 1 year and concluded that dietary vitamin D supplementation (2000 IU
daily) was associated with a subsequent reduced risk of T1D when adjusted for
neonatal, anthropometric, and social characteristics. It has been proposed that
vitamin D compounds act as selective immunosuppressants as exemplified by
their ability to either prevent or markedly suppress development of autoimmune
disease in animal models. Vitamin D given to mice genetically at risk to develop
diabetes is also associated with a reduced risk of T1D (55). Vitamin D has
been shown to stimulate transforming growth factor (TGF)-1 and interleukin
(IL)-4, which may suppress inflammatory T-cell TH 1 activity (56). As T1D
in the NOD mouse appears to be a TH 1-mediated disease, altering the balance
toward TH 2 production may be protective. In addition, there is evidence for
a genetic link between Vitamin D and diabetes risk. A recent study showed
that a vitamin D receptor initiation codon polymorphism in exon 2 influences
genetic susceptibility to T1D among the Japanese (57). The number of incident
cases, however, was small and, therefore, the absolute magnitude of the effect
needs to be further assessed. Although a Norwegian study demonstrated that
children born to women who took cod liver oil during pregnancy had a reduced
187
risk of T1D, infants taking cod liver oil or other vitamin D supplements in the
first year of life did not have an altered risk of diabetes (58). The results of this
study are difficult to interpret, because vitamin D levels were not measured
nor was there accurate quantification of intake.
Toxic doses of nitrosamine compounds can also cause diabetes because of
the generation of free radicals (59,60). The effect of dietary nitrate, nitrite,
or nitrosamine exposure on human T1D risk is less clear (61,62). Several
perinatal risk factors for childhood diabetes are also associated with the
development of T1D (63). The effect of maternalchild blood group incompatibility is fairly strong (both ABO and Rh factor with ABO > Rh) and
needs to be further explored. Other perinatal factors conferring increased
risk include preeclampsia, neonatal respiratory distress, neonatal infections,
caesarian section, birth weight, gestational age, birth order, and maternal age
(6468). It will be important to determine whether these factors contribute and
how they may act or be confounded by other unknown risk factors. Rodent
studies indicated that administration of diphtheriatetanuspertussis vaccine
at 2 months of age increased the incidence of diabetes compared with those
unvaccinated or vaccinated at birth. Prospective studies in children, however,
show no association between early childhood immunizations and -cell autoimmunity (69,70).
Recently, it has been argued that the rising incidence of T1D could be
accounted for by protective factors in the environment that have been lost (71).
There has been a parallel rise of asthma and allergy. The hygiene hypothesis
proposes that early exposure to infective agents in early childhood is necessary
for maturation of the immune response. In the absence of such exposure, there
would be a failure of early immune regulation that might permit, depending on
genetic susceptibility, the development of autoimmunity TH 1 or allergy TH 2
(71,72). This view is consistent with the fact that the NOD mouse is less likely
to develop diabetes in the presence of pinworms and other infections (72).
Type 2 Diabetes
The first cases of childhood T2D were reported in Native Americans and
Canadian First Nation People in 1979 and 1984 (4). Before 1994, the percentage
of children in the USA and in other parts of the world diagnosed with T2D
comprised less than 5% of all cases. (4,73). Over a period of 20 years, the
prevalence of T2D increased sixfold for Pima Indian adolescents from a prevalence of 9/1000 in the 15- to 24-year age group in the 1970s to 51/1000 in the
15- to 19-year age group in the 1990s. In addition, a prevalence of 22/1000
was demonstrated in the 10- to 14-year age group in the 1990s, whereas this
age group had no T2D (4). Similar trends have been reported among other
populations in the USA. In a Cincinnati-based pediatric diabetes clinic, 24%
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Stalvey and Schatz
of newly diagnosed diabetes patients had T2D between 1982 and 1992, with
a sharp increase to 16% by 1994. During the period of 19902000 at the
Montifiore Medical Center in Bronx, NY, the number of patients <18 years
diagnosed with T2D increased 10-fold (74). In 1990, T2D accounted for 12%
of the newly diagnosed diabetes patients. By 2000, almost 50% of the newly
diagnosed patients had T2D (4). In the USA, T2D now accounts for 845%
of all pediatric diabetes, and its prevalence appears to be increasing (2,73).
Outside of the USA, similar trends in children and adults have been noted
in both the developed and the developing worlds, based on reports which
vary from public health surveys to clinic series and which include varying
definitions of T2D. In Japan, 80% of all new instances of diabetes in children
and adolescents are T2D (75), with a female predominance of 2:1 (4), and
the increasing incidence over the past 20 years has paralleled the increase in
obesity (76). This shift has occurred as the traditional Japanese diet has been
replaced by one in which more calories as animal fat and protein are being
consumed (77).
There appears to be a close relation between rates of T2D in adults and
the appearance of the disorder in adolescents. This pattern has been noted
in most geographic regions and ethnic and cultural groups that have been
studied. Adolescents from minority groups in the USA (Pima Indians, African
Americans, and Hispanic Americans), Canada (First Nations people), Australia
(Aboriginal), and New Zealand (Maori) have a disproportionately high prevalence of T2D (4,7880). For example, in the Maori population between 1997
and 1999, T2D accounted for 12% of new cases of diabetes. This percentage
rose to almost 36% in 2001 (81). Similar trends are seen in both immigrants
and their offspring where analyses of social trends suggest that adoption of a
Western lifestyle is strongly associated with T2D in these populations (79).
These studies suggest that minority populations and immigrants have increased
rates of obesity. Asian-American and Hispanic adolescents born and raised in
the USA are more than twice as likely to be obese as those in their native
lands.
The rising incidence of T2D in children is closely linked to the obesity
explosion in the general population and, specifically, among children (Fig. 1).
Over the past 10 years especially, there has been an obesity explosion in
the Asia-Pacific region, Europe, and the USA in both adults and children,
paralleling the increasing incidence of T2D (82). Obesity is now the most
common nutritional disease of children and adolescents in the USA (83). In
2002, the US prevalence of overweight [body mass index (BMI) >25 in 2002]
was a staggering 66%. Obesity defined as BMI > 30% occurred in 30.5%
and extreme obesity (BMI > 40.0) in 5.1%. (84). Overweight children were
over four times more likely to be overweight adults than were normal weight
189
children (85). Obese adults beget obese children. If a child has two non-obese
parents, there is an 8% chance of adult obesity, whereas a 10- to 14-year-old
child has a 79% chance of obesity if at least one parent is obese (86).
Worldwide, the incidence of obesity continues to increase, reaching
pandemic proportions with more than a billion people affected (8790). As
previously discussed, developing countries have not been spared. The AsiaPacific subcontinent includes perhaps the largest populations of diabetes in the
world. Greater than 12% of Indians have diabetes and another approximately
14% demonstrate glucose intolerance (91). The incidence of diabetes in adults
continues to grow at an alarming rate, and by 2025, China is expected to
show an increase in incidence of up to 68%, followed closely by India with
59%, and the other Asian countries and the Pacific Islands (41%). These data
have implications for screening programs among youngsters and for public
obesity prevention programs. The thrifty genotype hypothesis, i.e. evolutionary
selection of individuals able to survive through periods of famine by enhanced
energy storage capabilities when food was obtainable, coupled with continuous
availability of food, explains this observed rising incidence of T2D in developing countries.
In the industrialized world, urbanization, easy access to motor vehicles,
and availability of school busing, have led to most children and adolescents
walking or cycling less than a few blocks to school or work after school. The
discontinuation of physical education (PE) in schools and the lack of time spent
in outside play by children have produced a generation of children accustomed
to a more sedentary lifestyle. Concerns for safety have resulted in reduced
neighborhood play, which has been replaced by television, video games, and
other computer activity. Nesmith noted that participation in school-based PE
decreased from 41.6% of students in 1991 to 24.5% in 1995. In addition, only
50% of the US children and adolescents aged 1221 years reported regular
vigorous physical activity and 25% reported no physical activity at all (92).
Proctor et al. have shown that time spent watching television is an independent
predictor of childhood BMI and skinfold thickness. BMI of early adolescent
children watching >3 h of television averaged 20.9 versus 18.6 kg/m2 for those
watching <1.75 h/day. The sum of five skinfolds for children who watch >3.0
h of television was 106 mm compared with 88 mm for children watching
less than 1.75 h/day (93). Gortmaker et al. (94) reported that children who
watched more than 5 h of television per day were five times more likely to be
overweight. In addition, the availability and low cost of fast foods contributes
to obesity. Pereira et al. (95) have shown on a positive association of body
weight and insulin resistance in individuals who consume fast food in excess
of two times per week. Children who buy school lunches have an increased
risk of being overweight (96).
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TACKLING THE PROBLEMS

Type 1 Diabetes
To prevent T1D, we must enhance our understanding of the mechanisms
leading to autoimmune-mediated -cell failure. These include the identification of potential environmental triggers and a better understanding of the
deviant interaction of genes, the environment, and the immune system, which
culminates in clinical disease. The ongoing NIH-funded The Environmental
Determinants of Type 1 Diabetes in Youth (TEDDY) study seeks to identify
infectious, dietary, or other environmental exposures and psychological factors
that trigger or prevent T1D in genetically susceptible individuals. From birth,
high-risk children from the general population and relatives of people with T1D
will be tested for exposures to candidate environmental factors. Over 200,000
newborn babies will be screened by six centers in the USA (Florida/Georgia,
Colorado, Washington state), Finland, Sweden, and Germany.
The unraveling of the natural history of pre-T1D, which has allowed for the
identification of at-risk individuals both by genetic and by islet autoantibody
testing of both high- and low-risk general populations, affords opportunities to
intervene at varying time points in the prediabetic period (Fig. 3)
Over the past decade, well-designed, randomized, controlled clinical trials
aimed at preventing T1D have been implemented. Although major transcontinental efforts (Diabetes Prevention Trial conducted in the USA and Canada)
and the European Nicotinamide Diabetes Intervention Trial were unsuccessful
in preventing T1D, both studies added significantly to our understanding of the
natural history of pre-T1D and generated collaborative interactions across and
GENETICALLY AT RISK
AUTOANTIBODY POSITIVE
BETA CELL MASS
LOSS OF FIRST PHASE

INSULIN RESPONSE
IMPAIRED GLUCOSE
TOLERANCE
GENETIC
PREDISPOSITION
INSULITIS
BETA CELL INJURY
PREDIABETES
DIABETES
TIME
CLINICAL DIABETES
Fig. 3. Natural history of Type 1 diabetes and opportunities for prevention.
191
between continents. The creation of multicenter cooperative groups (akin to

the childhood cancer collaborative centers) is vital to enable the simultaneous
testing of primary and secondary prevention strategies in different population
groups at different stages of the disease process. Studies are ongoing as part
of the NIH-funded TrialNet and Immune Tolerance Networks.
Type 2 Diabetes
Opportunities in preventing the occurrence of T2D are shown in Fig. 4.
Although there have been few metabolic studies in pre- and early T2D in
youth, it is likely that a similar disease process occurs as in adults with both
impaired insulin resistance and -cell failure occurring early (97).
Risk Factors
family history
high risk ethnic groups
gestational diabetes
early failure to thrive
PCOS
acanthosis nigricans
dyslipidemia
hypertension
Genetic
Predisposition
Obesity
Insulin
Resistance
Beta Cell
Dysfunction
IGT
Metabolic
Syndrome
Type 2
Diabetes
Diabetic
Complications
Nephropathy
Neuropathy
Retinopathy
Heart Disease
Fig. 4. Natural history of Type 2 diabetes in children and adolescents. Enhanced knowledge
of the natural history of the disease in children and adolescents affords multiple opportunities to potentially intervene prior to onset.
192
Stalvey and Schatz
Identifying and eliminating, or at least modifying, risk factors will be necessary

to reduce the disease frequency. Curbing the obesity epidemic is essential to
decreasing the T2D explosion as well as preventing early hyperlipidemia,
hypertension, and cardiovascular disease. Obesity and increased waist circumference in prepubertal children is associated with subsequent hyperlipidemia
and hypertension, impaired glucose tolerance, and T2D (98). Up to a third
of youth with T2D also have hypertension and hypertriglyceridemia (99), and
mico-albuminuria has been reported in 1422% of cases (80,100).
Substantial resources must be directed globally to effect lifestyle changes.
Communities, schools, and individuals must all be targeted. The challenges are
enormous in contemporary society where daily physical activity opportunities
are limited for our youth, entertainment is more sedentary than physically
challenging, labor-saving devices abound and high-fat, high-energy calorie
dense foods are cheap, ubiquitous, and heavily promoted.
Efforts at treating childhood obesity have been generally disappointing.
Other risk factors for T2D in youth include a strong family history of
T2D, visceral adiposity (an independent risk factor), acanthosis nigricans,
ethnicity (minority ethnic and immigrant populations), polycystic ovarian
disease, offspring of mothers with gestational pregnancy, and intrauterine
growth retardation. Because early identification and treatment of the disease
and comorbidities have been shown to prevent the development or progression
of complications, criteria for testing children and youth at risk for developing
T2D have been developed (Table 2) (101).
Individuals with IGT (defined as a fasting glucose >100, but <126 mg/dL,
and/or a 2-h postprandial glucose >140, but <200 mg/dL) should be targeted
for intervention. A recent report by Duncan (102) estimated the frequency
of impaired fasting glucose (IFG defined as BG > 100 mg/dl) to be about
11% in a tested subsample of 4370 youth aged 1219 years in the National
Health and Nutrition Examination Survey (NHANES). This is a substantial
percentage of such a young population to have IFG, especially considering
that the fasting serum glucose concentration rises later than does postprandial
glycemia in the evolution of T2D. Importantly, as in adults, IFG correlates
with subsequent progression to T2D and should trigger close attention to blood
pressure measurement and testing of lipids. Studies in adults with impaired
glucose tolerance indicate that lifestyle change (weight loss and increased
physical activity) is effective in decreasing progression to T2D over periods of
56 years (103105). Although these studies were conducted in self-selected
volunteers who were likely motivated to make lifestyle changes, there is reason
to anticipate that motivated youth might have a similar positive outcome to a
comprehensive intervention combining diet and physical activity changes. The
goal of the multicenter National Institute of Diabetes and Digestive and Kidney
193
Table 2
ADA Recommendations for Testing for Type 2 Diabetes in Children
Criteria*
Overweight (Body Mass Index of 85th percentile for age and sex, weight for
height 85th percentile, or weight 120% of ideal for height)
Plus any two of the following risk factors:
Family history of T2D in first- or second-degree relative
Race/ethnicity (American Indian, African-American, Hispanic, Asian/Pacific
Islander)
Signs of insulin resistance or conditions associated with insulin resistance
(acanthosis nigricans, hypertension, dyslipidemia, PCOS)
Initiation of screening: age 10 years or at onset of puberty if puberty occurs at a
younger age
Frequency of screening: every 2 years
Screening Method: fasting plasma glucose preferred
*Clinical judgment should be used to test for diabetes in high-risk patients who do not meet
these criteria.
Adapted from American Diabetes Association, Diabetes Care 2000, published with
permission (101).
Diseases (NIDDK) -funded Studies to Treat or Prevent Pediatric (STOPP)

T2D primary prevention protocol is to implement a population-based intervention in middle school children to prevent or decrease the development
of risk factors for T2D. The primary objective is to moderate risk factors
of adiposity and glycemic dysregulation, specifically decreasing BMI (>85th
percentile), IFG, and fasting insulin (30 U/ml). The study will involve
changes in the nutritional quality of food and beverage offerings throughout the
school, changes in the PE program, classroom activities designed to increase
knowledge and decision making skills, individual and group behavior change
initiatives aimed at enhancing healthier behaviors, family outreach activities
to involve parents/guardians, and school-wide communications to enhance
and promote changes in nutrition, activity, and behavior. The small Bienestar
population-based lifestyle intervention study suggested that risk factors for
T2D in children could be ameliorated. Twenty-seven elementary schools in San
Antonio, Texas, were provided with a multi-faceted health program to Mexican
American fourth graders (106). Mean fasting blood glucose was statistically
lower for children in the intervention schools compared with those in the
control schools. Other school-based programs in the USA and Singapore have
been shown to be effective (74). Rocchini et al. (107), in a study of 50 obese
adolescents, demonstrated weight loss, blood pressure, and improved insulin
sensitivity with lifestyle modification. Robinson studied 192 children who were
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randomized to reduce television viewing and video game play from 12 h per
week to 8 h per week. A decrease in both BMI and waist circumference was
observed over the 6 months of the study (108).
The avoidance of smoking in adolescents should not be forgotten because
smoking at any age, independently of obesity, is associated with greatly
increased risks of atherosclerosis, even in modest amounts (109).
CONCLUSION
Epidemics of both T1D and T2D in children and adolescents, beginning
about mid-twentieth century and in the last decade of the twentieth century,
respectively, are now evident. We must continue the pursuit of the epidemiologic and pathogenetic factors contributing to the increasing numbers of T1D,
while also turning our focus to altering the recognized environmental factors
predisposing to T2D. The obstacles to the latter effort are enormous in contemporary society. We must also continue to pursue the molecular understanding
of both T1D and T2D. It is to be hoped that the recognition of this public health
explosion will lead to an all-encompassing effort involving greatly augmented
government, research, community, and individual commitments to prevent
these disorders. The costs will be insignificant compared with the potential for
prevention.
ACKNOWLEDGMENTS
We thank Dr. Arlan Rosenbloom for his critical comments and editorial
assistance. Supported in part by grants U01 DK 60987-01, UO1DK60987-03,
and 2MO1RR0082 from the National Institute of Health.
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11
Weight Loss in Type 2 Diabetic

Patients
Is it Worth the Effort?
Rena R. Wing, PhD,

Heather M. Niemeier, PhD,
and Angela Marinilli Pinto,
PhD
CONTENTS
Lifestyle Intervention
Is Weight Loss Worth The Effort?
Are There Adverse Psychological Effects
of Weight Loss?
Does Anyone Succeed at Long-Term
Weight Loss?
What Diet Strategies Optimize Weight Loss
and Weight Loss Maintenance?
What Physical Activity Strategies
Optimize Weight Loss and Maintenance?
How Can Effective Strategies be
Disseminated to More People?
Conclusion
References
Summary
This chapter reviews the evidence regarding the role of weight loss in the
prevention and treatment of type 2 diabetes. Strategies to improve adherence
to diet and physical activity interventions that have been shown to be most
effective for individuals with type 2 diabetes are also reviewed. Evidence
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for the role of lifestyle changes in successful long-term weight loss maintenance is provided. Lastly, recent efforts to disseminate successful weight
loss interventions are described.
Key Words: weight loss, weight loss maintenance, dietary intervention,
physical activity, type 2 diabetes
LIFESTYLE INTERVENTION
It is well accepted that obesity and a sedentary lifestyle are related to the
development of type 2 diabetes. With the rapid increase in obesity over the
last few decades, a consequent increase in the rates of diabetes has already
been noted and is expected to worsen. The epidemic rates of obesity have
heightened interest in efforts to prevent obesity through interventions in young
children and public health approaches, such as development of walking paths
and taxation of junk foods. Although such efforts are important, they are
fueled in part by the belief that once a person becomes overweight, there is
no chance of recovery. The purpose of this chapter is to present evidence to
the contraryshowing that successful weight loss is indeed possible and that
lifestyle intervention can play an important role in the prevention and treatment
of diabetes. In addition, the chapter will address specific issues being debated
in the field, related to the type of diet and the level of physical activity that
should be prescribed for weight loss, whether behavioral weight loss programs
have adverse effects, and current efforts to effectively disseminate lifestyle
interventions to increase their accessibility.
IS WEIGHT LOSS WORTH THE EFFORT?

Weight Loss and the Prevention of Diabetes
Probably the strongest evidence for the benefits of lifestyle intervention
come from several large randomized controlled trials demonstrating convincingly that lifestyle intervention reduces the risk of developing type 2 diabetes.
Of particular note is the Diabetes Prevention Program (1) conducted in 27
clinical centers in the USA. This study involved 3234 overweight individuals
(BMI > 24 kg/m2 ; BMI >22 kg/m2 in Asian Americans) with impaired glucose
tolerance. Participants averaged 51 years of age: 68% were women and 45%
were members of minority groups. These participants were randomly assigned
to receive either intensive lifestyle intervention or standard lifestyle intervention combined with Metformin (850 mg twice daily) or placebo. The
intensive lifestyle intervention involved 16 individual sessions over 24 weeks
followed by a contact at least every 2 months (typically once a month)
throughout the trial. The goals of the lifestyle intervention were to lose 7%
Weight Loss in Type 2 Diabetic Patients
203
of initial body weight, maintain this weight loss, and achieve at least 150
min/week of physical activity using activities that were similar in intensity
to brisk walking. Physical activity was considered important for preventing
diabetes in its own right and also for improving weight loss and maintenance.
The findings from Diabetes Prevention Program (DPP) were very dramatic,
and thus the trial was stopped early, after an average follow-up of 2.8 years.
The lifestyle intervention used in DPP was effective in producing weight loss
and increased physical activity, both short and long term. Fifty percent of
lifestyle participants achieved the 7% weight loss goal at week 24, and 38%
achieved this goal at study end. Using self-reported diary data, 74% met the
physical activity goal at 24 weeks and 58% at the final visit.
The intervention was extremely effective in reducing the risk of diabetes.
The crude incidence of diabetes was 11.0, 7.8, and 4.8 cases per 100-person
year for placebo, metformin, and lifestyle, respectively. Thus, lifestyle intervention reduced the risk of diabetes by 58% compared with placebo, and
metformin reduced the risk by 31%. Moreover, lifestyle intervention was
effective in all age, gender, and ethnic subgroups.
Similar results were obtained in two other large trials. In the Finnish Diabetes
Prevention Study (2), lifestyle intervention also reduced risk of diabetes by
58% compared with the control group. The Da Quing Study (3) demonstrated
that diet, exercise, and the combination reduced the risk of diabetes by 3136%,
with no significant difference among these behavioral approaches.
With the exception of the Da Quing Study, the lifestyle intervention used in
these studies combined weight loss and physical activity, and thus it is difficult
to reach conclusions about the independent effects of each of these behavior
changes on diabetes risk. In a re-analysis of the DPP lifestyle intervention, it
has been shown that weight loss was the dominant determinant of the reduction
in disease risk (4). Although changes in diet and physical activity predicted
weight loss, these behavior changes had no independent effect on diabetes risk
in the entire DPP lifestyle cohort. For the lifestyle cohort as a whole, for each
kilogram of weight loss, there was a 16% reduction in diabetes risk. However,
in those who did not meet the weight loss goal, physical activity did have a
beneficial effect.
Thus, one effect of weight loss that suggests that it is indeed worth the effort
is the reduction of the risk of diabetes. However, this immediately raises the
question of the cost of providing such an intensive intervention. In the DPP,
investigators conducted an economic evaluation of the lifestyle and metformin
intervention from perspectives of the payer and society (5). From a societal
perspective, the lifestyle intervention implemented in DPP costs $24,000 per
case of the disease prevented and the metformin intervention costs $34,500.
From a payer perspective, the costs were $15,700 and $31,300 for lifestyle
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and metformin, respectively. Thus, the lifestyle intervention was more cost
effective than metformin. Ways of further reducing the costs of the lifestyle
intervention, for example, by using group treatment rather than individual case
management deserve further attention.
Weight Loss and Glycemic Control and Cardiovascular

Disease Risk Factors
In a chapter on evidence-based diabetes care, Wing (6) reviewed research
testing the effects of different types of weight loss intervention on glycemic
control. The conclusion was that with larger weight losses, achieved by behavioral programs, medication, or surgery, there was a clear long-term benefit
of weight loss on glycemic control; more modest weight loss produced more
variable outcomes.
The strongest evidence of a long-term benefit for individuals with type 2
diabetes comes from studies using gastrointestinal surgery. In the Swedish
Obesity Study (SOS), for example, diabetic patients who underwent surgery
for their obesity (typically vertical banded gastroplasty) had a relative risk of
recovery from diabetes (reducing glucose to <120 mg/dl with no drugs) of
3.7 compared with control subjects (7). The effect of weight loss on recovery
from diabetes was stronger than the effect on recovery from hypertension,
hypertriglyceridemia, or hypercholesterolemia.
Weight loss medications have also been shown to be beneficial for
individuals with diabetes. Orlistat (Xenical), a lipase inhibitor, was tested in
yearlong trials with type 2 diabetic patients on metformin, sulfonylureas, and
insulin (810). In each trial, Orlistat produced better weight losses than placebo
and consequently greater improvements in glycemic control. The effect of
Orlistat on glycemic control was directly related to improved weight loss.
However, Orlistat also improved serum lipid levels; at any given level of weight
loss, the improvements in lipids were greater on Orlistat than on placebo.
Likewise, Sibutramine (Meridia), which is a serotonin and norepinephrine
reuptake inhibitor, improves weight loss relative to placebo in diabetic and
non-diabetic individuals. For example, in a 1-year trial of 195 subjects with
type 2 diabetes treated with metformin, weight losses were 5.5, 8.0, and 0.2 kg
for patients treated with 15 mg Sibutramine, 20 mg Sibutramine, and placebo,
respectively (11). Glycemic control improved with this weight loss; subjects
who lost 10% of their body weight (which occurred in 15% of patients on
15 mg of Sibutramine and 27% of those on 20 mg of Sibutramine, but 0% on
placebo) had a 1.2% decrease in HbA1c. Again, the improvement in glycemic
control was directly related to the weight loss achieved. In contrast to these
positive changes, Sibutramine has been associated with increased pulse rate
and blood pressure.
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Finally, there are many lifestyle intervention studies showing that dietary
changes, physical activity, and their combination can result in improved
glycemic control and cardiovascular disease (CVD)-risk factors in individuals
with diabetes. Wing and colleagues (6) have conducted a large number of
studies on this topic. Based on 114 overweight type 2 diabetic patients followed
for 1 year, they concluded that modest weight losses (>6.9 kg) resulted in longterm improvements in HbA1, fasting glucose, insulin, high-density lipoprotein
(HDL)-cholesterol, and triglycerides (12). A doseresponse relationship was
observed between the magnitude of weight loss and the improvements in
these risk factors. In addition, the short-term effects of weight loss were more
dramatic than the long-term effects. However, the fact that even modest weight
losses can be beneficial for at least 1 year is an important positive message to
convey to patients attempting to lose weight.
Does Weight Loss Reduce CVD or All-Cause Mortality

in Individuals with Type 2 Diabetes?
As described above, there are a large number of clinical studies suggesting
that weight loss improves CVD risk factors and glycemic control. However,
most of these studies are short term. To date, no long-term trials have
been conducted evaluating the effects of weight loss on hard end points,
notably CVD or death. Several observational studies have raised concerns
about possible adverse effects of weight loss on cardiovascular and all-cause
mortality. In these studies, individuals with or without diabetes are followed
over time, and those who lose weight are compared with those who remain
weight stable (or gain) on the subsequent risk of mortality over an extended
follow-up. In a review of six observational studies of the effect of weight loss
in type 2 diabetic individuals (13), two studies found that weight loss was
associated with decreased mortality, one with increased mortality, one showed
no association, and in two the results differed by subgroup. A major concern
in these studies is that intentional weight loss cannot be distinguished from
unintentional weight loss. More recent studies have tried to distinguish intentional and unintentional weight loss. In a recent study (14), intentional weight
loss in individuals with diabetes was associated with 23% lower mortality rate
compared with those not reporting trying to lose weight, whereas unintentional
weight loss was associated with a 58% higher mortality rate. Another study
(15) of over 4000 men aged 5675 years suggested that even intentional weight
loss carried out because of a physicians advice or ill health (including the
diagnosis of diabetes) was associated with increased mortality; in this study,
only intentional weight loss for personal reasons was beneficial.
In contrast, an historical prospective study of intentional weight loss in
336 overweight individuals with at least one CVD-risk factor (16) found that
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those who underwent at least 6 months of dietary counseling and lost at least
4.5 kg had a risk factor adjusted odds ratio for coronary heart disease (CHD)
incidence, over 4 years of follow-up, of only 0.57 (CI = 0.390.84). In the
group of individuals with diabetes (n = 282), the odds ratio for CHD in those
losing 4.5 kg was also 0.57 (CI = 0.291.14).
Unfortunately, none of these studies can provide a definitive answer to the
question of the long-term health effects of weight loss, as none utilized a
randomized clinical trial design in which some participants are randomized
to lose weight and others (of comparable baseline characteristics) are not
provided with weight loss intervention. Such a randomized controlled trial is
currently underway. This study, entitled Look AHEAD (Action for Health in
Diabetes), is assessing the long-term effects (up to 11.5 years) of an intensive
weight loss program in over 5000 overweight and obese individuals with type
2 diabetes (17). Participants are randomly assigned to the lifestyle intervention
or to a control condition that is given diabetic education and support. The
primary outcome measure is time to incidence of a major CVD event. Other
outcomes, including CVD risk, cost and cost effectiveness, diabetes control
and complications, and hospitalizations, are also being assessed.
In answer to the question of whether weight loss is worth the effort, the
answer is YES. Weight loss has been found to improve several health parameters including decreasing the risk of diabetes, improving glycemic control,
and improving CVD risk factors. Its effect on CVD and mortality needs further
study; however, evidence to date suggests that weight loss should definitely
be recommended for overweight individuals.
ARE THERE ADVERSE PSYCHOLOGICAL EFFECTS

OF WEIGHT LOSS?
Questions have been raised regarding whether behavioral weight loss treatments, with their focus on regular weighing and dietary restriction, may lead
to or exacerbate eating disorders in participants. This concern is largely based
on the cognitive behavioral theory of the development of bulimia nervosa
and binge eating disorder (BED) which theorizes that strict dietary restriction
leads to binge eating. A recent study by Wadden et al. (18) addressed this
question. These investigators recruited 123 overweight women who did not
display disordered eating and randomly assigned them to a weight loss program
using 1000 kcal/day diet with meal replacement products (MRs), a 12001500
kcal/day conventional food diet, or a non-dieting approach. They found no
differences among the groups in the number of women who reported binge
eating episodes, and no participant in the study met criteria for BED at any time
during the study. There were also no differences among the groups on their
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reported level of hunger or disinhibition (a measure of thoughts, feelings, and

behaviors associated with loss of control and binge eating). Thus, the authors
concluded that behavioral weight loss does not contribute to the development
of binge eating in participants who do not display it before entering treatment.
Another approach to this question is to examine whether individuals with
eating disorders who undergo behavioral weight loss treatment experience an
exacerbation of their symptoms. BED, characterized by episodes of overeating
and feelings of loss of control without compensatory behaviors (such as
vomiting or laxative use), is prevalent among individuals seeking behavioral
weight loss; rates of BED range from 510% in such treatment-seeking populations (19). Several studies have shown that behavioral weight loss treatment
actually ameliorates binge eating in participants meeting criteria for BED
before treatment (20,21). Porzelius et al. (21)compared a standard behavioral
weight loss program to a program modified to specifically address binge eating
problems and found that both treatments significantly reduced binge eating at
both posttreatment and follow-up with no differences between the groups. Not
only do participants with BED experience a decrease in binge eating following
behavioral weight loss, but they also have been shown to lose as much weight
as non-BED participants in such programs (2224).
Therefore, from available evidence to date, a focus on weight loss through
dietary restriction in the context of behavioral weight loss programs does
not appear to create or exacerbate eating disorders in obese populations.
Conversely, such programs have been found to actively decrease binge eating
and also produce weight loss in participants with a diagnosis of BED. These
findings led the National Task Force on the Prevention and Treatment of
Obesity to recommend moderate caloric restriction and increased physical
activity for overweight and obese individuals regardless of binge status (25).
DOES ANYONE SUCCEED AT LONG-TERM WEIGHT LOSS?

Prevalence of Successful Weight Loss Maintenance
Another controversy facing the weight loss field is whether long-term weight
loss maintenance is even possible. There is tremendous pessimism regarding
the issue of successful long-term weight loss, but this belief does not appear to
be justified. Data showing the lack of success typically come from weight loss
treatment studies, where a group of participants are followed through one weight
loss effort. Such data may underestimate the prevalence of success, because it
may require several attempts before success is achieved. In addition, individuals
who join such weight loss programs may have more difficulty with weight loss
and maintenance than the general population of overweight individuals.
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Population-based studies suggest that approximately 20% of overweight

individuals will succeed in losing weight and maintaining it. McGuire surveyed
500 US adults regarding their lifelong weight history (26). Of those who were
overweight (BMI 27) at some point in their life (n = 228), 20.6% had lost at
least 10% of their weight and maintained it at least 1 year. In a re-analysis of
data reported by Moore (27), Phelan and Wing (28) found that 57% of healthy
overweight individuals who lost at least 1.8 kg over a 4-year period sustained a
1.8 kg loss over the next 4 years. Thus, there may be greater levels of success
than often recognized.
Another point to consider is that weight loss, even if followed by regain, may
help ameliorate the development of obesity observed during middle age. Using
data from the Nurses Health Study, Field et al. (29) found that women who
lost >10% of their body weight between 1989 and 1991 subsequently gained
more weight between 1991 and 1995 than those who had initially remained
weight stable. Despite their greater regain, however, these women were far
more successful overall (19891995). Thus, for example, women with a BMI
of 2529.9 (n = 9229) who initially lost >10% had a median weight reduction
of 10.0 kg in 19891991, followed by a median weight regain of 10.9 kg
and overall experienced no weight change. In contrast, those who did not lose
>10% experienced a 2.3 kg gain from 19891991, a further 4.5 kg gain from
19911995, and overall a 6.8 kg gain. This weight gain would increase these
womens risk of developing diabetes and CVD (30,31).
The National Weight Control Registry

In an effort to learn more about successful weight loss maintenance, Hill
and Wing established the National Weight Control Registry (NWCR) in 1994.
The registry enrolls individuals who are over 18 years of age and who report
having lost at least 30 pounds and kept it off at least 1 year (32). The NWCR
has received extensive media coverage, and individuals who read about the
registry are invited to enroll. Thus, the NWCR is a self-selected population
of successful weight losers; findings from the registry cannot be assumed to
generalize to the broader population of successful weight losers. However, the
self-reported weights of NWCR members have been shown to be very accurate
(33), and a population-based study of successful weight losers confirmed that
the behaviors reported by registry members are also observed in the general
population of successful weight losers (34).
Participants in the registry complete a variety of questionnaires when they
enroll and are then followed annually. At present, there are approximately
5000 individuals in the registry. The NWCR members are 77% women, 82%
are college educated, 95% are Caucasian, and 64% are married; average age is
46.8 years. These participants report having lost an average of 33 kg, reducing
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from a BMI of 36.7 kg/m2 to 25.1 kg/m2 . They have maintained a weight
loss of at least 30 lbs for an average of 5.7 years; 13% have maintained the
weight loss for at least 10 years. Thus by any criterion one would use, these
individuals are clearly successful.
Participants in the registry report that they lost their weight in different
ways. About one-third of the participants report that they lost weight on their
ownwithout help from a commercial program, dietician, or physician. Others
did it through commercial programs or working with a dietician or physician.
The common theme in how they lost their weight was that over 90% used both
diet and exercise to accomplish their weight reduction.
Registry members report that their successful weight loss came after many
previous unsuccessful attempts (35). This is an important message for clinicians
and for those attempting weight loss; it is reminiscent of the smoking cessation
literature, which suggests that many attempts are needed before a person
is successful. The fact that an individual is initially unsuccessful and later
becomes successful suggests that the difference between success and lack of
success is not due to differences in metabolism or psychological factors. Rather,
the same person is at one point unsuccessful and then subsequently becomes
successful. When asked what distinguished this successful weight loss from
prior unsuccessful attempts, registry members note that this time they were
more committed, they dieted more strictly, and exercise was a greater part
of their approach.
Although there is great variety in how registry members lost weight, there
appears to be certain common themes regarding the strategies used for maintenance. These include following a low-calorie, low-fat diet, maintaining high
levels of physical activity, and remaining vigilant about their weight (32). As a
whole, findings from population-based studies of successful weight loss among
overweight individuals and the registry suggest that it is indeed possible for
people to maintain weight loss long term.
Successful Weight Loss in Individuals with Diabetes

Data from the NWCR indicate that individuals with diabetes can indeed
be successful weight losers. Approximately 7.5% of members of the NWCR
report that prior to their weight loss they had been diagnosed with diabetes. Of
these, 93% report that their diabetes has improved, and 73% report that they
do not currently need medication to control their blood glucose.
However, it appears that it may be more difficult for individuals with
type 2 diabetes to lose weight than those without diabetes, and individuals
with diabetes may be more likely to regain their weight. In one study, 12
diabetic patients and their non-diabetic spouses were enrolled together in a
behavioral weight loss program. Although patients and spouses were of similar
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age and weight, those with diabetes lost only 7.5 kg over 20 weeks, whereas
their non-diabetic spouses lost 13.4 kg (36). In another comparison of 20
women with type 2 diabetes and 23 non-diabetic women treated together in a
16-week behavioral weight loss program, initial weight losses were comparable
(7.4 and 6.4 kg for diabetic and non-diabetic subjects, respectively), but at
1-year follow-up, those with diabetes maintained a weight loss of 2 kg, whereas
the non-diabetics retained a weight loss of 5.4 kg (37).
The same phenomenon has been observed in studies with weight loss
medications. In both within and between study comparisons, individuals with
diabetes have smaller weight losses than those without diabetes, and this
difference occurs in participants treated with the weight loss medication and
in those on placebo (38,39).
There are several reasons why individuals with diabetes may be less
successful at weight loss. As glycemic control improves with weight loss,
individuals with diabetes may have decreased excretion of calories in their
urine, thereby reducing their weight loss. As diabetics in poor glycemic
control have more elevated energy expenditure, this too may normalize with
weight loss and improved glycemic control. Physical problems associated
with diabetes, including neuropathy, may limit physical activity. There may
also be psychological reasons for poorer weight loss, including a longer
history of failure to lose weight, and perhaps more frequent occurrence of
depressive symptomatology. Finally, many of the medications used to improve
glycemic control, including sulfonylureas, thiazolidinediones, and insulin,
enhance anabolism and promote weight gain. As all of these factors may
make weight loss more difficult, more intensive approaches may be needed to
produce weight loss in individuals with diabetes. However, even individuals
with diabetes can indeed lose weight successfully.
WHAT DIET STRATEGIES OPTIMIZE WEIGHT LOSS

AND WEIGHT LOSS MAINTENANCE?
Evidence regarding the optimal dietary and physical activity prescriptions
for weight loss and weight loss maintenance comes from both the strategies
successfully used by registry members and randomized clinical trials testing
different approaches.
Dietary Intake in Registry Members

Registry members complete the Block Food Frequency Questionnaire (40)
indicating their dietary intake at the time of entering the registry when they are
maintaining their successful weight loss. The majority of participants report
a low-calorie, low-fat eating style. However, there has been some change
211
in the diet over the 10 years of the registry. In 1994, when the diet of the
first 784 members of the registry was assessed, the mean caloric intake was
1381 kcal/day, with 24% of calories coming from fat (35). As dietary reports
typically underestimate actual intake by 2030%, we assume that registry
members were eating closer to 1800 kcal/day. We have recently looked
again at the dietary intake of successful weight losers recruited in 2003. The
average caloric intake has remained fairly constant over time. However, the
percent of calories from fat has increased to 29.4%. This change may be due
to the popularity of the Atkins diet and other low-carbohydrate diets during
recent years.
Regular consumption of breakfast appears to be another characteristic of
successful weight losers (41). Only 4% of registry members indicate that they
never eat breakfast, whereas 78% state that they eat breakfast every day of the
week. The typical breakfast seems to be a meal of cereal and fruit.
Raynor et al. (42) recently reported on dietary variety in registry members.
Prior studies have suggested that the degree of variety in the diet is correlated
with BMI; those with lower BMI report less dietary variety, especially in highfat-dense foods (sweets and snacks) and greater variety in low-fat-dense foods
(vegetables). Moreover, during a behavioral weight loss program, participants
report a decrease in the amount of variety in high-fat-dense food categories
and an increase in the variety of fruits and vegetables. Thus, we expected
this pattern to be seen in registry members. Interestingly, however, registry
members reported low variety in all categories of foods including both high-fat
and low-fat-dense foods. As overall dietary variety was correlated with caloric
intake, it appears that registry members may reduce the variety in all categories
of their diet as a means to reduce overall intake.
Low-Fat Versus Low-Carbohydrate Diets

for Individuals with Diabetes
The diet consumed by members of the NWCR is quite similar to the diet
typically recommended for weight loss, namely a high-carbohydrate, low-fat,
energy-restricted diet (43). Such diets usually recommend that no more than
2030% of calories come from fat. These diets are consistent with governmental recommendations described in the Food Guide Pyramid (44) as well
as recommendations of many research and medical societies, including the
American Heart Association (45) and the American Diabetes Association (46).
A low-fat diet is the most commonly used in behavioral weight loss interventions (47), and therefore several randomized controlled trials have evaluated
outcomes of this approach. Low-fat, energy-restricted diets, when prescribed
in combination with standard behavioral interventions, achieve an average of
10.4 kg of weight loss at 6 months with an 8.1 kg weight loss being maintained
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by 18 months (43). In studies with individuals with type 2 diabetes, average

weight losses tend to be slightly lower. For example, Pascale et al. (48) reported
an average weight loss of 7.7 kg at 16 weeks in women with type 2 diabetes
following a calorie-restricted and fat-restricted diet, and at 1-year follow-up,
participants had maintained an average of 5.2 kg of weight loss. As noted
above, low-fat, energy-restricted diets combined with lifestyle intervention
have been shown to lead not only to weight loss but also to decreased risk
of the development of diabetes in those at risk (49) and improved glycemic
control in those with diabetes (48).
Although a low-fat, energy-restricted diet is recommended for those with
diabetes, low-carbohydrate, high-protein diets such as that promoted by Atkins
(50) have recently become popular weight loss approaches. Although popular
among the public, questions have been raised as to the safety of this type
of diet. Concerns include the effect of low-carbohydrate diets on metabolic
functioning, particularly in individuals with CVD, type 2 diabetes, dyslipidemia, and hypertension (51). Specifically, there are concerns that such a
diet may cause abnormal metabolism of insulin, promote hyperlipidemia, and
impair renal function among other potential negative consequences.
Several clinical trials have compared low-fat, hypocaloric diets with lowcarbohydrate diets (5256.) In both treatment conditions, participants received
education combined with minimal professional support. With the exception
of Samaha et al. (54) and their 12-month follow-up (55), in each study, the
low-carbohydrate diet prescribed a restriction of carbohydrate intake to <20 g
per day for the first 2 weeks followed by a gradual increase in the grams
of carbohydrates consumed as weight loss is achieved, consistent with the
Atkins diet (50). Samaha et al. (54) prescribed a diet containing fewer than
30 g of carbohydrate per day without the increase after 2 weeks. In each
of these studies, this ad libitum low-carbohydrate diet was compared with a
low-fat, energy-restricted diet. At 6 months, all studies showed greater weight
losses in the low-carbohydrate condition than the low-fat condition. For the
low-carbohydrate diet, 6-month weight losses ranged from 5.8 to 12.0 kg, and
for the low-fat diet conditions, 6-month losses ranged from 1.9 to 6.5 kg.
However, in the two studies that reported 12-month follow-up data, there were
no significant differences found in weight loss between the two diets (53,55).
Importantly, of the four studies, only Samaha et al. included individuals with
type 2 diabetes, and weight losses were not reported separately by diabetes
diagnosis. In addition, it is important to note that these studies achieved weight
losses that are less than those seen with more intensive behavioral weight loss
interventions that include regular professional contact (43).
Superior weight losses found in the low-carbohydrate diets at 6 months
suggest that although calories are not targeted by such approaches, participants
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reduce their caloric intake to a greater degree than do those in the low-fat,
energy-restricted conditions, at least for a period of time. There are several
potential explanations for the greater energy deficit achieved by the lowcarbohydrate diets, including decreased variety in the diet leading to reduced
intake (57), increased satiation due to increased protein intake (58), or the
relative simplicity of the diet (e.g., no calorie or fat gram counting). However,
as no differences in weight loss have been found with longer follow-up, longterm adherence to the low-carbohydrate approach does not appear to be superior
to adherence to the low-fat approach.
Interestingly, several differences were found between these dietary prescriptions in their effects on health parameters. Three studies found that the
low-carbohydrate diet was associated with greater decreases in triglycerides
(53,55,56) and greater increases (or less decrease) in HDL cholesterol levels
(53,55,56). With regards to total cholesterol and low-density lipoprotein (LDL)
cholesterol, there were no differences between the groups in any of the
studies (52,53,55,56). These findings contradict the hypothesized effect of lowcarbohydrate diets on lipid levels given the increased intake of saturated fat.
This may be because of the weight losses achieved by the low-carbohydrate
group counteracting the adverse effect of increased saturated fat intake on LDL
cholesterol concentrations (53).
Three of the studies included glucose and insulin testing (5255). In the
only study that included individuals with diabetes, Samaha et al. (54) found
greater reductions in glucose levels among diabetic participants in the lowcarbohydrate condition than in the low-fat condition; this difference was no
longer significant at the 12-month follow-up (55). However, at 12 months,
diabetic participants in the low-carbohydrate condition demonstrated greater
decreases in hemoglobin A1c than those in the low-fat condition. Samaha et al.
(55) also found greater increases in insulin sensitivity among non-diabetics
in the low-carbohydrate condition, but these differences were not significant
at the 1-year follow-up. Foster et al. (53) and Brehm et al. (52) did not find
significant differences between groups on insulin or glucose levels.
Reviewing these studies, it appears that the optimal macronutrient composition of weight loss diets for individuals with diabetes is still unclear.
Unfortunately, with one exception, the randomized controlled trials comparing
the low-carbohydrate and low-fat, energy-restricted approaches conducted to
date have excluded participants with type 2 diabetes. In addition, studies with
more extensive follow-up are needed to investigate the long-term health consequences of low-carbohydrate diets, particularly in those with diabetes and other
health conditions. Preliminary findings with the low-carbohydrate diet suggest
that this approach warrants further research as it produces greater initial weight
losses and does not appear to negatively impact key health parameters.
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Improving Dietary Adherence in Weight Loss Programs

In order for weight loss to be attained and maintained long term, adherence
to a reduced-calorie diet has to be achieved. Improving adherence is particularly
important in individuals with type 2 diabetes because they tend to have a
more difficult time achieving and maintaining weight loss. Several approaches
to improving adherence have been attempted. One of the most successful
approaches has been to increase the structure and simplicity of the diet through
the provision of portion-sized foods, the use of structured meal plans and
shopping lists, or the use of MRs (5961). When combined with standard
behavioral treatment (SBT), each of these techniques has been shown to
improve weight losses as compared with SBT alone. Jeffery et al. (59) found
that providing prepackaged, portion-controlled meals for 10 meals per week
significantly improved weight losses as compared with SBT throughout the
full 18 months of the study (6.4 vs. 4.1 kg of weight loss at 18 months). Wing
et al. (60) found that either the provision of prepackaged foods or the provision
of a structured meal plan and grocery list detailing the foods that should be
consumed improved weight losses after 6 months of treatment as compared
with SBT; this difference remained significant a full year after treatment (and
the end of provision of food or meal plans).
More recently, MRs have been utilized as a means of increasing structure
and simplicity of the diet in behavioral weight loss programs (6164). MRs
are nutritionally balanced drinks or bars typically prescribed as part of a
hypocaloric (12001500 kcal/day), low-fat (<30% kcals from fat) diet and
are used to replace two meals per day with the third meal being composed
of conventional foods. The use of MRs is compared with a self-selected,
conventional diet with identical calorie and fat gram goals. The use of MRs has
been consistently shown to improve both initial weight loss and maintenance
of weight loss over the long term (6264). Weight losses following the initial
weight loss period (ranging from 812 weeks) ranged from 6.47.8% with the
use of MRs compared with 1.54.9% in the conventional diet groups (6264).
Ditchuneit and Flechtner-Mors (62) found that significant differences between
weight losses were maintained a full 4 years later when 75% of their original
sample was reevaluated. The MR group maintained an average weight loss
of 8.4%, whereas the conventional diet group maintained an average weight
loss of 3.3%.
The use of MRs has been shown to lead to significant improvements in blood
pressure, glucose, insulin, triacylglycerol, total cholesterol, and LDL cholesterol (6164). These effects are likely due to the greater weight losses achieved.
The use of MRs in patients with type 2 diabetes has been questioned by
some health care providers due to the concerns that the simple sugars in
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such products may lead to hyperglycemia. Yip et al. (64) conducted a 12week randomized controlled trial comparing the use of two different types of
MRs (one containing lactose, fructose, and sucrose and the other in which
fructose and sucrose were replaced with oligosaccharides) with the use of the
Exchange Diet Plan in a group of obese patients with type 2 diabetes. Those
groups using MRs lost significantly more weight than the group using the
Exchange Diet (6.4 and 6.7% vs. 4.9%). There were no significant differences
between the two groups using MRs. Those using either MR products showed
significantly lower serum glucose concentrations than those using the Exchange
Diet and significant decreases over time in insulin levels and HbA1c; no
serious adverse events were reported with the use of MRs in this diabetic
sample.
In a recent study with obese individuals with type 2 diabetes, Redmon
et al. (65,66) combined the use of 10 mg of Sibutramine, MRs to replace one
meal and one snack per day, and the use of exclusively MRs (totaling 900
1300 kcal/day) for 7 consecutive days every 2 months. They compared this
combination group to a control condition receiving standard dietary counseling
recommending a reduced-calorie conventional food diet. Those in the combination therapy lost significantly more weight (6.4 vs. 0.8%) and displayed
a greater decrease in HbA1c (0.6 vs. 0.2%) than those in the standard
condition at the 1-year follow-up (65). After the first year, the standard group
received the combination therapy for 1 year, and the combination group
remained on the same regimen. At 2-year follow-up, despite continuation of
the diet and medications in the combination group, significant weight regain
occurred such that by the end of year 2, the combination group maintained a
total of 4.6 kg; the decrease in HbA1c was marginally significant at 0.5%.
However, because the standard condition received the same treatment in year
2, it is unclear whether these improvements would have been superior to
standard treatment alone. In combination with Yip et al. (64), this study does
support the safety and efficacy of the use of MRs in individuals with type 2
diabetes.
Achieving long-term adherence to a reduced calorie diet is a major challenge
in behavioral weight loss. There is consistent evidence that the use of food
provision, structured meal plans, and MRs improves weight loss outcomes in
both short and long term. This is likely due to the increased structure and
simplicity of the diet making reduction of calories and fat easier. With such
structure, there is a decreased need for measurement and planning as well
as increased ease of self-monitoring. In addition, such approaches reduce the
variety in the diet, which has been shown to be associated with decreased intake
and body weight (57). Recent work with participants with diabetes suggests
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that such an approach is not only safe and effective in this population but
also produces greater improvements in diabetes regulation than conventional
approaches.
WHAT PHYSICAL ACTIVITY STRATEGIES

OPTIMIZE WEIGHT LOSS AND MAINTENANCE?
The types of physical activity recommended for overweight and obese
patients with type 2 diabetes include moderate-intensity aerobic exercise such
as brisk walking, swimming, bicycling, and/or circuit-type resistance training
(with proper supervision) targeting major muscle groups (67,68). Regular
exercise (at least 150 min per week) offers significant benefits for patients with
type 2 diabetes, including improved insulin sensitivity and glycemic control,
and overall reductions in mortality (6972). In addition, frequent moderateintensity physical activity is an important element of any weight management
program and is one of the best predictors of successful weight loss maintenance (73). Given the benefits of weight management for patients with type 2
diabetes, this section will address a number of questions that have been raised
regarding the role of physical activity for successful weight loss.
Is Physical Activity Alone Effective for Weight Loss?

Current recommendations indicate that physical activity should be combined
with dietary change for most effective weight loss. Studies have shown that
while physical activity is an important part of weight loss maintenance,
exercise alone produces only minimal weight loss among overweight and obese
individuals (74). This conclusion was supported by a review conducted by the
Expert Panel on the Identification, Evaluation, and Treatment of Overweight
and Obesity convened by the National Heart, Lung, and Blood Institute in
combination with the National Institute of Diabetes and Digestive and Kidney
Disease (74). The Expert Panel identified randomized controlled trials with
varying sample sizes that involved at least 34 months of treatment examining
dietary interventions, exercise interventions, and their combination. Twelve
studies compared the weight loss effect of exercise alone (primarily aerobic
activity) to no treatment (74). Of these studies, two revealed no weight loss
benefit of exercise, whereas the other 10 showed a mean weight loss of 2.4 kg
in the exercise condition compared with controls (about 2.4% of body weight).
Therefore, the Expert Panel concluded that aerobic physical activity produces
modest weight loss among overweight and obese adults. This conclusion is
supported by several meta-analyses as well. For example, Ballor and Keesey
(75) reviewed 53 studies and revealed that interventions involving aerobic
activity alone (e.g., walking and running) produced a significant but modest
217
weight loss of 1.2 kg compared with no treatment over an average of 17 weeks

of treatment (0.1 kg per week). Garrow and Summerbell (76) showed that
compared with controls, aerobic exercise alone achieved weight losses of 3.0
kg and 1.4 kg for men and women, respectively, whereas resistance training had
little effect on weight loss but increased fat-free mass by approximately 2 kg in
men and 1 kg in women. Similar findings have been reported for exercise-only
interventions with diabetic patients. In a meta-analysis examining the effect of
exercise on body mass and glycemic control in patients with type 2 diabetes,
Boule and colleagues (69) demonstrated that while exercise-only interventions
improved HbA1c, there was no significant weight loss benefit compared with
controls.
Is Physical Activity Combined with Diet More Effective than Diet

Alone for Weight Loss?
In an effort to answer this question, the Expert Panel reviewed 15
randomized controlled trials that compared diet plus exercise to diet alone (74).
Of these studies, 12 showed that combined diet and physical activity interventions produce greater mean weight loss (1.9 kg) and greater mean reduction
in BMI (0.30.5) compared with diet-only interventions. A review by Wing
(77) reevaluated some of the studies identified by the Expert Panel as well as
several others and reported that while most studies report greater weight losses
for interventions that involve diet plus exercise, only two of the 13 studies
reviewed showed statistically significant differences in weight loss (78,79).
Therefore, the conclusion of Wing (77) is that although a majority of studies
show somewhat greater weight loss in the diet plus exercise condition compared
with diet alone, in most studies, the addition of exercise does not significantly increase initial weight loss above and beyond that achieved through
dietary change. A meta-analysis conducted by Miller and colleagues (80)
that compared interventions focusing on diet, exercise, and diet plus exercise
supports this conclusion. This analysis showed that on average, during 16
weeks of treatment, diet and diet plus exercise interventions produced comparable weight losses (10.7 vs. 11.0 kg, respectively), and both were significantly
greater than exercise-only interventions (3 kg). Studies of diabetic patients
have found similar results. For example, Giannopoulou et al. (81) compared
a 14-week program of hypocaloric high-monounsaturated diet alone, exercise
alone, or diet plus exercise in postmenopausal women with type 2 diabetes and
showed significant weight losses in the diet-alone and diet plus exercise groups
(4.5 kg vs. 1.7 for exercise only). Although all groups reduced waist circumference, visceral adipose tissue decreased significantly only in the exercise and
diet plus exercise conditions, suggesting a unique benefit of including exercise
in the treatment of women with type 2 diabetes.
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Although diet plus exercise does not appear to improve short-term weight
loss compared with diet alone, this combination is of benefit for longer term
weight loss maintenance. For example, the Expert Panel (74) identified three
long-term randomized controlled trials examining diet plus exercise versus diet
alone and revealed that all studies obtained a 1.53.0 kg greater weight loss in
the combined treatment over a period of 924 months (78,82,83). In Wings
(77) review, two of the six long-term studies evaluated demonstrated significantly greater weight losses at 1 year or more among patients in the diet plus
exercise condition compared with diet only (78,84). In the meta-analysis by
Miller and colleagues (80), the difference in weight loss maintenance at 1-year
follow-up between patients receiving diet plus exercise (8.6 kg) compared with
diet alone (6.6 kg) was not significant; however, the authors concluded that
combined treatment was superior, because those patients maintained 77% of
initial weight loss compared with 56% for patients in diet only programs.
Although many of the studies referenced above have been conducted with
non-diabetic overweight individuals, the same findings regarding the benefits
of activity are seen in studies with type 2 diabetic participants. Wing et al
(78) compared a diet-only program to diet plus exercise in overweight patients
with diabetes. Both groups attended three meetings per week for the first
10 weeks and then once a week for the next 10 weeks and monthly for
1 year. All participants were given an individualized calorie goal designed to
produce a 12 lb/week weight loss. In addition, both groups received training
in behavioral weight control techniques. The diet plus exercise group walked a
3-mile route at each of their meetings and were instructed to complete a fourth
exercise session each week on their own. The diet group was instructed not to
change their physical activity. As expected, participants in the two conditions
reported comparable changes in diet, but the diet plus exercise group reported
far greater increases in caloric expenditure from exercise (619 kcal/week at
baseline, 1522 kcal/week at week 10, and 1561/week kcal at 1 year) than the
diet-only condition (668, 816, and 853 kcal/week at the three time periods,
respectively). The differences in physical activity produced significant differences in weight loss. At the end of the 10 weeks of intensive intervention, the
diet-only group had lost 5.6 kg compared with 9.3 kg in diet plus exercise;
at 1-year follow-up, overall weight losses were 3.8 and 7.9 kg for diet-only
and diet plus exercise, respectively. Both groups experienced improved HbA1c
(1.9 and 2.4% for diet-only and diet plus exercise at week 10 and 0.8 and
1.4% at 1-year in the two groups, respectively) demonstrating the benefit
of weight loss for glycemic control. Decreases in hypoglycemic medication
were more frequent and larger in the diet plus exercise group. Moreover,
both changes in weight and physical activity were independently related to
improvements in glycemic control.
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An important consideration in evaluating long-term randomized controlled

trials is exercise adherence, as adherence declines over time (85,86). Data
indicate that patients who report continued adherence to exercise in combination with dietary change achieve greater weight losses than those who are
non-adherent. For example, Wadden et al. (87) showed that patients who
reported exercising regularly at 1-year follow-up had maintained significantly greater weight losses (12.1 kg) than their peers who were not
exercising (6.1 kg).
Additional support for the benefit of diet plus exercise for long-term maintenance of weight loss is provided by correlational studies that indicate that
individuals who continue to perform the most physical activity are the ones
who achieve the largest long-term weight losses (73). Research comparing
weight loss maintainers with regainers has shown that 90% of individuals who
maintained their weight loss for at least 2 years reported exercising regularly
(3 or more days/week for 30 min or more), whereas only 34% of regainers
report this level of physical activity (88).
How Much Exercise is Needed for Weight Loss?

There has been recent interest in determining the optimal amount of physical
activity for weight loss and improved health. In the short term, there appear
to be no differences in weight loss between exercising 30 min per day versus
60 min per day in addition to dietary change (89). However, several studies
have provided evidence for a doseresponse relationship between amount of
physical activity and long-term weight loss (35,90,91). In a study comparing
the impact of intermittent versus continuous exercise on weight loss among
women enrolled in an 18-month behavioral weight loss program, Jakicic and
colleagues (90) found that participants with the greatest amount of physical
activity achieved the greatest weight losses. Specifically, women who exercised
more than 200 min per week throughout the 18-month intervention lost more
weight than those exercising 150200 min per week and those exercising less
than 150 min per week.
Similarly, data from the NWCR suggest that successful weight loss
maintainers do high levels of physical activity. Over 90% of registry members
report using both diet and physical activity to lose weight and to maintain their
weight loss. Registry members complete the Paffenbarger Physical Activity
questionnaire (92) that assesses the amount of walking, stair climbing, and
sports activities over the prior week. Women in the registry report expending
2545 calories/week in their leisure-time activities and men report expending
3293 calories/week (35). These levels have remained very consistent over the
10 years of the registry. The most frequent type of activity is walking. Over
70% of participants report walking as part of their activity, but most (50%)
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report some other type of activity in addition to walking. It is estimated that

registry members are exercising at least 1 h a day to achieve their high level
of caloric expenditure from exercise.
The benefit of higher doses of physical activity for weight loss maintenance
has also been shown in a randomized clinical trial. Jeffery and colleagues (91)
randomly assigned overweight men and women to standard behavioral weight
loss treatment that included a physical activity goal of 1000 kcal/week in
energy expenditure (30 min of physical activity per day) or standard behavioral weight loss with a high physical activity goal of 2500 kcal/week of
energy expenditure (75 min of physical activity per day). Findings showed
that high levels of physical activity in the context of a behavioral weight
loss program produced significantly greater weight losses at 18 months
(M = 6.7 kg) compared with a standard weight loss program with conventional
physical activity goals (M = 4.1 kg). Findings from all of the above studies
have led to changes in the recommendations for the dose of activity for weight
loss maintenance. Currently, it is recommended that individuals attempting to
maintain their weight loss try to achieve at least 60 min of activity each day.
Does Physical Activity have to be Done all at Once

to be Effective for Weight Loss?
One of the primary reasons provided for non-adherence to an exercise
program is lack of time. In an effort to improve adherence and to develop
exercise prescriptions that may be more convenient for patients, researchers
have investigated the effects of dividing exercise into multiple short bouts
(e.g., 4 bouts of 10 min each) compared to exercising in one longer bout (e.g.,
40 min). Research suggests that exercise completed in several short bouts is
at least as effective as one longer bout of exercise in terms of weight loss
and in some cases may be even more effective because of its positive effect
on exercise adherence. For example, Jakicic and colleagues (93) randomly
assigned obese sedentary females enrolled in a 20-week behavioral weight loss
program to either a short bout or long bout exercise regimen. Both groups had
the same exercise goal, which was to gradually increase exercise to 200 min
per week. The long bout group was instructed to complete their exercise in one
session each day (beginning with 20 min and building up to 40 min), whereas
the short bout group was instructed to engage in several 10-min exercise
sessions throughout the day (beginning with 2 sessions per day and building
up to 4). Participants exercising in multiple short bouts had significantly better
adherence to exercise and a trend toward greater weight loss compared with
the long bout group (8.9 5.3 vs. 6.4 4.5 kg).
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In a long-term study, Jakicic et al. (90) compared three different exercise

formats among overweight and obese women enrolled in an 18-month behavioral weight loss program. Participants were randomly assigned to long bout
exercise, multiple short bout exercise, or multiple short bout exercise plus
home treadmills for the course of the study. As in the earlier study, all groups
had the same goal of reaching 40 min per day of exercise on 5 days a week.
Results at 18 months showed similar weight losses and improvements in
cardiorespiratory fitness between the multiple short-bout and long-bout groups.
Participants who received home exercise equipment maintained a higher
level of exercise than the long- and multiple short-bout groups not receiving
home treadmills, suggesting that access to exercise facilitates long-term
adherence.
In summary, the data indicate significant benefits of physical activity for
patients with type 2 diabetes, including improved insulin sensitivity, glycemic
control, and weight management. Although dietary restriction appears to be the
most effective for short-term weight loss, the combination of dietary change
and frequent moderate-intense physical activity, such as brisk walking, is
important for successful weight loss maintenance. Findings from the registry
and randomized controlled trials suggest that high levels of physical activity
(e.g., 200 min or more per week) are most effective. This can be done in one
long bout or multiple shorter bouts throughout the day.
HOW CAN EFFECTIVE STRATEGIES BE DISSEMINATED

TO MORE PEOPLE?
As this chapter has demonstrated, weight loss is highly beneficial in
improving health parameters for overweight and obese individuals with
diabetes. Currently, the gold standard approach to weight loss treatment is
professional, face-to-face delivery of standard behavioral weight loss programs.
However, this approach is time consuming and has limited accessibility to
many individuals seeking weight loss. In addition, although continued treatment
contact results in improved weight loss outcomes (9496), long-term studies
show that participant attendance at treatment sessions decreases sharply over
time (97). Concern about the accessibility of gold-standard programs has
led obesity researchers to develop lifestyle interventions that can be more
easily disseminated by replacing face-to-face therapist contact with weight loss
counseling through telephone, mail, or Internet (98101).
In a large-scale randomized trial implementing a low-cost non-clinic-based
intervention, Jeffery et al. (101) randomly assigned 1801 overweight members
of a managed care organization to usual care, telephone, or mail intervention.
The two active treatment groups received 10 behaviorally based lessons on
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nutrition, physical activity, and behavior management. Participants in the

telephone intervention received a series of phone calls from a therapist to
provide guidance about each lesson and those in the mail intervention received
written guidance. At 6 months, weight losses in the telephone condition (2.4 kg)
were greater than usual care (1.5 kg) but not different from participants in the
mail intervention (1.9 kg). No group differences were found at 12 months.
Wing and colleagues (100) evaluated the efficacy of a telephone-assisted intervention for weight loss maintenance among 53 women who had completed a
6-month weight loss program and had lost at least 4.5 kg. Participants were
randomly assigned to a no-contact control group or to receive weekly phone
calls for 12 months from a research assistant who collected data about selfmonitoring of weight and eating. Results at 1 year posttreatment showed that
although the telephone maintenance intervention was implemented relatively
easily and was successful in inducing behavioral skills such as self-monitoring,
average weight regain in this condition (3.9 kg) was not significantly different
from that in the control group (5.6 kg). The authors propose that failure to
find an effect of the telephone intervention may have been because of the
lack of statistical power or the fact that telephone calls were made by trained
staff rather than study therapists. In another study, Kirkman et al. (102) used
a minimal intervention designed to improve glycemic control in a sample of
primary care patients with type 2 diabetes. Patients were randomly assigned
to receive usual care or usual care plus monthly telephone contacts by a nurse
to review their medical regimen, which included diet, exercise, medication,
and glucose monitoring. At 12 months, patients receiving telephone contacts
had better glycemic control and were more likely to have seen a dietitian.
However, there were no group differences in weight loss, lipid profiles, or
self-reported adherence to diet and exercise recommendations. Taken together,
these studies suggest that while phone interventions are feasible and may have
some behavioral impact, their effect on weight loss and prevention of weight
regain are minimal.
Another promising area of research has involved using computer technology
to disseminate standard behavioral weight loss treatment. Tate et al. (99)
randomly assigned 92 overweight and obese participants at risk for type 2
diabetes to one of two Internet treatments: a basic Internet weight loss program
in which participants received a web-based weight loss tutorial, and weekly
resource links and e-mail reminders to submit weight, or a basic Internet weight
loss program plus individualized e-counseling. At 12 months, patients receiving
basic Internet plus individualized e-counseling achieved greater weight losses
(4.4 kg) than those receiving basic Internet alone (2.0 kg). These weight losses,
although less than those achieved in face-to-face behavioral programs, are
comparable to clinic-based commercial programs such as Weight Watchers
223
(103105) and are more than four times those of Internet-based commercial
programs like eDiets.com (106).
Researchers have also examined the utility of using the Internet to facilitate
weight loss maintenance. For instance, Harvey-Berino and colleagues (98)
randomized 122 overweight adults who had completed a 6-month face-to-face
standard behavioral weight loss program to one of three 12-month maintenance conditions: frequent in-person support, Internet support, or minimal inperson support. At 18-month follow-up, participants receiving Internet support
had sustained significantly smaller weight losses (5.7 kg) than both frequent
and minimal in-person support groups (10.4 kg). These results may reflect
the fact that participants found it difficult to transition from a face-to-face
approach used during treatment to an Internet maintenance program, a possibility supported by a second study by Harvey-Berino et al. (107). In this study,
255 overweight adults who had completed a 6-month behavioral weight loss
program delivered over interactive television were randomly assigned to one
of three 12-month maintenance conditions: frequent in-person support, Internet
support, or minimal in-person support. At 18 months, intent to treat analyses
revealed no differences in weight losses sustained across the three maintenance
conditions (3.9, 4.7, and 4.2 kg) for frequent in-person, Internet support, and
minimal in-person, respectively. Thus, Internet approaches may be helpful for
treatment and maintenance of weight loss, but they are currently less effective
than conventional face-to-face approaches.
The research discussed above demonstrates that disseminating standard faceto-face behavioral weight loss treatment through media-based alternatives is
feasible and can be implemented in different settings and various modalities. Such alternative approaches eliminate the need for travel and scheduling
for specific meeting times and may be more convenient for certain patients
than conventional programs. The data on telephone interventions suggest that
they may be beneficial for increasing certain behavioral skills such as selfmonitoring but appear to have little impact on weight loss or prevention of
weight regain. Internet-based standard behavioral programs appear to be more
promising, but further research is needed to refine these approaches and identify
individuals who are best suited to this mode of intervention.
CONCLUSION
Rapidly rising rates of obesity have been accompanied by increased prevalence of type 2 diabetes. This chapter presents evidence that lifestyle interventions that promote weight loss through diet and exercise are effective in
the prevention and treatment of diabetes. The literature reviewed demonstrates
that hypocaloric low-fat diets typically recommended in behavioral weight
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loss programs produce successful weight loss among diabetic individuals.

However, preliminary studies using low-carbohydrate diets have demonstrated
positive results in the short-term and warrant further investigation. Physical
activity plays an important role in long-term weight management and has
additional health benefits for diabetic patients including improved insulin sensitivity and glycemic control. Although there is some evidence to suggest that
diabetic patients may have more difficulty achieving weight loss and may
need more intensive approaches, studies show that successful weight loss is
indeed possible for individuals with diabetes and results in significant health
benefits.
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12
Unifying Hypothesis of Diabetic

Complications
Takeshi Matsumura, MD,
and Michael Brownlee, MD
CONTENTS
Introduction
A Unied Mechanism
Novel Therapeutic Approaches
References
Summary
Over the past four decades, several molecular mechanisms have been
implicated in glucose-mediated vascular damage: increased flux through the
polyol pathway, accumulation of advanced glycation endproduct precursors,
activation of protein kinase C isoforms, and increased hexosamine pathway
activity. Each of these mechanisms has been studied independently of the
others, and there has been no apparent common element linking them. Recent
discoveries have made clear that all of these seemingly unrelated mechanisms
arise from a single, hyperglycemia-induced process: the overproduction of
reactive oxygen species by the mitochondrial electron transport chain.
Key Words: Hyperglycemia, reactive oxygen species, diabetic complications
INTRODUCTION
Chronic hyperglycemia and development of diabetes-specific microvascular complications in retina, peripheral nerve, and renal glomerulus are
characteristic of all forms of diabetes. As a consequence of its microvascular
233
234
Matsumura and Brownlee
pathology, diabetes is the leading cause of blindness, various debilitating

neuropathies, and end-stage renal disease. Diabetics are the fastest growing
group of renal dialysis and transplant recipients, and in the USA, their
5-year survival rate is only 21%, worse overall than that for all forms of
cancer combined. Over 60% of diabetic patients suffer from neuropathy,
which includes mononeuropathies, distal symmetrical polyneuropathy, and
various autonomic neuropathies causing erectile dysfunction, urinary incontinence, gastroparesis, and nocturnal diarrhea. Fifty percent of all nontraumatic
amputations in the USA are due to diabetic peripheral neuropathy, often in
conjunction with lower extremity arterial disease (National Diabetes Data
Group, Diabetes in America, 2nd edition, National Institutes of Health, NIH
Publication 951468, 1995). Atherosclerotic macrovascular disease affecting
arteries that supply the heart, brain, and lower extremities is also a characteristic feature of chronic diabetes. This condition resembles the macrovascular disease in nondiabetic patients; however, the atherosclerotic process
is more extensive, more rapidly progressive, and characterized by a greater
incidence of multi-vessel disease and an increased number of diseased vessel
segments compared with nondiabetic patients (1). As a consequence, patients
with diabetes have a much higher risk of myocardial infarction, stroke, and
limb amputation. Although macrovascular complications are often thought
to occur primarily in type II diabetics, a recent study of type 1 diabetics
in their 40s showed that coronary artery atheromatosis was present in all
subjects (2).
The Diabetes Control and Complications Trial (DCCT) and the U.K.
Prospective Diabetes Study (UKPDS) established that hyperglycemia is the
initiating cause of the diabetic tissue damage that we see clinically (3,4). This
process is modified by both genetic determinants of individual susceptibility
and independent accelerating factors such as hypertension or hyperlipidemia.
The mechanisms by which hyperglycemia causes micro- and macrovascular
damages are discussed.
Increased Flux Through the Polyol Pathway

Aldose reductase normally has the function of reducing toxic aldehydes
in the cell to inactive alcohols, but when the glucose concentration in the
cell becomes too high, aldose reductase also reduces that glucose to sorbitol,
which is later oxidized to fructose. In the process of reducing high intracellular glucose to sorbitol, the aldose reductase consumes the cofactor NADPH
(5). However, NADPH is also the essential cofactor for regenerating a critical
intracellular antioxidant, reduced glutathione. By reducing the amount of
reduced glutathione, we found that the polyol pathway increases susceptibility
Unifying Hypothesis of Diabetic Complications
235
to intracellular oxidative stress. It has been reported that nerve conduction

velocity in the diabetic dogs decreased over time as it does in patients; however,
in diabetic dogs treated with an aldose reductase inhibitor, the diabetes-induced
defect in nerve conduction velocity was prevented (6).
Intracellular Production of Advanced Glycation

Endproduct Precursors
Advanced glycation endproducts (AGEs) are found in increased amounts
in diabetic retinal vessels (7) and renal glomeruli (8), where they can cause
damage. These AGEs were originally thought to arise from nonenzymatic
reactions between extracellular proteins and glucose. However, it seems likely
that intracellular hyperglycemia is the primary initiating event in the formation
of both intracellular and extracellular AGEs (9). These AGE precursors can
diffuse out of the cell and modify extracellular matrix molecules nearby (10),
which changes signaling between the matrix and the cell and causes cellular
dysfunction (11). These AGE precursors also modify circulating proteins,
such as albumin, in the blood. These modified circulating proteins can then
bind to AGE receptors and activate them, thereby causing the production
of inflammatory cytokines and growth factors, which in turn cause vascular
pathology (1221). The potential importance of AGEs in the pathogenesis
of diabetic complications is suggested by the observation in animal models
that two structurally unrelated AGE inhibitors partially prevented various
functional and structural manifestations of diabetic microvascular disease in
retina, kidney, and nerve (2224). In endothelial cells exposed to high glucose,
intracellular AGE formation occurs within 1 week (25). Proteins involved
in macromolecular endocytosis are modified by AGEs, as the increase in
endocytosis induced by hyperglycemia is prevented by overexpression of the
methylglyoxal-detoxifying enzyme glyoxalase I (26). Glyoxalase-I overexpression also completely prevents the hyperglycemia-induced increase in
Muller cell expression of angiopoietin-2 (27), a factor that has been implicated in both pericyte loss and capillary regression (28), suggesting that
hyperglycemia-induced production of methylglyoxal is one of the accelerators of diabetic complication. Moreover, in a large randomized, double-blind,
placebo-controlled, multi-center trial of the AGE inhibitor aminoguanidine
in type I diabetic patients with overt nephropathy, aminoguanidine lowered
total urinary protein and slowed progression of nephropathy, over and
above the effects of existing optimal care. In addition, aminoguanidine
reduced the progression of diabetic retinopathy (K.K. Bolton, personal
communication).
236
Activation of Protein Kinase C

Protein kinase C (PKC) comprises a family of at least eleven isoforms, nine of
which are activated by the lipid second messenger diacylglycerol (DAG). Hyperglycemia inside the cell increases DAG content primarily by increasing its de
novo synthesis from the glycolytic intermediate dihydroxyacetonephosphate by
reduction to glycerol-3-phosphate and stepwise acylation (29). Increased de novo
synthesis of DAG activates PKC in cultured vascular cells (30,31) as well as
in retina and glomeruli of diabetic animals (29,30). When PKC is activated by
intracellular hyperglycemia, it has various effects on gene expression, examples
of which are shown in the row of open boxes in Fig. 1. In each case, the things
that are good for normal function are decreased and the things that are bad
are increased. For example, starting from the far left of Fig. 1, the vasodilatorproducing endothelial nitric oxide (NO) synthase (eNOS) is decreased, whereas
the vasoconstrictor endothelin-1 is increased. Transforming growth factor- and
plasminogen activator inhibitor-1 are also increased. At the bottom of Fig. 1, the
row of black boxes lists the pathological effects that may result from the abnormalities in the open boxes (3236). It is well known that hyperglycemia-induced
PKC activation is important from many animal studies such as several published
by George King, showing that inhibition of PKC prevented early changes in the
diabetic retina and kidney (33,37,38).
Increased Hexosamine Pathway Activity

Excess intracellular glucose may also cause several manifestations of
diabetic complications by increasing flux through the hexosamine pathway
(39,40). As shown schematically in Fig. 2, when glucose is high inside a cell,
Fig. 1. Consequences of hyperglycemia-induced activation of protein kinase C (PKC).
237
Fig. 2. Hyperglycemia increases flux through the hexosamine pathway. From ref. 45a.
most of that glucose is metabolized through glycolysis, going first to glucose6-phosphate, then fructose-6-phosphate, and then on through the rest of the
glycolytic pathway. However, some of that fructose-6-phosphate gets diverted
into a signaling pathway in which an enzyme called glutamine : fructose6-phosphate amidotransferase (GFAT) converts the fructose-6-phosphate to
glucosamine-6-phosphate and finally to uridine diphosphate (UDP) N-acetyl
glucosamine. What happens after that is the N-acetyl glucosamine gets put
onto serine and threonine residues of transcription factors, just like the more
familiar process of phosphorylation, and overmodification by this glucosamine
often results in pathologic changes in gene expression (3941) For example,
in Fig. 2, increased modification of the transcription factor Sp1 results
in increased expression of transforming growth factor-1 and plasminogen
activator inhibitor-1, both of which are bad for diabetic blood vessels (42).
Although this hexosamine pathway is the most recent to be recognized as
a factor in the pathogenesis of diabetic complications, it has been shown to
play a role both in hyperglycemia-induced abnormalities of glomerular cell
gene expression (39) and in hyperglycemia-induced cardiomyocyte dysfunction
in cell culture (43). In carotid artery plaques from type 2 diabetic subjects,
238
modification of endothelial cell proteins by the hexosamine pathway is also

significantly increased (44).
A UNIFIED MECHANISM
There are many reports that are involved in the pathogenesis of diabetic
complications. However, there was no apparent common element linking these
mechanisms to each other, and clinical trials of inhibitors of these pathways
in patients were all disappointing. We hypothesized that all these mechanisms
were linked to a common upstream event and that the failure to block all
the downstream pathways could explain the disappointing clinical trials with
single-pathway inhibitors. We discovered this single unifying process, which is
the overproduction of superoxide by the mitochondrial electron transport chain.
We have reported that a consistent differentiating feature common to all cell
types that are damaged by hyperglycemia is an increased production of reactive
oxygen species (ROS) (42,45). Although hyperglycemia had been associated
with oxidative stress in the early 1960s (46), neither the underlying mechanism
that produced it nor its consequences for pathways of hyperglycemic damage
were known.
How Does Hyperglycemia Increase Superoxide Production

by the Mitochondria?
There are four protein complexes in the mitochondrial electron transport
chain, called complexes I, II, III, and IV (Fig. 3). When glucose is metabolized
through the tricarboxylic acid (TCA) cycle, it generates electron donors. The
main electron donor is NADH, which gives electrons to complex I. The other
electron donor generated by the TCA cycle is FADH2 , formed by succinate
dehydrogenase, which donates electrons to complex II. Electrons from both
these complexes are passed to coenzyme Q, and then from coenzyme Q they
are transferred to complex III, cytochrome-C, complex IV, and finally to
molecular oxygen, which they reduce to water. The electron transport system
is organized in this way so that the level of ATP can be precisely regulated.
As electrons are transported from left to right as shown in Fig. 3, some of
the energy of those electrons is used to pump protons across the membrane
at complexes I, III, and IV. This generates what is in effect a voltage across
the mitochondrial membrane. The energy from this voltage gradient drives the
synthesis of ATP by ATP synthase (47,48). Alternatively, uncoupling proteins
(UCPs; Fig. 3) can bleed down the voltage gradient to generate heat as a way
of keeping the rate of ATP generation constant. On the contrary, in diabetic
cells with high glucose inside, there is more glucose being oxidized in the
TCA cycle, which in effect pushes more electron donors (NADH and FADH2 )
239
Fig. 3. Hyperglycemia-induced production of superoxide by the mitochondrial electron

transport chain.
into the electron transport chain. As a result of this, the voltage gradient across
the mitochondrial membrane increases until a critical threshold is reached.
At this point, electron transfer inside complex III is blocked (49), causing
the electrons to back up to coenzyme Q, which donates the electrons one
at a time to molecular oxygen, thereby generating superoxide (Fig. 3). The
mitochondrial isoform of the enzyme superoxide dismutase (SOD) degrades
this oxygen-free radical to hydrogen peroxide, which is then converted to H2 O
and O2 by other enzymes. Indeed, we looked at diabetic cells with a dye
that changes color with increasing voltage of the mitochondrial membrane
and found that intracellular hyperglycemia did indeed increase the voltage
across the mitochondrial membrane above the critical threshold necessary to
increase superoxide formation (50). To prove that the electron transport chain
indeed produces superoxide by the mechanism we proposed, we examined
the effect of overexpressing either UCP-1 or manganese SOD (MnSOD) on
hyperglycemia-induced ROS generation. Hyperglycemia caused a big increase
in production of ROS. In contrast, an identical level of hyperglycemia does
not increase ROS at all when we also collapse the mitochondrial voltage
gradient by overexpressing UCP (45). Similarly, hyperglycemia does not
increase ROS at all when we degrade superoxide by overexpressing the
enzyme MnSOD. These data demonstrate two things. First, the UCP effect
shows that the mitochondrial electron transport chain is the source of the
hyperglycemia-induced superoxide. Second, the MnSOD effect shows that
240
the initial ROS formed is indeed superoxide. We further examined the effect
of either UCP-1 overexpression or MnSOD overexpression on each of these
four hyperglycemia-activated pathways. Hyperglycemia did not activate any
of the pathways when either the voltage gradient across the mitochondrial
membrane was collapsed by UCP-1 or the superoxide produced was degraded
by MnSOD (45). We have verified all these endothelial cell culture experiments
in transgenic mice that overexpress MnSOD (M. Brownlee, personal communication). When wild-type animals are made diabetic, all four of the pathways
are activated in tissues where diabetic complications occur. In contrast, when
MnSOD transgenic mice are made diabetic, there is no activation of any of
the four pathways. In endothelial cells, PKC also activates nuclear factor B
(NF B), a transcription factor that itself activates many proinflammatory
genes in the vasculature. As expected, hyperglycemia-induced PKC activation
is prevented by either UCP-1 or MnSOD, both in cells and in animals. Importantly, inhibition of hyperglycemia-induced superoxide overproduction using
a transgenic approach (SOD) also prevents long-term experimental diabetic
nephropathy in the best animal model of this complication: the db/db diabetic
mouse (51).
Hyperglycemia-Induced Mitochondrial Superoxide Production

Activates the Four Damaging Pathways by Inhibiting
Glyceraldehyde-3-Phosphate Dehydrogenase
Figure 4 shows the scheme we proposed for how all these data link
together. This model is based on a critical observation we made: diabetes
in animals and patients, and hyperglycemia in cells, all decrease the activity
of the key glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase
(GAPDH). Inhibition of GAPDH activity by hyperglycemia does not occur
when mitochondrial overproduction of superoxide is prevented by either UCP-1
or MnSOD (42). As shown in Fig. 4, the level of all the glycolytic intermediates that are upstream of GAPDH increases. Increased levels of the
upstream glycolytic metabolite glyceraldehyde-3-phosphate activates two of
the four pathways. It activates the AGE pathway because the major intracellular
AGE precursor methylglyoxal is formed from glyceraldehyde-3-phosphate.
It also activates the classic PKC pathway, as the activator of PKC, DAG,
is also formed from glyceraldehyde-3-phosphate. Further upstream, levels of
the glycolytic metabolite fructose-6-phosphate increase, which increases flux
through the hexosamine pathway, where fructose-6-phosphate is converted
by the enzyme GFAT to UDPN-acetylglucosamine (UDPGlcNAc). Finally,
inhibition of GAPDH increases intracellular levels of the first glycolytic
metabolite, glucose. This increases flux through the polyol pathway, where
241
Fig. 4. Mitochondrial overproduction of superoxide activates four major pathways of hyperglycemic damage by inhibiting GAPDH. From ref. 45a.
the enzyme aldose reductase reduces it, consuming NADPH in the process. To
rule out the possibility that any other hyperglycemia-induced metabolic change
accounted for these observations, we inhibited GAPDH activity using antisense
DNA, so that the level of GAPDH activity in cells cultured in 5 mmol/L
(90 mg/dL) glucose was reduced to that normally found in cells exposed to
hyperglycemia. With reduced GAPDH activity, the only perturbation in these
cells, the activity of each of the four pathways in 5 mmol/L glucose was
elevated to the same extent as that induced by hyperglycemia (52).
Hyperglycemia-Induced Mitochondrial Superoxide Production

Inhibits GAPDH by Activating Poly(ADP-Ribose) Polymerase
To clarify the mechanism of inactivation of GAPDH, we next investigated
the chemical modifications of GAPDH that correlated with the hyperglycemiainduced decrease in GAPDH activity. Hyperglycemia-induced superoxide
inhibits GAPDH activity in vivo by modifying the enzyme with polymers of
ADP-ribose (Fig. 5) (52). By inhibiting mitochondrial superoxide production
with either UCP-1 or MnSOD, we prevented both modification of GAPDH
by ADP-ribose and reduction of its activity by hyperglycemia. Most importantly, both modification of GAPDH by ADP-ribose and reduction of its
242
Fig. 5. Reactive oxygen species (ROS)-induced DNA damage activates poly(ADP-ribose)

polymerase (PARP) and modifies GAPDH.
activity by hyperglycemia were also prevented by a specific inhibitor of

poly(ADP-ribose) polymerase (PARP), the enzyme that makes these polymers
of ADP-ribose. This established a cause-and-effect relationship between PARP
activation and the changes in GAPDH. Normally, PARP resides in the nucleus
in an inactive form, waiting for DNA damage to activate it (Fig. 5). When
increased intracellular glucose generates increased ROS in the mitochondria,
these free radicals induce DNA strand breaks, thereby activating PARP.
Both hyperglycemia-induced processes are prevented by either UCP-1 or
MnSOD (52). Once activated, PARP splits the NAD+ molecule into its two
component parts: nicotinic acid and ADP-ribose. PARP then proceeds to make
polymers of ADP-ribose, which accumulate on GAPDH and other nuclear
proteins. Although GAPDH is commonly thought to reside exclusively in the
cytosol, in fact it normally shuttles in and out of the nucleus, where it plays
a critical role in DNA repair (53,54). A schematic summary showing the
elements of the unified mechanism of hyperglycemia-induced cellular damage
is shown in Fig. 6. When intracellular hyperglycemia develops in target cells
of diabetic complications, it causes increased mitochondrial production of
ROS. The ROS cause strand breaks in nuclear DNA, which activate PARP.
PARP then modifies GAPDH, thereby reducing its activity. Finally, decreased
GAPDH activity activates the polyol pathway, increases intracellular AGE
formation, activates PKC and subsequently NFB, and activates hexosamine
pathway flux.
243
Fig. 6. The unifying mechanism of hyperglycemia-induced cellular damage.
How Does the Unifying Mechanism Explain

Diabetic Macrovascular Disease?
Although the pathogenesis of diabetic microvascular complications can be
explained by the unifying mechanism described in the preceding section (A
UNIFYING MECHANISM), the relationship between a unifying mechanism
and diabetic macrovascular disease is not fully understood. Using both cell
culture and animal models, we found that the unappreciated consequence of
insulin resistance is increased free fatty acid (FFA) flux from adipocytes into
arterial endothelial cells (Fig. 7). In macrovascular, but not in microvascular,
endothelial cells, we found that this increased flux results in increased FFA
Fig. 7. Insulin resistance causes mitochondrial overproduction of reactive oxygen species

(ROS) in macrovascular endothelial cells by increasing free fatty acid (FFA) flux and
oxidation. From ref. 55a.
244
oxidation by the mitochondria. As both -oxidation of fatty acids and oxidation

of FFA-derived acetyl CoA by the TCA cycle generate the same electron
donors (NADH and FADH2 ) generated by glucose oxidation, increased FFA
oxidation causes mitochondrial overproduction of ROS by exactly the same
mechanism described in the preceding section (A UNIFYING MECHANISM)
for hyperglycemia. And, as with hyperglycemia, this FFA-induced increase
in ROS activates the same damaging pathways: AGEs, PKC, the hexosamine
pathway (GlcNAc), and NF B. In insulin-resistant nondiabetic animal models,
inhibition of either FFA release from adipocytes or FFA oxidation in arterial
endothelium prevents the increased production of ROS and its damaging effects
(55). Although more work certainly needs to be done, these data support a major
role for the unifying mechanism in the pathogenesis of diabetic macrovascular,
as well as microvascular, complications.
NOVEL THERAPEUTIC APPROACHES

Transketolase Activators
When increased superoxide inhibits GAPDH activity, the glycolytic intermediates above the enzyme accumulate and are then shunted into the
four pathways of hyperglycemic damage. Two of these glycolytic intermediates, fructose-6-phosphate and glyceraldehyde-3-phosphate, are also the final
products of the transketolase reaction, which is the rate-limiting enzyme in
another metabolic pathway, the pentose phosphate pathway (56). Although
this pathway is traditionally taught as flowing from pentose phosphates to
glycolytic intermediates, in fact it can also flow from glycolytic intermediates
to pentose phosphates, depending on the concentrations of substrate presented
to the transketolase enzyme. As we know that in diabetes, the concentration
of the glycolytic intermediates is high, we reasoned that if we could activate
transketolase, then we could decrease the concentration of these two glycolytic
metabolites and thus divert their flux away from three of the damaging
pathways normally activated by hyperglycemia. As this enzyme requires the
vitamin thiamine as a cofactor, we tried different thiamine derivatives and
measured their effects. After 9 months of diabetic rats treated with benfotiamine, there was a complete prevention of hexosamine pathway activation and
diabetes-induced increases in intracellular AGE formation, PKC activation,
and NF B activation (56).
PARP Inhibitors
Although we had shown that increased superoxide produced by the
mitochondria in response to both hyperglycemia and increased FFA activates
PARP, and that this PARP activation then modifies and inhibits GAPDH
245
(Fig. 5), we predicted that that PARP inhibition would block the four major
pathways of hyperglycemic damage that are activated by GAPDH inhibition. In
cultured endothelial cells, a specific PARP inhibitor prevents hyperglycemiainduced activation of PKC, NF B, intracellular AGE formation, and the
hexosamine pathway (48). In long-term experimental diabetes, treatment with
a PARP inhibitor also completely prevented the major structural lesion of
both human nonproliferative retinopathy and experimental diabetic retinopathy:
acellular capillaries (H.P. Hammes, M. Brownlee, personal communications).
Catalytic Antioxidants
The enzymes that are particularly important for vascular biology are eNOS
and prostacyclin synthase. eNOS is a very important antiatherogenic enzyme
with great relevance to diabetic macrovascular disease. Prostacyclin synthase is
also critical endothelial antiatherosclerotic enzyme. To prevent direct oxidative
inactivation of these key enzymes, we must directly reduce the amount of
superoxide. However, conventional antioxidants are unlikely to do this effectively. Conventional antioxidants neutralize reactive oxygen molecules on a
one-for-one basis, whereas hyperglycemia-induced over production of superoxide is a continuous process. What is needed, then, is a new type of antioxidant, a catalytic antioxidant, such as an SOD/catalase mimetic (57), that
works continuously like the enzymes for which these compounds are named.
Hyperglycemia-induced reactive oxygen overproduction directly reduces eNOS
activity in diabetic aortas by 65%. However, when these diabetic animals are
treated with an SOD/catalase mimetic, there is no reduction in activity of
this antiatherogenic enzyme. Similarly, but more dramatically, hyperglycemiainduced reactive oxygen overproduction directly reduces prostacyclin synthase
activity in diabetic aortas by 95%. Treatment of these diabetic animals with an
SOD/catalase mimetic completely prevents diabetes-induced oxidative inactivation of aortic prostacyclin synthase. These data strongly suggest that therapeutic correction of diabetes-induced superoxide production may be a powerful
new approach for preventing diabetic complications.
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13
The Diabetic Foot

Andrew J. M. Boulton,
MD, DSC (HONS),
FRPC
CONTENTS
Introduction
How to Screen for the At-Risk Foot
Ofoading: Its Importance and Application
Infection or Colonization
Osteomyelitis or Charcot Neuroarthropathy?
Are Expensive Adjunctive Therapies Justied
to Heal the Diabetic Foot Wound?
The Role of Footwear
What Does the Future Hold?
References
Summary
Diabetic foot problems remain all too common and are likely to increase in
prevalence over the next few decades. It has been estimated that an individual
with diabetes now has a 25% risk of developing a foot ulcer at some time
during their lifespan. A number of controversies are discussed in this chapter
starting with the key question of the best screening methods for the at risk
foot for ulceration. The key message is that simple clinical techniques of
examination of the feet and lower limbs are probably the most accurate way
to assess for further risk of foot lesions. A foot ulcer will normally heal
if the circulation is intact, infection is treated and pressure is taken off the
lesion. Physicians find it hard to believe that patients with large plantar foot
lesions would actually walk on this lesion, but they forget that sensory loss
in the diabetic foot permits walking without discomfort. Thus offloading is
frequently neglected and if applied properly, will lead to satisfactory healing
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in most plantar neuropathic ulcers. In the area of infection, the key question
is whether an ulcer is infected or colonized and this is discussed in some
detail as is the differential diagnosis between osteomyelitis and Charcot
neuroarthropathy. The use and abuse of expensive topical treatments is then
discussed and finally the role of footwear in the prevention of recurrent
ulcers is described.
Key Words: Diabetic neuropathy, diabetic foot ulceration, charcot
neuroarthropathy, offloading, foot infection.
INTRODUCTION
2005 was an important year for the diabetic foot as the International Diabetes
Federation chose the diabetic foot and reducing amputations as their focus topic
for that year. It was estimated that in 2005, for every 30 s a lower limb is lost
somewhere in the world as a consequence of diabetes (1). This is a particularly
depressing statistic because of all the late complications of diabetes, foot
problems are probably the most preventable. Thus, over 70 years ago, Joslin
wrote that Diabetic gangrene is not heaven sent, but earth born. Thus, the
development of foot ulceration results from the way we care for our patients or
the way in which patients care for themselves. These observations suggest that
early identification of those patients with risk factors for the development of
foot problems, followed by their education in prevention, should ultimately lead
to a reduction in foot ulcers and consequently amputations. This was the focus
of the Year of the Diabetic Foot during which there were news conferences
and publicity in every continent and the publication of a book Time to Act
which focused on many aspects of the identification and management of those
at risk of foot problems (2).
As the lifetime incidence of foot ulceration in diabetic patients was recently
estimated to be as high as 25% (3), understanding the pathways that result in
the development of an ulcer is increasingly important. A number of controversies regarding the diagnosis and management of diabetic foot problems will
be included in this chapter. Surprisingly, controversy remains as how best to
identify those at risk of foot problems: a clear understanding of the etiopathogenesis of ulceration is essential if we are to succeed in reducing the incidence
of foot ulceration and ultimately amputations. As the vast majority of amputations are preceded by foot ulcers, a thorough understanding of the causative
pathways to ulceration is important if we are to reduce the depressingly high
incidences of ulceration and amputation (4). Moreover, as lower limb complications are the commonest precipitants of hospitalization in diabetic patients
in most Western countries, there are potential economic benefits to be gained
from preventative strategies (1).
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The Diabetic Foot
Other controversies relating to the management of foot problems to be

discussed in this chapter include the question of offloading the foot wound
and how best to achieve this, the role of footwear in preventing foot ulcers,
the question of infection and its management, the difference between Charcot
neuroarthropathy (CN) and osteomyelitis, and finally, the place of some of the
expensive adjunctive therapies in the management of diabetic foot wounds.
HOW TO SCREEN FOR THE AT-RISK FOOT

Pathway to Ulceration
Despite the increased attention that has been focused on the diabetic foot
in recent years (5), particularly in 2005, routine screening for diabetic patients
to assess their risk of foot lesions remains woefully inadequate. Tapp et al.
(6), for example, reported that in a population-based study from Australia
that foot screening remained poor with less than one half of the population
reporting a regular examination for foot complications. A number of groups
have programs in communities to improve screening of the diabetic foot: when
such a system was established in Idaho, the proportion of patients receiving
the recommended annual foot exam increased by 14% (7). However, much
remains to be done: failure to screen and identify risk factors for foot ulceration
may have disastrous consequences as illustrated in Fig. 1 (8). When discussing
the optimal screening method for use in day-to-day clinical practice, it is
important to have an understanding of the pathways that result in diabetic foot
ulceration.
Foot ulceration invariably results from an interaction of a number of
component causes, none of which is sufficient alone to cause ulceration but,
when combined, complete the causal pathway to skin breakdown. Knowledge
of these component causes and their potential to interact facilitates the design
of preventive foot programs. These include all three components of diabetic
neuropathy (sensory, motor, and autonomic), peripheral vascular disease,
callus deformity, and high foot pressures and trauma. Chronic sensorimotor
neuropathy is common as noted in Chapter 7, and it has been estimated that
up to 50% of older type 2 diabetic patients have risk factors for foot ulceration
(9). As many of these patients may have no neuropathic symptoms and be
completely aware of their risk, the diagnosis can only be made by careful
clinical examination. Sympathetic autonomic dysfunction affecting the lower
limbs results in reduced sweating, dry skin, and the development of cracks and
fissures. In the absence of large vessel arterial disease, there may be increased
blood flow to the foot leading to the warm but at-risk foot. The importance of neuropathy is a major contributory cause to foot ulceration has been
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Fig. 1. This demonstrates the dangers of failing to screen the feet of diabetic patients
regularly for foot ulcer risks. This patient had never had a foot screen, and when he
developed neuropathic symptoms, he sought treatment from alternative medicine. These
burns are caused by the inappropriate application of moxibustionthe application of
a burning incense stick to meridians for people with vascular disease. This patient could
feel no pain, and the burning sticks remained for too long and too close giving rise to
symmetrical burns on the limb.
confirmed: the risk in those with neuropathy is seven-fold higher than in those
without (10).
Peripheral vascular disease is also more common in diabetic patients, and in
combination with minor trauma, this may lead to ulceration. Early identification
of those at risk for peripheral vascular disease is essential, and appropriate
investigation involving non-invasive studies together with arteriography may
lead to bypass surgery or angioplasty to improve blood flow to the extremities.
Motor dysfunction, with imbalance of the flex or extensor muscles in the
foot, frequently results in foot deformity, with prominent metatarsal heads and
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The Diabetic Foot
clawing of the toes. In turn, the combination of proprioceptive loss due to

neuropathy and prominence of the metatarsal heads may lead to increased foot
pressures and loads under the diabetic foot, whereas plantar callus has been
shown in cross-sectional and prospective studies to be a significant marker of
foot ulcer risk, removal of plantar callus is associated with the reduction in
foot pressures and thus a reduction in foot ulcer risk (11).
It is the combination of two or more of the earlier described risk factors
that usually results in diabetic foot ulceration. In 1999, a North American/UK
collaborative study assessed risk factors that resulted in ulceration in more
than 150 consecutive foot ulcer cases. From this study, a number of causal
pathways were identified but the most common triad of component causes that
was present in nearly two-thirds of ulcers comprised neuropathy, deformity,
and trauma (12). This summarizes the risk factors and pathways that result
in ulceration, but it must also be remembered that the most at-risk
patient is the individual with a past history of foot ulceration or amputation
(Fig. 2).
Suggestions for Screening

It is essential that all patients with diabetes should have at least annually an
assessment of their risk for the development of foot problems. Those found to
have risk factors require more frequent review, education in self foot care, and
podiatric assessment. There is, however, no universal consensus as to how this
screening should be carried out. The following are recommended:
History
1. Neuropathic symptoms.
2. Past history of ulcer.
3. Other diabetic problems, especially retinopathy/impaired vision.
4. History of claudication/rest pain/vascular surgery.
5. Home circumstancesfor example, living alone.
Examination
Inspection. Shoes and socks must be removed.
1.
2.
3.
4.
5.
6.
Skin status: thickness, dryness, and cracking.

Infection: check between the toes as well.
Ulceration.
Deformity: for example, Charcot changes or clawing of the toes.
Foot shape.
Skin temperature: compare the feet. A unilateral, warm swollen foot with intact
skin would suggest the possibility of acute CN. Moreover, prior to neuropathic
ulceration, there is a local increase in temperature (13).
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Fig. 2. The at-risk neuropathic foot. This demonstrates wasting of muscles in the lower
tibial region and in the intrinsic muscles of the foot. There are signs of diabetic dermopathy
on the lower shins, dystrophic nails, and prominent metatarsal heads. There is some clawing
of the lateral toes.
7. The patients footwear and gait should also be assessed. Walking without a
limp with a plantar ulcer is diagnostic of neuropathy.
Neurological Assessment
1. Neuropathy can easily be documented by a simple clinical examination of large
fiber function (e.g., 128-Hz tuning fork for vibration), small fiber function (e.g.,
pin prick and hot/cold rods), and ankle reflexes. A simple composite score
comprising these measures has been shown to be useful in the prediction of
those at risk of future ulceration (10).
2. Ten-gram monofilamentthis tests pressure perception and is frequently used
to assess foot ulcer risk status (14). Although simple to perform, general
agreement is lacking as to which site should be tested, and not all filaments
accurately assess pressure at 10 g (15). Moreover, the number of sites that
The Diabetic Foot
257
should be tested is unknown: for example, the 128-Hz tuning fork vibration
assessment tested at two sites was recently shown to be as sensitive as the
monofilament tested at eight sites (16).
Vascular Assessment
1. Posterior tibial and dorsalis pedis pulses should be palpated.
2. Bedsides, assessment of the circulation using a doppler ultrasound probe can be
useful. However, the presence of diabetes and neuropathy make the usual tests
such as the ankle brachial index (AB1) less efficacious: wave form analysis
and toe pressures are more effective (17). Although it was suggested in a recent
American Diabetes Association Consensus Statement (18) that all patients over
50 years of age with diabetes should have an annual measurement of the ABI,
this has not been universally accepted. As noted above, neuropathy and vascular
calcification might lead to false elevation in the ABI inaccurate. Thus, a patient
with neuropathy and stiffened arteries might have an apparently normal ABI
in the presence of peripheral vascular disease. In summary, for the vascular
assessment, a careful clinical examination of the foot assessing the peripheral
pulses and skin temperature may be sufficient for the annual review.
Other Assessments
Other more detailed assessments such as quantitative sensory testing (QST)
and foot pressure studies may be added in specialist centers but are not
necessary in routine clinical practice (9). The use of simple semi-quantitative
mat systems for assessment of foot pressure may be useful. PressureStat, for
example, is an inexpensive and semi-quantitative foot print mat that takes only
a minute or two to measure, and higher pressures are associated with darker
areas. This can provide a powerful educational tool to help patients understand which areas under their foot are at particular risk (19). In summary,
although some controversy remains regarding which particular simple clinical
test should be used in the annual foot screening, the most important step that
could be taken to reduce amputations in diabetes as emphasized during the
Year of the Diabetic Foot (1)would be that every time a patient with diabetes
was seen by a physician or any other health care professional, the shoes and
socks should be removed and a careful clinical inspection of the foot should
be made.
QST
1. Vibration assessment: The biothesiometer, neurothesiometer, and vibration
perception threshold (VPT) meters are simple, hand-held tests of vibration
perception that can easily be used in the outpatient setting: loss of vibration
as assessed with these instruments is strongly predictive of subsequent ulceration (19).
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2. Temperature perception: A new hand-held instrument, the NeuroQuick (20),

that tests cold sensation is now available. This may in future be useful in
screening for early neuropathy.
3. Other QST instruments: Other more elaborate equipments to assess distal
sensory function are available (16). However, most of these are expensive and
time consuming and restricted to clinical research usage.
4. Electrophysiology: Although nerve conduction studies strongly predict future
ulcers (20), their use is generally restricted to clinical research studies.
OFFLOADING: ITS IMPORTANCE AND APPLICATION

It is generally accepted that a diabetic foot wound will heal if three factors
are attended to:
1. There is adequate arterial inflow to the foot.
2. The wound is debrided and any infection treated with appropriate antibiotics.
3. Pressure over the wound and surrounding area is minimized.
It is the last of these three points that is frequently neglected. A normal

individual with a foot wound will limp to avoid putting pressure on the wound
as this is painful, hence the early observation in leprosy that a patient who walks
on a plantar wound without limping must have neuropathy. Peripheral sensory
loss in patients with diabetes therefore permits weight bearing on an active
plantar ulcer, which in turn impairs healing. Thus, the use of a total contact
cast (TCC) was proposed first in leprosy and second in diabetes to manage the
patient with a plantar neuropathic ulcer. The principal of this treatment is that
pressure is mitigated, but in addition, as the device is irremovable, adherence
with the treatment is enforced and mobility is reduced. Following a number
of published case series, the first randomized trial of casting was published by
Mueller et al. in 1989. In this study, significantly faster healing was reported
in the TCC compared with accommodative footwear with an absolute risk
reduction of 59%. Subsequent to this and previous studies, the TCC was
accepted as the gold standard for managing the plantar neuropathic ulcer by the
American Diabetes Association (22), although a systematic review concluded
that further confirmatory studies were required. A second, larger randomized
trial was performed in which the TCC was compared with a removable cast
walker (RCW) and half shoe (23). Again, the TCC proved superior to the other
two modalities. Surprisingly, previous gait laboratory studies had confirmed
that the RCW reduces pressure to approximately the same degree as the TCC
(24), leaving the question as to why the TCC was consistently superior in
terms of wound healing compared to the RCW.
The most likely answer is related to patient adherence to wearing the RCW.
A subsequent study tested this hypothesis and confirmed that although patients
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The Diabetic Foot
with plantar diabetic foot ulcers were asked to wear the RCW whenever they
were walking, in practice they only wore the device for 28% of all footsteps
(25). Thus, the main reason for the poorer performance of the RCW in clinical
trials was indeed due to the fact that these were frequently not worn while
walking. Accordingly, an alternative to the TCC was proposed by Armstrong
et al. (26) and named the instant total contact cast (iTCC). This technique
involves taking an RCW and rendering it irremovable by wrapping it with one
or two bands of plaster of paris, therefore addressing most of the disadvantages
of the TCC but preserving irremovability. Two recent randomized controlled
trials using the iTCC have confirmed that (i) the iTCC has equal efficacy to
the TCC in healing plantar foot wounds (27) and (ii) that the iTCC is superior
in terms of healing rates when compared with the RCW (28).
Evidence from Italy suggests that maintained pressure on a wound maintains
the chronicity of a lesion: after a period of offloading, a chronic neuropathic
foot ulcer has many of the histopathological features of an acute wound,
with angiogenesis and granulation (29). These important observations strongly
suggest that repetitive pressure on a neuropathic foot wound contributes to the
chronicity of the wound, and offloading therefore can help to promote wound
healing. It was therefore proposed in an editorial that future trials of new treatments for diabetic foot ulcers should have standardized offloading, preferably
irremovable using a TCC or iTCC, thereby removing one of the most important
confounding variables that has probably contributed to many negative clinical
trials of proposed new therapies for neuropathic foot ulcers (30).
Two recent publications provide further help in the use of total contact
casting. First, it was shown that the TCC can be used not only in neuropathic
ulcers but also effectively in neuroischemic ulcers, provided that there is no
evidence of infection (31). The same group later confirmed that it is safe to use
TCC recurrently in patients who have repetitive episodes of foot ulcer (32).
INFECTION OR COLONIZATION
Controversy has existed for many years regarding the management of
infection in diabetic foot wounds, regarding whether or not the wound is
infected, and regarding which antibiotics to use and for how long to continue
treatment.
Some help in this difficult area has come from the International Consensus
Working Group on diagnosing and treating the infected diabetic foot, which
published guidelines in 2004 (33). With respect to the diagnosis of infection,
it must be remembered that all skin wounds harbor microorganisms, and
therefore, the diagnosis of infection is a clinical one and not a microbiological
one. Help in the diagnosis can be made by looking for clinical systemic signs
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of infection such as purulent secretions or at least two local findings of inflammation (including redness, warmth, induration, pain, and tenderness). Other
signs that might suggest infection include the presence of necrosis, a foul odor,
or failure of a properly treated wound to heal.
Any wound showing clinical signs suggestive of infection should be
cultured, and this is best achieved using a curette, a wound biopsy, wound
aspiration that should be obtained aseptically from the base of a wound after
debridement.
With respect to treatment, those with a severe infection should usually
be hospitalized for possible surgical intervention, control of metabolic
derangement, and other forms of resuscitation.
For less severe infection, outpatient treatment is possible remembering that
management of infection is only one of the aspects of wound management. The
initial choice of antibiotic regimen is usually empirical, and commonly used
agents would include Clindamycin, Augmentin (Amoxycillin and Clavulanic
acid), or a cephalosporin.
Detailed management of diabetic foot infections is beyond the scope of this
chapter, and readers are directed to some excellent recent reviews (33,34).
Another rhetorical question relates to the duration of antibiotic treatment: again,
this should be judged clinically, but there is little evidence to suggest that
antibiotics should be continued until complete wound healing is achieved.
One of the dangers of overuse of antibiotics is the development of resistant
organisms such as Methicillin-resistant staphylococcus Aureus (MRSA).
Reports suggest that MRSA is increasing in diabetic foot clinics (35,36).
However, the presence of MRSA is usually suggestive of opportunistic
colonization rather than true pathogenetic infections. There is generally no
indication to use specific agents active against MRSA unless this organism is
clinically suspected as the primary pathogen.
OSTEOMYELITIS OR CHARCOT NEUROARTHROPATHY?

CN is a progressive condition affecting the bones and joints of the foot and
is characterized by joint dislocation, subluxation, and pathological fractures
of the foot in neuropathic patients resulting often in debilitating deformities.
Permissive features for the development of CN include both peripheral and
autonomic neuropathy, an intact peripheral circulation, and some form of
trauma although this may go unnoticed in neuropathic patients. CN typically
presents with a unilateral warm, swollen, and sometimes painful foot. Diagnosis
at this stage and early intervention may prevent the progression to the typical
deformities seen in chronic CN (Fig. 3). Unfortunately, as many such cases
are painless, acute CN is often misdiagnosed as a variety of other conditions
The Diabetic Foot
261
Fig. 3. Healing burn to Charcot foot. This shows chronic deformity due to Charcot
neuroarthropathy at the cuneiform-metatarsal joints. This patient felt that his feet were cold,
so he sat in front of the fire but unfortunately fell asleep. An example of a preventable
deformity and a preventable injury.
including cellulitus, osteomyelitis, or even an inflammatory arthropathy. The

differential diagnosis from osteomyelitis can be difficult as both can be
associated with local warmth, erythema, and swelling. However, in a patient
with a history of minor trauma and the absence of any skin breaks in the foot,
the clinical diagnosis should be that of CN until proven otherwise. A further
problem can be that the x-ray might be normal in the early stages of both
osteomyelitis and CN.
In contrast, the diagnosis of osteomyelitis is more likely if there is active
ulceration, particularly if bone is visible or palpable at the base of the ulcer. If
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the involved area is one of the toes, the so-called sausage toe, a red swollen digit
(37), frequently indicates underlying osteomyelitis. The probe-to-bone test
using a sterile blunt metal probe that is positive when the distinctive gritty or
stony feeling of bone is encountered is highly suggestive of osteomyelitis (38).
Although osteomyelitis has typical radiological changes, these tend to occur
late (Fig. 4) and therefore are not particularly helpful in the early differential
diagnosis between CN and osteomyelitis.
Fig. 4. Osteomyelitis of distal phalanx of hallux. Note, first, the extensive vascular calcification and even periarticular calcification. A soft tissue defect is seen at the apex of the
hallux with bony destruction typical of osteomyelitis.
The Diabetic Foot
263
Perhaps, the most useful tests in differentiating between these two conditions
in the acute or early stages are the three-phase 111 In-labelled leukocyte (white
blood cell) scan and magnetic resonance imaging (MRI) (34).
ARE EXPENSIVE ADJUNCTIVE THERAPIES JUSTIFIED

TO HEAL THE DIABETIC FOOT WOUND?
A number of new and mostly expensive adjunctive therapies have been
proposed to enhance wound healing in the diabetic foot (20,21). These include
platelet-derived growth factors, skin substitutes, negative pressure wound
therapy (NPWT) and hyperbaric oxygen (HBO): this review considers the last
two of these.
Over the last few years, NPWT has emerged as a commonly employed
option in the treatment of complex wounds including diabetic foot lesions. This
involves the delivery of intermittent or continuous sub-atmospheric pressure
through a specialized pump connected to a resilient open-celled foam surface
dressing covered with an adhesive drape to maintain a closed environment.
NPWT appears to optimize blood flow, decrease local tissue oedema, remove
excessive discharge, and exudate and promote the development of healthy
granulation tissue. Until recently, the only support for the use of this therapy in
complex diabetic foot wounds has come from published case series. A recent
study (39), however, provides evidence from a randomized controlled clinical
trial to support the use of NPWT in complex wounds usually after surgery
in the diabetic foot. Patients were randomized either to NPWT or standard
therapy that comprised moist wound care according to consensus guidelines.
NPWT was delivered through the vacuum-assisted closure (VAC) therapy
system. This study confirmed more rapid healing in the NPWT group and a
trend toward fewer amputations in the NPWT group compared with standard
treatment.
A recent consensus conference focusing entirely on targeting diabetic foot
wounds considered the use of NPWT and agreed that this should be reserved
for larger, deeper, and often post-surgical debridement/partial foot amputation
wounds. It was also agreed that NPWT should be used until there is healthy
granulation tissue: NPWT may even be used in conjunction with removable
offloading by bridging the tubing from the plantar surface to the dorsum of the
foot (40). In conclusion, it appears that NPWT is a useful adjunct to healing
complex diabetic foot wounds often in the post-operative situation.
Even more controversy surrounds the use of HBO in diabetic foot wounds.
The evidence for HBO in the diabetic foot was reviewed by Bakker in 2000,
and it was concluded that multiple anecdotal reports and retrospective studies
of HBO therapy in diabetic foot wounds suggested some efficacy, but because
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most of these published studies suffered from methodological problems, HBO

could not be recommended at this time as standard therapy in patients with foot
ulcers (41). If HBO was to be used, Bakker suggested that those most likely
to benefit would have ischemic lesions treated unsuccessfully by standard
methods when amputation seems a possibility. This review has been followed
by several further randomized controlled trials. The first of these (42) was
in patients without vascular disease and suggested that HBO might improve
the healing rate. However, as many of these ulcers were plantar lesions, they
may well have been better treated with appropriate offloading rather than
expensive HBO. Another randomized trial looked at patients with ischemic
non-healing lower extremity ulcers and provided evidence that HBO might
enhance healing of such lesions and could be a valuable adjunct to conventional
treatment.
A subsequent Cochrane analysis suggested that there might be some benefit
for HBO in patients with ischemic lesions, the modest number of patients,
methodological shortcomings, and poor reporting in trials suggested that such
results need to be interpreted with caution. Thus in this area, there is still
a need for an appropriately powered trial with high methodological rigor to
confirm the potential benefits of HBO in ischemic diabetic foot wounds.
THE ROLE OF FOOTWEAR

It may seem surprising that the role of footwear appears as a controversial
issue in overall diabetic foot care. However, although it is well recognized that
inappropriate footwear is a major cause of injury to the insensate foot (3,4,12),
the role of special shoes in the protection of the neuropathic feet from recurrent
ulceration is far less clear (43) although there is almost universal clinical
opinion and experience that appropriate therapeutic footwear can reduce the
incidence of primary and recurrent ulceration. Several small studies have
suggested that patients randomized to therapeutic footwear after ulcer healing
had a lower incidence of recurrent ulcers (43,44). The most recent trial (45)
by Reiber et al. (43) surprisingly found no benefit of specialist footwear in
reducing recurrent ulcer rates although this study was somewhat controversial
because of the unusual patient population recruited and the type of shoe
gear chosen. Moreover, guidelines for the prescription of footwear are not
well established, and few practitioners measure plantar pressures at previous
ulcer sites to ensure that high pressures are reduced by the footwear (20,43).
Research is ongoing into the use of computer-aided design and manufacture
of specialist therapeutic shoes. The future might herald the use of intelligent
footwear design with on-board systems available to monitor features of the
foot-ground interface (43).
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The Diabetic Foot
WHAT DOES THE FUTURE HOLD?

Recent technological developments have led to promising breakthroughs in
the treatment of chronic wounds (21). There is great potential in the delivery
of stem or progenitor cells, either applied topically or recruited from the
circulation (46). Preliminary work suggests that topically applied autologous
bone marrow-cultured cells and the subsequent grafting of epidermal sheets
might accelerate wound healing in intractable diabetic foot ulcers (21,47).
Thus, there is good reason to believe that in the near future, further therapy
to advances will further aid in the healing of chronic diabetic foot ulcers.
However, this will never be achieved without a dedicated clinical team of
individuals working together to try and reduce the morbidity and even mortality
associated with diabetic foot problems.
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Podotrack and the optical pedobarograph in the assessment of pressures under the diabetic
foot. Diabet Med 16, 154159.
20. Boulton AJM, Malik RA, Arezzo JC, Sosenko JM. Diabetic Somatic Neuropathy. Diabetes
care 2004; 27: 14581486.
21. Ziegler D, Siekerka-Klaiser E, Meyer B, Schweers M. Validation of a novel screening
device, Neuroquick for quantitative assessment of small nerve fibre dysfunction as an early
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diabetic plantar ulcers; controlled clinical trial. Diabetes Care 12, 384388.
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(2001). Offloading the diabetic foot wound: a randomized clinical trial. Diabetes Care 24,
10191022.
25. Braumhauer JF, Wervery R, McWilliams J, Harris GF, Shereff MJ. (1997) A comparative
study of plantar foot pressure in a standardized shoe, total contact cast prefabricated
pneumatic walking brace. Foot Ankle Int 18, 2633.
26. Armstrong DG, Lavery LA, Kimbriel HR, Boulton AJM (2003). Activity patterns of
patients with diabetic foot ulceration: patients with active ulceration may not adhere to a
standard pressure offloading regimen. Diabetes Care 26, 25952597.
27. Armstrong DG, Short B, Espensen EH, Abu-Ramman PL, Nixon BP, Boulton AJM. (2002).
Technique for fabrication of an instant total contact cast for treatment of neuropathic
diabetic foot ulcers. J Am Podiatr Assoc 92, 405408.
28. Katz IA, Harlan A, Miranda-Palma B, Prieto-Sanchez L, Armstrong DG, Bowker JH,
Mizel MS, Boulton AJM. (2005) A randomized trial of two irremovable off-loading devices
in the management of plantar neuropathic diabetic foot ulcers. Diabetes Care 28, 555559.
29. Armstrong DG, Lavery LA, Wu S, Boulton AJM (2005). Evaluation of removable and
irremovable cast walkers in the healing of the diabetic foot wounds: a randomized controlled
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30. Piaggesi A, Viacava P, Rizzo L, del Prato S. (2003) Semi-quantitative analysis of
the histopathological features of the neuropathic foot ulcer effects of pressure relief.
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for a paradigm shift? Diabetes Care 26, 26892690.
32. Nabuurs-Franssen MH, Sleegers R, Huijberts MS, Sanders AP, Schaper NC. (2005) Total
contact casting of the diabetic foot in daily practice: a prospective follow-up study.
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33. Nabuurs-Franssen MH, Sleegers R, Huijberts MS, Schaper NC. (2005) Casting of recurrent
diabetic foot ulcers: effective and safe? Diabetes Care 28, 14931494.
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the infected diabetic foot. Diabet Metab Res Rev 20(suppl 1), S68S77.
35. Lipsky BA, Berendt AR, Embil J, De Lalla F. (2004) Diagnosing and treating diabetic foot
infections. Diabet Metab Res Rev 20(suppl 1), S56S64.
36. Tentolouris N, Jude EB, Smirnoff I, Knowles EA, Boulton AJM. (1999) Methicillinresistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med
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37. Dang CN, Prasad YD, Boulton AJM, Jude EB. (2003) Methicillin-resistant Staphylococcus
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38. Rajbhandari SM, Sutton M, Davies C, Tesfaye S, Ward JD. (2000) Sausage toe: a reliable
sign of underlying osteomyelitis. Diabet Med 17, 7477.
39. Grayson ML, Gibbons GW, Balogh K, Levin E, Karchmer AW. (1995) Probing to bone
in infected pedal ulcers. A clinical sign of underlying osteomyelitis in diabetic patients.
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40. Armstrong DG, Lavery LA. (2005) Negative pressure wound therapy after partial diabetic
foot amputation: a multicentre, randomized controlled trial. Lancet 366, 17041710.
41. Armstrong DG, Attinger CF, Boulton AJM, Frykberg RG, Kirsner RS, Lavery LA. (2004)
Guidelines regarding negative wound therapy (NPWT) in the diabetic foot. Ostomy Wound
Manage 50(4B suppl), 3S27S.
42. Bakker DJ. (2000) Hyperbaric oxygen therapy and the diabetic foot. Diabet Metal Res Rev
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43. Kessler I, Bilbault P, Ortega F, Crasso C, Passemard R, Stephan D, Pinget M, Schneider F.
(2003) Hyperbaric oxygenation accelerates the healing rate of non-ischemic chronic diabetic
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44. Cavanagh PR. (2004) Therapeutic footwear for people with diabetes. Diabet Metab Res Rev
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prevention of diabetic foot ulcers. Diabetes Care 18, 13761378.
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therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled
trial. JAMA 28, 25522558.
47. Conrad C, Huss R. (2005) Adult stem cell lines in regenerative medicine and reconstructive
surgery. J Surg Res 124, 201208.
48. Yamaguchi Y, Yoshida S, Sumikawa Y, Hosokawa K, Hearing VJ, Itami S. (2004) Rapid
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14
Coming of Age for the Incretins

Jens Juul Holst, MD,
and Carolyn F. Deacon,
DR. MED SCI
CONTENTS
Introduction: The Incretin Effect
Effects of Native GLP-1 in 2DM
GLP-1 Analogs (Incretin Mimetics)
Inhibitors of DPP-IV
Conclusion
References
Summary
The incretin hormones, glucose-dependent insulinotropic polypeptide
(GIP) and glucagon-like peptide-1 (GLP-1), may be responsible for up to
70% of postprandial insulin secretion. In type 2 diabetes (2DM), the incretin
effect is severely reduced. Secretion of GIP is normal, but its effect on
insulin is lost. GLP-1 secretion may be impaired, but its actions may restore
insulin secretion to near normal levels. Substitution therapy with GLP-1
might therefore be possible. GLP-1 actions include potentiation of glucoseinduced insulin secretion, up-regulation of insulin and other -cell genes,
stimulation of -cell proliferation and neogenesis and inhibition of -cell
apoptosis, inhibition of glucagon secretion, inhibition of gastric emptying,
and inhibition of appetite and food intake. It may also have cardioprotective
and neuroprotective actions. These actions make GLP-1 particularly attractive
as a therapeutic agent for 2DM, but GLP-1 is rapidly destroyed in the body by
the enzyme, dipeptidyl peptidase IV (DPP-IV). Clinical strategies therefore
include (i) the development of metabolically stable activators of the GLP-1
receptor and (ii) inhibition of DPP-IV. Orally active DPP-IV inhibitors are
currently undergoing clinical trials, and recent clinical studies have provided
269
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Holst and Deacon
long-term proof of concept. Metabolically stable analogs/activators include

the structurally related lizard peptide, exendin-4, or analogs thereof, as well
as GLP-1-derived molecules that bind to albumin and thereby assume the
pharmacokinetics of albumin. These molecules are effective in animal experimental models of 2DM and have been employed successfully in clinical
studies of up to 82 weeks duration, and exendin-4 has just been approved
for add-on therapy of 2DM.
Key Words: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent
insulinotropic polypeptide), DPP-IV (dipeptidyl peptidase IV), glucagon,
insulin, type 2 diabetes mellitus.
INTRODUCTION: THE INCRETIN EFFECT

The incretin effect designates the amplification of insulin secretion elicited
by hormones secreted from the gastrointestinal tract. In the most strict sense,
it is quantified by comparing insulin responses to oral and intravenous glucose
administration, where the intravenous infusion is adjusted so as to result in the
same (isoglycemic) peripheral (preferably arterialized) plasma glucose concentrations (1,2). In healthy subjects, oral administration causes a two-fold to
three-fold larger insulin response compared with the intravenous route. The
increase is mainly due to the actions of insulinotropic gut hormones, although
changing hepatic uptake of insulin may play a minor role. The same gut
hormones are also released by mixed meals, and given that their postprandial
concentrations in plasma are similar and that the elevations in glucose concentrations are also similar, it is generally assumed that the incretin hormones are
playing a similarly important role for the meal-induced insulin secretion. If the
analysis is based on measurements of C-peptide instead of insulin, it is possible
to avoid errors introduced by hepatic extraction of insulin (since C-peptide
is not taken up by the liver), and such measurements applied to isoglycemic
glucose challenges indicate a similar amplification of beta cell secretion. By
applying C-peptide kinetics and deconvolution it is possible to calculate the
actual prehepatic insulin secretion rate, which shows a similar increase after
oral compared with intravenous glucose (3).
Many hormones have been suspected to be responsible for the incretin effect
(4), but today, there is ample evidence to suggest that the two most important
incretins are glucose-dependent insulinotropic polypeptide (GIP), previously
designated gastric inhibitory polypeptide, and glucagon-like peptide-1 (GLP-1).
Both have been established as important incretin hormones in mimicry experiments in humans, where the hormones were infused together with intravenous
glucose to concentrations approximately corresponding to those observed
during oral glucose tolerance tests. Both hormones powerfully enhanced insulin
271
secretion, actually to an extent that could fully explain the insulin response
(5,6). Likewise, administration of GLP-1 and GIP receptor antagonists to
rodents or immunoneutralization has clearly indicated that both hormones play
an important role for the incretin effect (7,8). Recent human experiments,
involving clamping of blood glucose at fasting and postprandial levels, exact
copying of the meal-induced concentrations of both GLP-1 and GIP indicated
that both are active with respect to enhancing insulin secretion from the
beginning of a meal (even at fasting glucose levels) and that they contribute
almost equally, but with the effect of GLP-1 predominating at higher glucose
levels (9). The effects of the two hormones with respect to insulin secretion
have been shown to be additive in humans (10). From studies in mice with
targeted lesions of the both GLP-1 and GIP receptors, it was concluded that
both hormones are essential for a normal glucose tolerance and that the effect
of deletion of one receptor was additive to the effect of deleting the other
(11). Thus, there is little doubt that the incretin effect plays an important role
in postprandial insulin secretion and, therefore, glucose tolerance in humans
and animals.
It is now well established that type 2 diabetes (2DM) is characterized not
only by insulin resistance but also by a beta cell defect , which renders the
beta cells incapable of responding adequately to the insulin resistance (12).
Therefore, it is relevant to ask how the incretin effect functions in these patients.
Careful studies by Nauck et al. (13) indicated that the incretin effect is severely
reduced or lost in type 2 diabetic patients. In a similar study carried out in
our own laboratory in obese subjects with 2DM (those studied by Nauck et al.
were relatively lean), we could confirm the loss of the incretin effects and also
observed that the amount of intravenous glucose required for copying of the
oral glucose response was similar to the oral dose, another indication that in
these patients, the route of administration did not result in different handling
of the glucose (unpublished studies). Thus, there is little doubt that the loss of
the incretin effect contributes to the glucose intolerance of these patients.
Given that GLP-1 and GIP are the most important incretin hormones, it
is possible also to dissect their contribution to the defective incretin action
in diabetic patients. Such contributions could consist in defects with respect
to secretion, action, or metabolism. Detailed studies of the secretion of GIP
and GLP-1 in response to mixed meals in patients with 2DM revealed a
slightly impaired secretion of GIP but a more pronounced impairment with
respect to the secretion of GLP-1. In fact, the GLP-1 response, expressed as
the incremental area under the curve, was reduced to approximately 50% in
the patients compared with healthy glucose tolerant controls. The decreased
response was related to both BMI (lower the higher the BMI) and to the actual
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Holst and Deacon
diabetic state but was independent of the presence of neuropathy. Thus, an

impaired secretion of GLP-1 may contribute to the failing incretin effect.
The metabolism of GIP and GLP-1 was compared by Vilsboll et al. (14) in
diabetic patients and controls, but both hormones were metabolized at similar
rates (and unpublished studies). With respect to the effects of the incretin
hormones, it was discovered in 1993 (15) that infusion of GLP-1 resulted
in near normal insulin responses in patients with 2DM, whereas GIP had no
significant effect. Similar observations were made by Elahi and coworkers
(16). In subsequent studies involving infusion of various doses of GLP-1
during stepwise increases in plasma glucose, it was possible to analyse the
influence of GLP-1 on the beta cell sensitivity to glucose (17). It was found
that although GLP-1 at a low infusion rate (0.5 pmol/kg x min) was capable
of restoring beta cell sensitivity to glucose to completely normal values, the
sensitivity of the diabetic islets to GLP-1 was nevertheless severely decreased.
Combined with the finding that the secretion of GLP-1 is reduced, one may
infer that the insulinotropic effects of endogenous GLP-1 may be severely
compromised in 2DM. Therefore, it can be concluded that decreased efficacy
characterizes the incretin action of both GLP-1 and GIP in 2DM. On the other
hand, whereas GIP is ineffective regardless of dose (18), GLP-1 retains the
capability to enhance glucose-induced secretion, raising the possibility that
GLP-1, in pharmacological doses, could be used clinically to enhance insulin
secretion in 2DM. The following sections describe the extent to which this is
possible in clinical practice. Finally, one may ask whether the incretin defect is
a primary event, perhaps a major etiological contributor to the beta cell failure
that characterizes 2DM. Several observations, however, suggest that this is not
the case. Thus, the impaired secretion of GLP-1 seems to be a consequence
of diabetes (19). In identical twins, that were discordant for type 2DM, mealinduced GLP-1 secretion was reduced only in the diabetic twin (20), and in
first-degree relatives of patients with 2DM, 24-h incretin hormone profiles were
normal (actually there was a significant increase in the secretion of GIP but no
difference for GLP-1) (21). A reduced insulinotropic action of GIP to almost
diabetic levels was observed in about 50% of first-degree relatives of patients
with 2DM, suggesting that this might represent a primary, genetic defect
(22). However, subsequent observations have questioned this interpretation.
Vilsboll et al. (23) studied insulin responses to GIP in patients with diabetes
of different etiologies, including diabetes secondary to pancreatitis. In these
patients, there was a similar loss of insulinotropic effects of GIP as observed in
the classical type 2 diabetic subjects. These findings suggest that the lost effect
of GIP is also secondary to the diabetic condition. Similarly, in women with
previous gestational diabetes, which constitute a high risk group for diabetes
273
development, GIP secretion and action was completely normal, precluding an

early GIP defect to play a role for subsequent diabetes development (24).
Thus, although a therapeutic strategy based on incretin hormones may restore
beta cell responsiveness to glucose in 2DM, the incretin defect is not a primary
cause of diabetes.
It should be emphasized that it is currently unknown whether the lost effects
of GIP are permanent in 2DM. This is relevant because reports have recently
appeared showing that stabilized analogs of GIP may have antidiabetic potential
in animal models of 2DM, notably ob/ob mice (25).
EFFECTS OF NATIVE GLP-1 IN 2DM

The acute insulinotropic effects of GLP-1 raised interest for the use of this
peptide in diabetes treatment. Moreover, the peptide possesses a number of
additional effects which in the context of diabetes treatment must be considered
favorable.
Effects on the Islets

Not only does GLP-1 stimulate insulin secretion in a glucose-dependent
manner (thereby minimizing the risk of causing hypoglycemia), it also enhances
all steps of insulin biosynthesis as well as insulin gene transcription (26),
thereby providing continued and augmented supplies of insulin for secretion.
Important steps in the GLP-1 receptor signaling include activation of adenylate
cyclase with subsequent accumulation of cAMP as well as increases in intracellular calcium levels. However, many of the subsequent changes that occur
in the beta cells are protein kinase A independent. Thus, cAMP-regulated
guanine nucleotide exchange factors (in particular Epac 2) appear to act as
downstream mediators (27). Also the actions of GLP-1 on the insulin gene
promoter appear to be mediated by both PKA-dependent and PKA-independent
mechanisms, the latter possibly involving the MAP kinase pathway (28). The
transcription factor pancreatic duodenal homeobox-1 (PDX-1), a key regulator
of islet growth and insulin gene transcription, appears to be essential for most of
the glucoregulatory, proliferative, and cytoprotective actions of GLP-1 (29). In
addition, GLP-1 up-regulates the genes for the cellular machinery involved in
insulin secretion, such as the glucokinase and glucose transporter-4 (GLUT-2)
genes (30). Much attention was aroused by the finding that GLP-1 appeared
to be essential for conveying glucose competence to the beta cells, that is,
without GLP-1 signaling, beta cells would not be responsive to glucose (31,32).
However, the beta cells of mice with disruption of the GLP-1 receptor gene
show preserved glucose competence (33).
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Holst and Deacon
Finally, GLP-1 also has trophic effects on -cells (34). Not only does it
stimulate -cell proliferation (35,36), it also enhances the differentiation of
new -cells from progenitor cells in the pancreatic duct epithelium (37). Most
recently, GLP-1 has been shown to be capable of inhibiting apoptosis of beta
cells including human beta cells(38). As the normal number of beta cells is
maintained in a balance between apoptosis and proliferation, this observation
is of considerable interest and also raises the possibility that GLP-1 could
be useful in conditions with increased beta cell apoptosis. The complicated
mechanisms whereby GLP-1 may exert these effects on the beta cells were
reviewed recently (39,40).
GLP-1 also strongly inhibits glucagon secretion (41). As in patients with
2DM, there is fasting hyperglucagonemia as well as exaggerated glucagon
responses to meal ingestion (19), and as it is likely that the hyperglucagonemia
contributes to the hyperglycemia of the patients (42), this effect may be
as important as the insulinotropic effects. Indeed, in patients with type
1 diabetes and complete lack of beta cell activity (C-peptide negative),
GLP-1 is still capable of lowering fasting plasma glucose concentrations,
presumably as a consequence of a powerful lowering of the plasma glucagon
concentration (43).
Effects on the Gastrointestinal Tract

Further important effects of GLP-1 include inhibition of gastrointestinal
secretion and motility, notably gastric emptying (44,45). By this mechanism,
GLP-1 may curtail postprandial glucose excursions (46) and thereby reduce
the number of episodes with high postprandial glucose levels. There has been
concern that the powerful inhibitory effect could represent a problem in patients
with gastroparesis, but so far, there has not been a single reported case. It
has also been speculated that the capability of high doses of GLP-1 to cause
nausea and eventually vomiting might be a consequence of its actions of the
stomach. However, GLP-1 may also cause nausea in the fasting state, so this
is unlikely. Furthermore, in studies where GLP-1 infusions caused complete
arrest of gastric emptying of a meal for several hours, the subjects were not
nauseated and incapable of sensing the inhibition (46). Recent studies by
Schirra et al. (47), involving administration of the GLP-1 receptor antagonist
to humans, have clearly shown that the inhibitory actions of GLP-1 on gastric
motility are among the physiological actions of the hormone.
Effects on Appetite and Food Intake

GLP-1 inhibits appetite and food intake in normal subjects (48) as well as
in obese subjects with 2DM (49,50), and it is thought that GLP-1 is one of the
gastrointestinal hormones that normally regulates food intake (50).
275
Other Effects
It has been known for some time that there are GLP-1 receptors in the
heart (51). A physiological function for these receptors was indicated in recent
studies in mice lacking the GLP-1 receptor, which exhibits impaired left
ventricular contractility and diastolic functions as well as impaired responses to
exogenous epinephrine (52). Recent studies in rats showed that GLP-1 protects
the ischemic and reperfused myocardium in rats by mechanisms independent
of insulin (53). These findings may have important clinical implications. Thus,
Nikolaidis et al. (54) studied patients treated with angioplasty after acute
myocardial infarction but with postoperative left ventricular ejection fractions
as low as 29%. In these patients, GLP-1 administration significantly improved
the ejection fraction to 39% and improved both global and regional wall motion
indices. Recently, GLP-1 was reported to dramatically improve left ventricular
and systemic hemodynamics in dogs with induced dilated cardiomyopathy, and
it was suggested that GLP-1 may be a useful metabolic adjuvant in decompensated heart failure (55). Finally, GLP-1 was recently found to improve
endothelial dysfunction in type 2 diabetic patients with coronary heart disease,
again a finding with interesting therapeutic perspectives (56). GLP-1 may
also possess neurotropic effects. Thus, intracerebroventricular GLP-1 administration was associated with improved learning in rats and also displayed neuroprotective effects (57,58), and GLP-1 has been proposed as a new therapeutic
agent for neurodegenerative diseases, including Alzheimers disease (59).
In agreement with the findings of preserved insulinotropic actions of GLP-1
in 2DM (15), intravenous infusion of GLP-1 at 1 pmol/kg min was demonstrated to be able to completely normalize plasma glucose in patients with longstanding severe disease, admitted to hospital for insulin treatment (60). Subsequent studies in patients with moderate disease showed that plasma glucose
concentrations could be near normalized by an intravenous GLP-1 infusion
covering the night time and the next day including two meals (61). In another
study, a continuous intravenous administration of GLP-1 for 7 consecutive days
was demonstrated to dramatically lower both fasting and postprandial glucose
concentrations with no sign of tachyphylaxis over 7 days (62). In this study,
which included four different infusion rates, glucose concentrations were not
completely normalized at the two lowest infusion rates (4 and 8 ng/kg min
approximately corresponding to 1 and 2 pmol/kg min), whereas the higher
rates (16 and 24 ng/kg min) had to be discontinued because of side effects
(nausea and vomiting). So in these studies, it was not possible within the
therapeutic window to completely normalize plasma glucose concentrations.
Clearly, continuous intravenous infusion is clinically irrelevant, but the
effect of subcutaneous injections of GLP-1 given to both patients and healthy
subjects (63) on plasma glucose and insulin concentrations turned out to be
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Holst and Deacon
very short lasting, even after maximally tolerated doses (1.5 nmol/kghigher
doses resulted in nausea and vomiting) (64). The short duration of action
was demonstrated to be due to an extremely rapid and extensive metabolism
of GLP-1 in the body (65,66) leaving the intact peptide with an apparent
half-life of 12 min in the body and a plasma clearance amounting to two to
three times cardiac plasma output (14). The degradation is due to the actions
of the ubiquitous enzyme, DPP-IV, which catalyses the removal of the two
N-terminal amino acids of the molecule rendering it inactive (65). It has been
demonstrated that the metabolite, GLP-1 (936) amide, may act as a GLP-1
receptor antagonist (67) and that prevention of its generation might enhance
the antidiabetic actions of GLP-1. Recent studies, however, clearly showed
that glucose-lowering effects of GLP-1 in humans were the same whether the
metabolite was present or not (68).
The metabolic instability of GLP-1 clearly restricts its clinical usefulness, but
Zander et al. (69) carried out a clinical study in which GLP-1 or saline was administered as a continuous subcutaneous infusion (using insulin pumps) for 6 weeks
to a group of 2DM patients. The patients were evaluated before, after 1 week, and
after 6 weeks of treatment. No changes were observed in the saline-treated control
group, whereas in the GLP-1 group, fasting and average plasma glucose concentrations were lowered by approximately 5 mmol/l, hemoglobin A1c [glycated
hemoglobin, a long-term (months) measure of mean plasma glucose concentrations] decreased by 1.2%, free fatty acids were significantly lowered, and the
patients had a gradual weight loss of approximately 2 kg. In addition, insulin
sensitivity, determined by a hyperinsulinamic euglycemic clamp, almost doubled,
and insulin secretion capacity (measured using a 30 mmol/l glucose clamp +
arginine) greatly improved. There was no significant difference between results
obtained after 1 and 6 weeks of treatment, but there was a tendency toward further
improvement of plasma glucose as well as insulin secretion. There were very few
side effects and no differences between saline-treated and GLP-1-treated patients
in this respect. Despite the marked metabolic improvement, plasma glucose levels
were not completely normalized, but the dose given (4.8 pmol/kg min) may not
have been optimal. Thus, in a different study, higher infusion rates were actually
more efficacious and still did not elicit prohibitive side effects (70).
This study, therefore, provided proof-of-concept for the principle of GLPbased therapy of 2DM, and further attempts to utilize the therapeutic potential
of GLP-1 have included on one hand the development of stable, DPP-IVresistant analogs (71), and on the other hand, inhibitors of DPP-IV demonstrated to be capable of protecting the peptide from degradation and thereby
augmenting its insulinotropic activity (72).
277
GLP-1 ANALOGS (INCRETIN MIMETICS)

Stable peptide agonists of the GLP-1 receptor have given great hope with
respect to future diabetes therapy. The compound most advanced with respect
to clinical development is exenatide, produced by the Amylin Corporation,
Amylin, San Diego, Ca, US in collaboration with Eli Lilly, Indiana polis,
Indiana, US a synthetic replica of exendin 4, a peptide derived from the
salivary glands of a lizard, the Gila Monster. It has 53% sequence homology
with GLP-1 but is not the GLP-1 of the Gila monster and is therefore designated a GLP-1 receptor activator or incretin mimetic. It activates the GLP-1
receptor with about the same potency as native GLP-1 but survives much
longer in the circulation, both because of its resistance to DPP-IV and because
of reduced renal elimination (73,74). Upon single subcutaneous injection of
10 g, the recommended dose, there is an exposure for about 67 h in humans
(75). Exenatide is therefore given twice daily. Otherwise, exenatide seems
to share all of the effects of native GLP-1 (73). The compound has been
tested in several clinical trials, most recently in three controlled pivotal trials
comprising 1494 patients. Exenatide was given for 30 weeks as an add-on
therapy to type 2 diabetic patients inadequately treated with sulfonylureas
(76), metformin (77) or a combination of metformin and sulfonylureas (78).
After 30 of weeks treatment, fasting blood glucose concentrations were significantly reduced, HbA1c levels were reduced by approximately 0.8% in all
groups, and to or below 7% (a recommended value) in 41, 46, and 34%
of the patients in the three groups. Adverse effects were mild and generally
gastrointestinal. Mild hypoglycemia was noted in 2836% of patients also
receiving sulfonylurea. An important result was a significant, dose-dependent
and progressive weight loss of 1.6 kg (SU and SU + metformin) and 2.8 kg
(metformin) from baseline. In open-label extensions of these studies, exenatide
has been given for a total of 82 weeks with continued effects on HbA1c and
body weight (http://www.amylin.com). However, some patients (about 38%
of patients after 30 weeks) appear to develop low titre antibodies against
exenatide, and 6% developed antibodies with higher titres. In about half of
these, the glucose-lowering effect of exenatide appeared attenuated. The three
pivotal studies provided the basis for an application for approval of exenatide
as a new drug for the treatment of diabetes, and this was approved by the
FDA in April 2005. Information about the new drug, which is named Byetta,
is available on the web site of the company (http://www.BYETTA.com). It
appears from the label that an increased rate of benign C-cell adenomas were
observed with a dose-dependent frequency in female rats, whereas a study in
mice was negative. As there are GLP-1 receptors on the C-cells in several
species (79), including humans, this could represent a class effect and will
require careful observation, although apparently such adenomas have not been
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Holst and Deacon
observed in humans. Calcitonin levels were not affected during the 6 weeks of
continuous GLP-1 administration to diabetic patients mentioned above (unpublished studies). Most recently, the Amylin Corporation has developed a slow
release formulation of exenatide (80). Exenatide long-acting release (LAR) is
a poly-lactide-glycolide microsphere suspension containing 3% exenatide that
exhibits sustained dose-dependent glycemic control in diabetic fatty Zucker rats
for up to 28 days following a single subcutaneous injection. In 30 patients with
2DM previously treated with diet/exercise and/or metformin, weekly injections
of exenatide LAR for 15 weeks was reported to reduce fasting plasma glucose
by 3 mmol/l, to reduce HbA1c by 1.7%, and to cause a weight loss of
3.8 kg in the group with the highest dose. Notably, the enhanced efficacy was
associated with a markedly reduced incidence of side effects (nausea). This
supports the concept that it is essential to maintain a constant level of high
GLP-1 activity for optimal treatment results. In conclusion, exenatide represents an efficacious supplement to failing conventional oral antidiabetic agents,
and the sustained effect observed in the extension studies and its continued
weight-lowering effects must be considered very promising.
Other analogs currently in clinical development include slightly modified
versions of the GLP-1 molecule that, by various means, attach to albumin
and thereby acquire the pharmacokinetic profile of albumin. One such analog
is Liraglutide produced by NovoNordisk, Bagsvrd, Denmark. It consists of
a slightly modified GLP-1 sequence to which is attached a palmitoyl chain.
Thereby, the molecule obtains affinity for and binds to albumin and, as a
result, escapes both DPP-IV and renal elimination. The plasma half-life of this
compound is approximately12 h, and it therefore provides exposure for more
than 24 h after a single injection (81). The compound seems to possess all
of the activities of native GLP-1(82). A recent report describes administration
of increasing doses of Liraglutide to patients with 2DM for 3 months (83).
Liraglutide lowered fasting blood glucose and HbA1c dose-dependent manner
(by up to 0.75% points from a base line level of 7.6%) and also significantly
lowered body weight in some doses. There were very few side effects and no
antibody formation. The strength of this compound seems to be its attractive
pharmacokinetic profile, providing a rather stable plateau of active compound
in plasma upon single daily injections. In this way, side effects (nausea and
vomiting) associated with large excursions in the plasma concentration of
more rapidly metabolized compounds after s.c. injection may be avoided. In a
recent study (84), Liraglutide was given in doses up to 2 mg OD in a 5-week
period with weekly up titrations to patients with high HbA1c levels (810%).
In particular when added on to metformin, Liraglutide powerfully reduced
fasting glucose levels (from 13 to 9 mmol/l) and caused a weight loss (of
2.4%). Gastrointestinal side effects were transient and led to withdrawal in
279
only 4%. Most recently, results from a 14-week trial of Liraglutide given once
daily as monotherapy to 165 patients were reported on the companys web site
(http://www.novonordisk.com). HbA1c was reported to decrease by 1.52%,
fasting blood glucose by >3 mmol/l and body weight to decrease by 3 kg from
90 kg. Notably, there were very few side effects, primarily a low rate of very
mild nausea initially and decreasing with time.
Other compounds include the Conjuchem compound, C-1131, composed of
a D-alanine-8-substituted GLP-1 molecule with a linker and a reactive moiety
(maleimidoproprionic acid) attached to the C-terminus, but the development
of this compound has recently been terminated.
The Albugon compound from Human Genome Sciences, Rockville, MD,
US which is a fusion protein between human albumin and a resistant GLP-1
analog, has recently attracted interest, because it was demonstrated (85) that
this large molecule not only had antidiabetic activity in animal models of
diabetes but also was capable of activating the neural mechanisms whereby
the much smaller molecules, GLP-1 or exenatide, influence gastrointestinal
motility, appetite, and food intake. In glucose-intolerant mice and in diabetic
rats, a single injection near normalized glucose levels for 24 h. The half-life
was said to be 3 days in monkeys (86).
INHIBITORS OF DPP-IV
The therapeutic use of inhibitors of the enzyme responsible for the inactivation of GLP-1 as antidiabetic agents was first proposed in 1995 (66) based
on the finding that GLP-1 seems uniquely sensitive to cleavage by DPP-IV,
and compounds of this class have now reached phase III clinical trials.
DPP-IV inhibition results in the N-terminal degradation of GLP-1, which
normally occurs in vivo being completely prevented, leading to significant
enhancement of its insulinotropic activity (72) . Studies in Vancouver diabetic
fatty rats have shown that chronic oral administration of the Probiodrug DPPIV inhibitor, isoleucine thiazolidide (P32/98), for 12 weeks improves glucose
tolerance, insulin sensitivity, and -cell responsiveness (87). The longer acting
Ferring inhibitor, FE 999-011, continuously inhibited plasma DPP-IV activity
and not only normalized the glucose excursion after oral glucose administration in insulin-resistant Zucker obese rats but also delayed the onset of
hyperglycemia in Zucker diabetic fatty rats (88). These effects were, at least
partly, due to increased intact GLP-1 concentrations that were also implicated
in the improved islet function seen after chronic treatment of high fat-fed
(glucose intolerant and insulin resistant) mice with valine-pyrrolidide (89).
Further support for the involvement of DPP-IV in mediating glucose tolerance
comes from studies in animal models, which lack DPP-IV activity (Fischer
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Holst and Deacon
rats, which have a mutation in the catalytic site, and CD26 knockout mice,
in which the gene encoding DPP-IV has been disrupted). Such animals
have improved glucose tolerance compared with their wild-type counterparts
(9092). The impairment in glucose tolerance that normally accompanies aging
is prevented in DPP-IV-negative Fischer rats and DPP-IV inhibitor-treated
control animals(92,93), whereas both Fischer rats and CD26 knockout mice
are protected against diet (high fat)-induced insulin resistance and glucose
intolerance (9395) . Again, the mechanism of action is thought to involve
preservation of endogenous GLP-1 levels, because the concentrations of intact
GLP-1 are elevated.
After these promising preclinical studies, the first clinical proof-of-concept
was obtained using the short-acting Novartis inhibitor, NVP-DPP728 (96).
When given twice or thrice daily for 4 weeks in patients with relatively mild
2DM (mean HbA1c of 7.4%), both fasting and prandial glucose levels were
lowered significantly, resulting in a reduction in HbA1c of 0.5%, and despite
the fall in glycemia, fasting and post-prandial insulin levels were sustained.
NVP-DPP728 appeared to be well tolerated, with only minor adverse events
being reported. However, some of these symptoms (pruritis and nasopharyngitis) may be a property of the compound itself rather than being class specific,
because they were not reported for another inhibitor, LAF237, subsequently
developed by Novartis. NVP-DPP728 has now been dropped in favor of
LAF237, which is longer acting and suitable for once-daily administration. A
clinical study with this compound was recently reported, showing it to have
a pharmacodynamic profile upon once daily administration which was similar
to that of its predecessor given two or three times daily (97). The mechanism
of action was suggested to be incretin mediated, because LAF237 treatment
increased both baseline and prandial active GLP-1 levels. As with NVP-DPP78,
insulin levels were not actually increased, but interestingly, glucagon levels
were significantly suppressed. Most recently, clinical data from long-term
studies, namely a 12-week controlled study in patients already on metformin
treatment, followed up by an extension period of 40 weeks, were published
(98). LAF 237 significantly lowered HbA1c levels from 7.7 to approximately
7% after 3 of months treatment, and this level was maintained for the remaining
period, whereas in the control group a significant increase was noted, resulting
in a difference between placebo-treated and LAF 237-treated patients of 1.1%.
In addition, meal-induced insulin secretion was impaired in the placebo group
and remained unaltered in the treatment group despite significantly lower
glucose levels. A post hoc analysis of these data indicated that the treatment
lead to significant and progressive improvements in beta cell function and
insulin sensitivity (99). This could indicate that LAF 237 exerted a beta cell
protective effect not noted in the placebo groups. Side effects were mild,
281
and importantly, hypoglycemia was not reported. However, in contrast to the

GLP-1 analogs, there was no change in body weight. Details regarding the
binding kinetics, type of inhibition, and selectivity with respect to other peptidases for the inhibitor, which is now called Vildagliptin or Galvus , were
recently published (100). In a recent clinical study, details regarding its action
on beta cell function and hormone levels were studied. The inhibitor significantly increased insulin secretion rate at 7 mmol/l glucose (the so-called insulin
secretory tone) and inhibited glucagon secretion while increasing levels of
active GLP-1 and GIP (101). A New Drug Application was filed with the
FDA in the spring of 2006 but approval has so far been delayed. In a recent
news release from the company, some of the phase III results were described.
Vildagliptin given once or twice daily was as effective as rosiglitazone in a
direct comparison study, and nearly as effective as metformin, and gave further
improvements when added to either metformin or rosiglitazone. Interestingly,
when added to existing but insufficient insulin therapy, vildagliptin improved
HbA1c levels, was associated with decreased insulin use, and completely
prevented hypoglycemia.
The Merck company (Merck & Co., Inc., Whitehouse Station, NJ, US) has an
inhibitor (MK-0431, now known as sitagliptin or Januvia ) and recently filed
a new drug application with the FDA (http://www.msd.com), but so far, less is
known about this compound (102). Results of placebo-controlled, single-dose
studies were recently published (103). MK-0431 was well-tolerated and caused
significant reductions in the glycemic excursion following an oral glucose
tolerance test (OGTT), associated with increases in intact GLP-1 and insulin,
and reductions in glucagon secretion. According to websites, several other
companies are developing DPP-IV inhibitors, including Bristol-Meyer-Squibb
(www.bms.com) (Phase III) and Prosidion (www.prosidion.com) (P93/01;
phase II). Single doses of P93/01 were reported to have good tolerability and
result in dose-related reductions in prandial glucose in type 2 diabetic subjects
when HbA1c was above 6% (104).
The clinical studies with DPP-IV inhibitors which have been reported so
far have not been associated with any serious adverse side effects, but there
has been understandable concern that undesirable side effects could arise from
inhibiting an enzyme with multiple substrates or because of non-mechanismbased actions (i.e., not related to the selective inhibition of DPP-IV). With
regard to the former, although a number of regulatory and neuropeptides,
chemokines, and cytokines have been identified as potential substrates from
in vitro kinetic studies [reviewed by (105)], it is uncertain how many of
them are actually endogenous substrates, and if so, whether DPP-IV-mediated
degradation is their primary route of elimination. In addition to GLP-1, the
other incretin hormone, GIP, is an endogenous DPP-IV substrate, as is the
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neuropeptide pituitary adenylate cyclase activating peptide (PACAP) (106),

but inhibition of their degradation would be expected to contribute to the
antidiabetic effects of DPP-IV inhibitors (107). The evidence for a physiological role for DPP-IV in the degradation of many of the other potential
substrates remains to be demonstrated. DPP-IV also has some other roles that
potentially could be compromised by DPP-IV inhibition. It is present on the
surface of T-cells (where it is usually known as the T-cell marker CD26) and
contributes to T-cell activation and proliferation through its interaction with
other membrane-expressed molecules such as CD45, although it is uncertain
whether the enzymatic activity is involved or even whether its presence is
mandatory (108). In this context, a family of DPP-IV-related enzymes is now
known to exist, which have similar catalytic activities. Selective inhibition of
two of these enzymes (DPP 8 and DPP 9) was recently reported to affect Tcell activation in vitro and be associated with severe, even lethal, side effects
in preclinical species (109), whereas selective DPP-IV inhibition was not,
suggesting that DPP 8 and 9 could be responsible for some of the functions
previously ascribed to DPP-IV. In turn, this raises the possibility that some
of the potential or reported side effects of DPP-IV inhibition could be due to
inhibition of DPP 8 and 9 rather than DPP-IV itself. It is, therefore, highly
relevant that the rodents that lack DPP-IV enzymatic activity (the Fischer rat
and the CD26 knockout mouse) are completely viable and seem to suffer no
ill effects because of the lack of DPP-IV. Selectivity data for the inhibitors in
development has so far only been released for the Merck compound, which
is reported to have >2500-fold selectivity for DPP-IV relative to DPP 8 and
9 (110) and for vildagliptin, which has 75-fold selectivity for DPP-IV relative
to DPP 8 (100) and between 32-fold and 250-fold relative to DPP 9 (Novartis
website).
CONCLUSION
As detailed in the sections on GLP-1 analogs and DPP-IV inhibitors, there is
ample evidence to suggest that treatment of 2DM will be feasible using either
DPP-IV inhibitors or GLP-1 analogs/receptor activators. One GLP-1 receptor
activator (Byetta) and one of the DPP-IV inhibitors are already on the market
and other compounds are in late phases of development or awaiting approval.
The question arises which principle to choose. If the DPP-IV inhibitors continue
to show minimal side effects, it would be tempting to suggest their use for
the treatment of very early 2DM, perhaps even prevention in groups with
a high risk for 2DM (familial disposition, obesity, glucose intolerance, and
previous gestational diabetes). On the other hand, as their ability to elevate the
levels of active endogenous GLP-1 is limited, it may be preferable to chose
283
an injectable GLP-1 analog in patients with long-standing disease and limited

beta cell capacity. The DPP-IV inhibitors are weight neutral in patients with
2DM, which in itself is an attractive feature, but the analogs appear to provide
a reliable weight loss. The most important parameter, however, is undoubtedly
the potential of the compounds to protect beta cells and, thereby, possibly break
the otherwise inevitable progression of disease. Although hard data regarding
this in humans are still lacking, the stable HbA1c levels observed in patients
treated long-term with both inhibitors and analogs as opposed to increasing
levels in placebo-treated controls may indeed indicate that progression has
been halted. Future studies directly addressing the beta cell protective effects
of either group of compounds will be of the greatest interest, also regarding
the choice of therapeutic principle.
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15
Controversies in Evaluation
and Management of Lipid
Disorders in Diabetes
Ronald B. Goldberg,
MD
CONTENTS
Introduction
Is Diabetes Really a Coronary Heart Disease
Risk Equivalent?
Are low carbohydrate diets more effective
than low fat diets in the initial
management of diabetic dyslipidemia, and
should greater use be made of weight loss
medicines and bariatric surgery in obese
diabetic subjects with comorbidities?
The First Priority in the Pharmacotherapy
of Diabetic Dyslipidemia is to Lower
LDL-C with a Statin; the Target Should
be an LDL-C of <100 Mg/Dl, and the
Benet is Due to LDL Lowering
Should antidylipidemic agents such as
brates, niacin or sh oil be added to
statin treatment for most patients given
the frequency of hypertriglyceridemia
and/or low HDL-C in type 2 diabetes?
Is it Time to Include Newer Lipoprotein
Measures in the Assessment
and Management of Diabetic Dyslipidemia?
References

291
292
Goldberg
Summary
Dyslipidemia is a key factors contributing to the high risk of cardiovascular
disease (CVD) in diabetes and its management is of prime importance.
However there are a number of controversies in this area which are dealt
with in this chapter. One of these is the extent to which diabetes increases
CVD risk, which turns out to vary considerably. A second question deals
with the preferred dietary and other weight loss therapies and their benefits
in dyslipidemic subjects. The third topic discussed deals with the question
of how low to go with LDL-cholesterol lowering, and in a fourth issue the
indications and approach to the use of second or third lipid-modifying agents
in combination with statin therapy is discussed. Finally the controversial
issue of whether apolipoprotein or lipoprotein subfraction measurements add
to the value of the standard lipid profile is debated.
Key Words: Diabetic dyslipidemia, management, cardiovascular disease
INTRODUCTION
Cardiovascular disease (CVD) is the major cause of morbidity and mortality
in diabetes (1), and thus identification and effective management of its determinants are crucial in the effort to improve health status and extend survival
in people with diabetes. Dyslipidemia is one of the major risk factors predisposing to CVD (2), and over the past decade, controlled clinical trials with
lipid-modifying agents have led to considerable advances in our understanding
of the relationships between the predictive value of lipids and lipoproteins for
CVD and the extent to which these interventions produce benefit (3). Despite
this, the evidence indicates that the majority of diabetic subjects are not at
lipid and lipoprotein targets (4), and given the fact that progress in reducing
CVD events in diabetic subjects over the past decade or two has been minimal
(5), more attention is required to convey to health care providers the requisite
urgency needed in targeting and achieving optimal lipoprotein levels. It is with
these considerations in mind that this discussion of controversial issues in the
evaluation and management of dyslipidemia in diabetes is presented.
IS DIABETES REALLY A CORONARY HEART DISEASE

RISK EQUIVALENT?
The advent of the National Cholesterol Education Programs (NCEP) Adult
Treatment Panel III (ATP III) guidelines for management of hypercholesterolemia did more than any other program to promote a risk-based approach
to the problem of CVD and its prevention (6). In particular, the concept of
Controversies in Evaluation and Management of Lipid Disorders
293
a coronary heart disease (CHD) risk equivalent state (20% 10-year risk of
hard CHD events) introduced the idea that individuals without heart disease,
but with the same risk for an event as those with established CHD, should be
as aggressively treated as the latter. Although this strategy has not formally
been accepted for management of other risk factors, the results of clinical
intervention trials in subjects with CHD statins has led to widespread support
for this approach as far as low-density lipoprotein cholesterol (LDL-C) levels
and therapeutic decision-making are concerned. Thus, the report from Finland
in 1998 that type 2 diabetic subjects without CHD had essentially the same risk
of myocardial infarction (MI) as did non-diabetic subjects who had already
experienced an MI (7) prompted the NCEP ATP III panel to label essentially
all type 2 diabetic subjects as having a CHD equivalent risk (6). This finding
garnered support quite soon from the Organization to Assess Strategies for
Ischemic Syndromes (OASIS) study (8), although an Australian study found
that the risk for CHD in diabetic individuals without CHD was significantly
lower than that in non-diabetic subjects with CHD (9). Since then, there have
been at least five reports indicating that men and women with diabetes but no
evident CHD have approximately a third to a quarter less relative risk for CHD
than do non-diabetic individuals with established CHD (913). The reason for
these discrepancies are unknown but likely have to do with differences in the
diabetic populations being surveyed, including factors such as age, severity,
and duration of diabetes (10,11).
More people with type 2 diabetes are being diagnosed at a younger age,
and age is a powerful CVD risk factor even in diabetes. In a prospective
observational study (14) of the incidence of macrovascular disease in 7844
newly diagnosed diabetic subjects in a large health maintenance organization
(mean follow-up 3.9 years), individuals diagnosed before the age of 45 years
(mean age at diagnosis was 38 years) had an MI incidence of 4.6% as compared
with 23.4% in those diagnosed after 45 years of age (mean age 60 years). The
respective incidences of stroke were 1.6 and 11.1%. There is far less clear-cut
evidence on how to grade the CVD risk of subjects with type 1 diabetes. The
Joslin clinic experience indicates that juvenile onset type 1 diabetic subjects
begin to develop a significant increase in CVD events by 40 years of age
irrespective of whether the onset of their disease was in the first or second
decade of life (15). It seems likely that in most diabetic subjects under the age
of 30 years, the 10-year risk of CHD events is considerably <20%, and health
care providers may wish to treat such individuals as they would the population
with intermediate risk.
Another issue of increasing importance, as the global explosion of diabetes
takes hold and with the expansion in numbers of immigrants and minority groups,
is the effect of ethnicity. In the Center for Disease Control and Prevention data
294
Goldberg
set (16), White men had a CVD prevalence of 38.7% (26% more frequent than
White women), Black men 31.3% (7.6% more frequent than Black women), and
Hispanic men 29.9% (26% more frequent than Hispanic women). In a 20-year
cohort study reported in 1996 from London, compared with Europeans, AfroCaribbean diabetic subjects had a risk ratio for CVD of 0.33 and for CHD of
0.37 (17), and in two studies from the Netherlands, both Moroccan and Turkish
immigrants with diabetes had significantly lower CVD mortality rates than did
diabetic subjects in the indigenous population (18,19). In the USA, earlier
data had suggested that despite greater rates of obesity and diabetes, MexicanAmericans had lower CVD mortality rates than did non-Hispanic Whites,
giving rise to the so-called Hispanic paradox. However, this was likely due
to migration factors and selection, because a more recent study indicated
that Mexican-American diabetic subjects born in the USA had higher CVD
mortality rates than Mexican-born individuals and indigenous non-Hispanic
Whites (20). It is also well-recognized that in the USA, Black subjects have
a higher risk of stroke than do Whites, but this does not appear to be the
case for diabetic individuals (21). Other factors influencing incidence of CVD
include the presence of hypertension (22,23) and, perhaps most significantly,
renal disease (24,25). Ultimately, the implications of these differences may be
important for individualized therapeutic decisions, but they do not significantly
minimize concern for the heightened risk of CVD in diabetic subjects.
ARE LOW CARBOHYDRATE DIETS MORE EFFECTIVE THAN

LOW FAT DIETS IN THE INITIAL MANAGEMENT OF DIABETIC
DYSLIPIDEMIA, AND SHOULD GREATER USE BE MADE
OF WEIGHT LOSS MEDICINES AND BARIATRIC SURGERY
IN OBESE DIABETIC SUBJECTS WITH COMORBIDITIES?
To begin with, it is important to be clear what the goals of lifestyle intervention in the management of diabetic dyslipidemia are. Most subjects with
type 2 diabetes are overweight or obese, and moderate weight loss may
improve diabetic dyslipidemia and other CVD risk factors as well lower glucose
levels. Therefore, weight loss is an important therapeutic strategy in targeting
all overweight or obese dyslipidemic individuals with diabetes. The primary
approach for achieving weight loss, in the vast majority of cases, is therapeutic
lifestyle change, which includes a reduction in energy intake and an increase
in physical activity, both of which are more likely to be facilitated in the
setting of a behavior modification program. A moderate decrease in caloric
balance (5001000 kcal/day) will result in a slow but progressive weight loss
(12 lb/week). For most patients, weight loss diets should supply at least
10001200 kcal/day for women and 12001600 kcal/day for men, and very
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low-calorie diets are not generally recommended. A low-fat diet is the conventional approach to initiating weight reduction as these have shown long-term
success (26). However, there is a recent interest in the use of low-carbohydrate
hypocaloric diets, because in the short term, they may result in greater
weight loss and better control of glycemia and dyslipidemia than conventional weight-reducing diets (27) as discussed further in this section. Physical
activity is an important component of a comprehensive weight management
program (28). Regular, moderate intensity, physical activity enhances longterm weight maintenance. Regular activity also improves insulin sensitivity,
glycemic control, and dyslipidemia, and increased aerobic fitness decreases
the risk of CHD. Initial physical activity recommendations should be modest,
based on the patients willingness and ability, gradually increasing the duration
and frequency to 3045 min of moderate aerobic activity 35 days per week
when possible (29). Greater activity levels of at least 1 h/day of moderate
(walking) or 30 min/day of vigorous (jogging) activity may be needed to
achieve successful long-term weight loss; however, exercise testing should
be performed at the discretion of the primary care physician before vigorous
exercise, particularly in patients with diabetes.
With respect to the effects of diet composition on improvement of diabetic
dyslipidemia, both NCEP and American Diabetes Association (ADA) guidelines
give first priority to lowering of LDL-C in the management of diabetic dyslipidemia as discussed further in the next section. They further concur in recommending that the intake of saturated fatty acids and trans-saturated fatty acids be
reduced to lower LDL-C levels (6,30). ATP III recommends limiting the intake
of saturated fat to less than 7% of the daily calories and the intake of cholesterol
to less than 200mg/day. This diet, also known as the step 2 diet, has been shown
in a meta-analysis to be associated with a 16% LDL-C reduction (31). Additional
dietary options to lower LDL-C include increasing the amount of soluble dietary
fiber to 1025 grams daily, adding 2 grams daily of plant stanols/sterols, and
including soy protein in the diet. These interventions have been associated with
a 515% reduction in LDL-C values (3235). However, as mentioned already in
relation to dietary weight loss approaches, the distribution of macronutrients in
the diet is a matter of debate particularly in individuals with diabetic dyslipidemia.
Low-fat, high-carbohydrate (>60% of total caloric intake) diets have been
associated with an increase in triglyceride and a fall in high-density lipoprotein
cholesterol (HDL-C) levels (36). When monounsaturated fat is substituted for
saturated fat in the diet, the LDL-lowering effect is similar to that obtained with
a low-fat, high-carbohydrate diet without the raise in triglyceride and the fall in
HDL levels (37). ATP III recommends limiting the intake of carbohydrates to
less than 60% in individuals with the metabolic syndrome and type 2 diabetes.
Furthermore, for individuals with elevated triglyceride and low HDL-C levels,
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lower carbohydrate intake (i.e., 50% of calories) could be considered, but very
low carbohydrate intake is not recommended. The ADA also recommends
replacing saturated fat with carbohydrates or monounsaturated fat (30) but does
not formally recommend very low-carbohydrate diets.
Low-carbohydrate diets have been used for many years and have recently
become even more popular. Though these diets may have short-term beneficial
effects on serum lipids, fasting glucose, and weight reduction (27), these
apparent benefits have not been shown to persist over a more lengthy period
and do not appear to lower LDL-C compared with higher carbohydrate, lower
fat diets (38). Furthermore, low-carbohydrate diets have not been adequately
evaluated in individuals with diabetes and hyperlipidemia, and their long-term
safety and efficacy remain unknown. Additional research is needed to clarify
the long-term efficacy and safety of low-carbohydrate diets, particularly in
patients with diabetes.
The role of weight loss medications and bariatric surgery in the management
of obesity in diabetes has not been well defined. Although there is clinical trial
evidence showing that the two currently available prescription medications with
an indication for weight reduction, sibutramine and orlistat plus dietary recommendations do increase weight loss, reduce HbA1c, and improve lipids in subjects
with type 2 diabetes compared with placebo and diet (39,40); the question as
to whether or when patients should receive these medications long-term given
their side effects, expense and unproven benefit except in short-term studies, is
unknown. Similarly, although bariatric surgery is reported to lead to withdrawal
of antihyperglycemic medications in approximately 60% of cases and to reductions of medicines in many others, most of these procedures are performed
for reasons other than for management of diabetes and its complications (41),
and most reports have been uncontrolled or inadequately controlled. What is
needed are long-term controlled clinical trials with the primary objective of
assessing whether bariatric surgery is more efficacious, safe, and cost effective
in the management of diabetes compared with standard medical therapy.
THE FIRST PRIORITY IN THE PHARMACOTHERAPY

OF DIABETIC DYSLIPIDEMIA IS TO LOWER LDL-C
WITH A STATIN; THE TARGET SHOULD BE AN LDL-C
OF <100 MG/DL, AND THE BENEFIT IS DUE
TO LDL LOWERING
At first glance, this statement appears to be non-controversial, but each
part of it has been and continues to be a subject of considerable debate,
and the issues at stake are considered to be crucial to a full understanding
of modern therapeutic strategies. Although the lipid profile in subjects with
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type 1 diabetes is usually unremarkable, it is well-recognized that the typical

abnormality in the lipid profile in subjects with type 2 diabetes is that of
elevated triglyceride and/or reduced HDL-C occurring together with average
LDL-C levels (42). It may be tempting therefore to view the high triglyceride/low HDL-C abnormality as the primary target for treatment. This would
require the preferential use of fibrates and niacin in pharmacotherapy after
lifestyle intervention rather than statins that have more modest effects on
triglycerides and HDL-C. However, the MRFIT study demonstrated that the
total cholesterola surrogate of LDL-Cis a powerful predictor of CVD
mortality in diabetic individuals (22), and the United Kingdom Prospective
Diabetes Study (UKPDS) established that in newly diagnosed type 2 diabetic
subjects, LDL-C was the most important predictor of CVD events, followed
by HDL-C, and then the HbA1c (43). The triglyceride level was not a significant predictor, as is the case in most epidemiologic studies of CVD risk
factors. Whether lipoprotein subfractions are more powerful CVD risk factors
than traditional lipid measures as discussed in the section dealing with newer
lipoprotein measurements.
For many years, LDL-C lowering in diabetes was included together with
the treatment of all subjects with elevated LDL-C levels, and diabetes (without
evident heart disease) was just another risk factor that helped to set the
boundary between what was an acceptable LDL-C level and what required
medical treatment. In 2001, when the ATP III panel recommended that diabetes
be considered a CHD-risk equivalent (6), treatment strategies changed. Given
the importance of LDL-C as a CVD predictor in diabetes even though LDL-C
levels typically are not elevated in these subjects, the concept developed that
highly active atherogenesis might progress in the presence of even below
average LDL-C levels because of ramped up arterial wall inflammation and that
this scenario operates in individuals with diabetes. Even though LDL-C levels
might be low, highly atherogenic small LDL particle numbers are frequently
elevated, and this has been advanced as a potentially important factor driving
progression of vascular disease (as discussed in the last section). Whatever
the mechanisms, the results of recent statin trials in high-risk and very highrisk subjects has borne out the correctness of this idea, demonstrating that
benefit accrues from the use of statins in subjects with relatively and recently,
absolutely low LDL-C levels irrespective of their triglyceride or HDL-C levels.
The modern paradigm, best illustrated in the Heart Protection Study (HPS)
appears to be that whatever the LDL-C level is in subjects with a CHD-risk
equivalent, statin therapy will reduce CVD if it achieves at least a 30% LDL-C
lowering (44). In HPS, the relative risk reduction from 40 mg/day simvastatin
treatment in subjects with CHD and/or diabetes and with a baseline LDL-C
130 mg/dl was the same as in those with an LDL-C 100 mg/dl, namely
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approximately 25%. Although there were only a small number of diabetic

subjects who fitted criteria for type 1 diabetes in HPS, they appeared to
benefit from simvastatin therapy in similar fashion to the rest of the diabetic
cohort. The participants in HPS were a mixed group of mostly non-diabetic
individuals with CVD, as well as of diabetic subjects with and without heart
disease, and therefore, the study was not able to address the question as to
whether this conclusion applied specifically to the majority of diabetic subjects
(6075%) who do not have overt CVD and whose absolute CHD risk may be
somewhat lower than 20% over 10 years. However, the Collaborative Atorvastatin Diabetes Study (CARDS) only randomized diabetic subjects without
evident CVD (and with one CVD risk factor) and with a baseline LDL-C < 160
mg/dl to atorvastatin 10 mg/day versus placebo treatment (45). They were able
to show that subjects above and below the mean LDL-C of 118 mg/dl had the
same relative risk reduction ( 35%) attributable to atorvastatin treatment. This
gives support to the notion that primary prevention in subjects with diabetes
should be considered even in subjects with below average LDL-C levels.
Based on the HPS results as well as those from PROVE-IT, a study demonstrating in a cohort with an acute coronary syndrome that subjects with atorvastatin 80 mg/day treated down to a median LDL-C of approximately 70 mg/dl
benefited more than those treated with pravastatin 40 mg/day whose median
LDL-C was approximately 100 mg/dl (46), the NCEP ATP III panel proposed
an optional lower LDL-C target of 70 mg/dl in very high-risk patients. The
panel continues to recommend a standard target of <100 mg/dl for subjects with
a CHD-risk equivalent, which includes those with diabetes but no CVD (47).
Although the PROVE-IT trial included subjects with diabetes plus CHD, the
results of this study in individuals presenting with an acute coronary syndrome
that is associated with a very high event rate cannot be extrapolated to the
majority of high-risk subjects with stable CHD. However, definitive evidence
that additional benefit accrues to subjects with stable CHD (as opposed to the
very high-risk group with an acute coronary syndrome) and average LDL-C
(130 mg/dl) levels treated down to a mean LDL-C of 77 mg/dl compared
with those treated to a mean of 101 mg/dl has now been demonstrated in
the Treatment to New Targets (TNT) Study (48). Although similar results
were demonstrated in the TNT subgroup with diabetes to that of the entire
cohort (49), there were no diabetic subjects without evident CHD in that
study. Thus, although the evidence may point to added benefit resulting from
statin treatment down to an LDL-C of 77 mg/dl in diabetic subjects with a
clear CHD equivalent, this is not established for younger, less complicated
diabetic subjects without CHD. It is also appears from TNT that the 22%
relative risk reduction achieved in lowering LDL-C from approximately 100
to 70 mg/dl is somewhat smaller than what has been reported in previous
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statin intervention trials with baseline LDL-C levels of 115 mg/dl, where
it is typically 2535%. In addition, despite the efficacy of modern LDL-C
lowering treatment, achievement of these very low LDL-C levels may not
always be attained. For example, at LDL-C levels 145 mg/dl, no more than
50% of subjects will attain an LDL-C of 70 mg/dl despite maximum doses of
potent statins in combination with ezetemibe (50). Finally, there is a greater
risk of adverse events at maximum statin doses. Like the NCEP ATP III, the
primary treatment strategy recommended by the ADA is directed at LDL-C.
The recommended LDL-C target is <100 mg/dl in individuals without established CHD and in those >40 years of age or in those with overt CVD, the
ADA recommends achieving an LDL-C reduction of approximately 3040%
regardless of baseline LDL-C levels; in addition, an optional target of 70 mg/dl
is indicated for those with CVD (51).
There has been considerable evidence that statins have pleiotropic antiinflammatory and antithrombotic effects (52), and the recognition that
atherosclerosis is characterized by inflammatory change in the vascular wall
has raised the possibility that statins might reduce CVD events through their
pleiotropic actions, in addition to effects on lowering of LDL-C. Although
it seems clear from statin intervention trials that there is a close relationship
between CVD event reduction and the degree of LDL-C lowering that is
either linear or more likely curvilinear (6), several clinical trials have provided
some suggestive evidence that there may be therapeutically important statin
effects independent of LDL-C lowering. Use of high-dose statin therapy in the
4-month myocardial ischemia reduction with aggressive cholesterol lowering
(MIRACL) study trial that demonstrated beneficial effects of statins in subjects
with an acute coronary syndrome (53) suggested the possible induction of
acute and subacute beneficial vascular changes not easily explained by the
traditional concepts of how statins reduce events, namely by slowing of
plaque progression through LDL-C reduction. Furthermore, subanalyses of the
coronary atherosclerosis and recurrent events (CARE) (54) and PROVE-IT
(55) trials showed that statin-induced decreases in levels of high-sensitivity C
reactive protein (CRP), a marker of subclinical inflammation and a powerful
predictor of CVD events, appear to predict benefit independently of LDL-C
lowering. In the PROVE-IT trial, the investigators showed that the benefit
achieved in lowering LDL-C levels below 70 mg/dl with statin treatment as
compared to those with values >70 mg/dl, approximated the benefit accruing to
those whose CRP levels were reduced to <2 mg/l by statin therapy relative to
those with CRP levels >2 mg/l and that the LDL-C-lowering and CRP-lowering
effects were additive. More support for this concept may be obtained if similar
results are obtained in the JUPITER trial in which subjects without CVD and
with levels of LDL-C < 130 mg/dl and CRP > 2 mg/l have been randomized to
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either 20 mg rosuvastatin or placebo treatment for a 3- to 4-year period (56).

This issue may have special importance for the prevention of CVD in diabetic
subjects in whom circulating markers and vascular levels of inflammation are
known to be elevated compared with non-diabetic comparators (57,58).
SHOULD ANTIDYLIPIDEMIC AGENTS SUCH AS FIBRATES,

NIACIN OR FISH OIL BE ADDED TO STATIN TREATMENT
FOR MOST PATIENTS GIVEN THE FREQUENCY
OF HYPERTRIGLYCERIDEMIA AND/OR LOW HDL-C
IN TYPE 2 DIABETES?
The prevalence of dyslipidemia in individuals with diabetes depends on the
criteria used to define it. Overall, 3040% of patients with type 2 diabetes
have triglyceride levels >200 mg/dl and 10% >400 mg/dl (59). Sixty two
percent of participants with diabetes in NHANES III aged 50 years and older
had triglyceride levels >150 mg/dl and 60% had low HDL cholesterol levels
(<40mg/dl in men and <50 mg/dl in women) (60). In the UKPDS, baseline
HDL-C levels were 9% lower in newly diagnosed men with type 2 diabetes
and 23% lower in diabetic women compared with non-diabetic controls (61).
Triglyceride levels were 50% higher in diabetic subjects than in controls,
whereas LDL-C values were similar in diabetic men and higher in diabetic
women compared with their non-diabetic controls. The frequency of LDL
phenotype B (preponderance of small-dense LDL particles) in diabetic subjects
is two-fold higher than in the rest of the population (62). As a comparison,
in subjects with impaired glucose tolerance 46% have triglyceride levels >150
mg/dl, 57% have HDL-C < 40 mg/dl in men and <50 mg/dl in women, and
41% of men and 25% of women have the small dense LDL phenotype (63).
After achieving LDL-C targets, NCEP ATP-III and ADA guidelines for
dyslipidemia management differ somewhat. That there is a need for further
antidyslipidemic therapy arises from the recognition that while benefits from
statin intervention trials are significant and robust, despite statin therapy, CHD
continues to develop in treated diabetic subjects at rates greater than that in the
general population. In addition, statins do not typically restore all components
of the lipid profile to an acceptable range. It has also been demonstrated
that achievement of all three lipid goals is more likely with combination
therapy (6466) in short-term studies. However, the added complexity and
risks of combination therapy in the absence of robust clinical trial evidence
for additional CVD benefit should place some limitations on the use of these
combinations. The presence of CVD would appear to be such an indication
because of the very large risk for recurrent events in these diabetic subjects; in
those without evident CVD, it would seem appropriate for subjects above the
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age of 40 years and/or with other major CVD risk factors, such as hypertension
or albuminuria. The presence of renal disease is a relative contraindication to
statinfibrate combinations.
According to ATP-III, for individuals with triglyceride levels >200mg/dl,
the secondary lipid target is the non-HDL-C (total cholesterolHDL-C). NonHDL-C correlates well with apoB levels and includes the cholesterol content of
all atherogenic lipoproteins that contain apo B, namely, LDL, lipoprotein (a),
intermediate-density lipoprotein, and very low-density lipoprotein (VLDL) (6).
The goal for non-HDL-C is set 30 mg/dL higher than the LDL target (<130
mg/dl for diabetic subjects). When triglyceride values are 500 mg/dl, triglyceride lowering becomes the first priority because of concerns about the risk
of pancreatitis. Low HDL-C is the third priority for management and HDLC-raising strategies may be considered in high-risk individuals with HDL-C
levels <40 mg/dl. However, in the NCEP guidelines, HDL-C target levels were
not established. By contrast, after achievement of LDL-C targets, the ADA
guidelines recommend raising reduced HDL-C and lowering elevated triglyceride levels as the second and third priorities, respectively, with low-risk levels
for HDL-C of >40 mg/dl in men and >50 mg/dl in women and for triglyceride <150 mg/dl (51). The ADA guidelines also emphasize the importance
of glycemic control and lifestyle interventions such as weight loss, exercise,
and smoking cessation in the management of hypertriglyceridemia and low
HDL-C levels. Improved glycemic control regardless of type of treatment is
associated with improved lipid values in individuals with moderate to severe
hyperglycemia. In the Veterans Affairs Cooperative Study in type II diabetes,
intensive glycemic control with insulin therapy, in which HbA1c was reduced
from 9.3 to 7.2%, was associated with a 31% reduction in triglyceride levels
after 1 year and 23% reduction at 2 years (67). LDL-C and HDL-C did not
change significantly from baseline in the intensive treatment group. Metformin
has been shown to lower triglyceride concentrations between 10 and 29%, with
beneficial changes of lesser magnitude in LDL-C and HDL in some but not
all studies (68). Both rosiglitazone and pioglitazone raise HDL-C and LDL-C
and increase the size of LDL, with pioglitazone increasing HDL-C up to 15%,
in one study, almost twice that achieved by rosiglitazone; pioglitazone, but not
rosiglitazone, lowers triglyceride and apo C-III (69).
Based on these considerations and using the more stringent ADA criteria
for elevated triglyceride and reduced HDL-C, about 60% of subjects will
require treatment for these abnormalities, whereas the corresponding number
for the NCEP criteria is about 40%. The focus of the NCEP on non-HDL-C as
the secondary treatment target tends to place further emphasis on statins and
ezetemibe, because of their effectiveness in lowering non-HDL-C. Statins are
the most effective agents for the lowering of non-HDL-C levels, because in
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addition to lowering LDL-C, they also reduce VLDL-C and IDL-C, probably by
enhancing their removal rates through the LDL receptor. It has been suggested
that at high doses, statins may reduce VLDL secretion as well (70). Therefore,
even if LDL-C are at target levels on statin therapy, increasing the dose of
statin or switching to a more potent statin would achieve greater non-HDLC and triglyceride lowering and help to achieve secondary lipid-lowering
goals. Furthermore, if significant triglyceride lowering is achieved with highdose statins, there is evidence that an increase in LDL particle size may be
achieved (71). In addition, treatment with statins also results in a greater
reduction of the total number of LDL particles and apo B concentration than
other agents. In this regard, it has been argued that apo B may be a better
marker of dyslipidemia than non-HDL-C (as discussed in the last section). In
comparison fibrates, niacin and high-dose fish oil have a rather modest nonHDL-C-lowering effect (10 mg/dl reduction of non-HDL-C for every 50 mg/dl
triglyceride lowering) except in more severe hypertriglyceridemia, where the
effect may be significant. By contrast, the ADA has had HDL-C raising as
its secondary target. Niacin is by far the most efficacious agent for raising
of HDL-C, as neither statins nor fibrates consistently produce >10% HDL-C
raising, whereas as little as 1000 mg Niaspan was shown in a year-long clinical
trial to produce a 21% increase in HDL-C, with little effect on non-HDL-C (72).
Thus, the two sets of guidelines tend to favor somewhat different secondline pharmacotherapeutic approaches. In part, these disparities result from a
lack of clearcut additional evidence for benefit resulting from the lowering of
non-HDL-C or raising of HDL-C. Each strategy is supported by circumstantial
evidence. In the case of non-HDL-C lowering, there are good data to indicate
that non-HDL-C is a better predictor of CHD than LDL-C (73), as well as
studies to show that each of the lipoprotein components of non-HDL-C are
atherogenic. However, there is as yet no data to show that lowering nonHDL-C with LDL-C held steady at its target has any additional benefit for
CHD outcomes. Similarly, there is extensive data demonstrating that HDL-C
is a powerful inverse predictor of CHD together with studies indicating that
HDL is antiatherogenic through its mediation of reverse cholesterol transport,
as well as through anti-inflammatory and antioxidant properties. The only
evidence that raising HDL-C is beneficial using traditional lipid-modifying
pharmacotherapy in a setting where the LDL-C is at target and kept constant
was reported in the recently published Arterial Biology for the Investigation
of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study. In this
study, 167 subjects with CHD on statin therapy and HDL-C levels <45 mg/dl
were randomized either to extended release niacin 1000 mg daily or placebo for
a year, and carotid wall intimal medial thickness (IMT) as a surrogate of CHD
progression was measured (72). Subjects receiving niacin had no significant
303
progression of carotid IMT as compared with those in the placebo group

which progressed significantly. HDL-C levels increased by 21%, and LDL-C
levels were unchanged (range of means before and after in placebo and niacin
groups was 8591 mg/dl). However, triglyceride levels fell significantly by 30
mg/dl, so that even in this study, the beneficial effects cannot be attributed to
HDL-C raising alone. There is also evidence from the Veterans Administration
HDL Intervention Trial (VA HIT) in which gemfibrozil treatment in statinfree men with CHD and a mean LDL-C of 111 mg/dl was associated with a
significant reduction in non-fatal MI and CHD death and that about 20% of the
beneficial effect could be ascribed to the modest net 6% increase in HDL-C
accompanying this treatment (74). Gemfibrozil treatment was also associated
with a 25% reduction in triglyceride levels, but this did not correlate with event
reduction. The absence of data that triglyceride lowering per se is associated
with CVD event reduction suggests that assigning a triglyceride target has
little practical value, and the ADA cutpoint of <150 mg/dl for triglyceride
probably serves best to identify increased CVD risk rather than a target for
treatment. Aside from these two studies, there is also evidence that infusion of
nascent HDL as synthetic apo A-I-Milano/phospholipid vesicles is associated
with rather rapid angiographic evidence of regression (75). Thus, although
there is some evidence supporting both the NCEP and the ADA second-line
therapeutic recommendations, clearly more work is needed to substantiate the
validity of these strategies.
From a more practical standpoint, the question of what to do beyond
LDL-C lowering is limited by the available pharmacotherapeutic agents. These
consist of fibrates, niacin, and high-dose omega-3 fatty acids. Combinations
of statin + fibrate, statin + niacin, and statin + fish oil have all demonstrated
short-term effectiveness in achieving treatment goals in type 2 diabetes or in
subjects with combined hyperlipidemia (6466). Whether these combinations
provide additive benefit beyond that achievable with statins is more debatable.
Evidence that gemfibrozil which like other fibrates has little effect on LDL-C,
but does lower triglyceride and increases HDL-C and LDL particle size,
reduced CVD events in the Helsinki Heart Study (76) and in the VA HIT (77)
provided support for the concept that fibrates prevent CVD in a different
manner to statins and would therefore likely have an additive vasculoprotective effect when added to statin therapy. Furthermore, in the VA HIT,
gemfibrozil appeared to be effective only in subjects with diabetes or insulin
resistance (78). However, the Bezafibrate Infarction Prevention and the recently
reported Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)
trials did not demonstrate a significant effect of these agents on their primary
endpoints (79,80). The results of the FIELD study are particularly disappointing, because it was conducted only in type 2 diabetes, most of whom
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did not have CVD, and it was hoped that this would finally provide the hard
event- based evidence in type 2 diabetes for fibrate therapy that the earlier,
smaller, and positive placebo-controlled angiographic Diabetes Atherosclerosis
Intervention Study (DAIS) using fenofibrate had hinted at (81). In FIELD,
the primary endpointnon-fatal MI plus CHD deathwas reduced by a nonsignificant 11% combined; separately, CHD death was increased by 19%
(non-significant), and non-fatal MI was reduced significantly by 24%. It is
difficult to understand why the results of the VA HIT and FIELD studies
differed so significantly, except that participants in the VA HIT trial all had
CHD and were not taking statins, whereas, as mentioned, most of those in
FIELD did not have CHD, and there was a significant statin drop-in rate.
Given these results, it is suggested that until further data are available (Action
to Control Cardiovascular Risk in DiabetesACCORD in 2010), combination
treatment with a statin and a fibrate should be used with caution, as the
risk of myopathy is increased, particularly in individuals with predisposing
conditions like renal failure (82). Myopathy and rhabdomyolysis have been
reported with simvastatin, cerivastatin, lovastatin, and atorvastatin in combination with gemfibrozil (8385). However, several short-term to medium-term
studies (n = 81420 subjects) evaluating the efficacy and safety of different
statinfibrate combinations in patients with combined hyperlipidemia have
shown a very low incidence of clinically significant myopathy and no cases
of rhabdomyolysis (8689). Additionally, gemfibrozil and fenofibrate differ
in their effects on statin pharmacokinetics. Gemfibrozil has been shown to
significantly inhibit the glucuronidation of statins, an important but previously
unrecognized metabolic pathway of statin catabolism, whereas fenofibrate
has little effect (90,91). This probably explains why plasma statin levels are
significantly increased with gemfibrozil treatment and not with fenofibrate.
In addition, analysis of national databases in the USA found fewer case of
rhabdomyolysis associated with fenofibrate compared with gemfibrozil therapy
in combination with statin treatment (92). Prior to the results of the FIELD
study, fenofibrate has been preferred to gemfibrozil for use in combination
therapy with statins but not in the presence of renal insufficiency (93). It is
now more difficult to justify this preference in light of the new data.
The addition of niacin to statin therapy has significant lipid-modifying
benefit as niacin lowers triglycerides by 2050%, reduces LDL-C by 525%,
raises HDL-C by 1535%, and lowers non-HDL-C and lipoprotein (a) moderately (94,95). Treatment with niacin also results in a shift in LDL and HDL
particle density from small dense to larger, more buoyant particles (96). The
only study that has evaluated the effect of niacin monotherapy on cardiovascular events is the Coronary Drug Project (CDP), published in 1975 (97). In
this study, 1119 men with a history of MI were allocated to treatment with
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niacin 13 g/day, and 2789 participants received placebo. The mean baseline
total cholesterol and triglyceride values were 250 mg/dl and 177 mg/dl, respectively. Despite a lack of benefit on total mortality, the risk of recurrent non-fatal
MI was reduced by 27% with niacin. A recent re-analysis showed that the
benefit of niacin treatment on recurrent MI was similar in patients at all levels
of blood glucose, including those with fasting blood glucose >126 mg/dl (98).
Evidence for a beneficial effect arising from the addition of niacin therapy to
statin treatment was suggested by the HDL Atherosclerosis Treatment Study
(HATS) (99). In this trial, the effect of combination therapy with simvastatin
and niacin compared with placebo on angiographic end points was evaluated
in 160 individuals with prior CHD and low HDL-C levels of whom 16% had
diabetes. Simvastatin plus niacin resulted in a significant angiographic benefit
with actual regression of lesions, an effect that has not clearly been documented
with statin therapy alone. Furthermore, despite the small sample size, treatment
with niacin plus simvastatin was associated with a significant 60% reduction in
cardiovascular events (CHD death, non-fatal MI, stroke, or revascularization
for worsening ischemia), which is a numerically greater effect than has been
demonstrated in monotherapy trials. Unfortunately, this study did not have a
statin-alone treatment arm, so the conclusions that niacin had an additive effect
on simvastatin therapy remain somewhat conjectural, although the ARBITER
2 results discussed above in this section (72) strengthen this position. A 5-year
clinical trial comparing simvastatin alone versus simvastatin plus extendedrelease niacin on recurrent events in subjects with established CVD and which
includes subjects with type 2 diabetes has just been launched (AIM HIGH)
and should answer this question definitively.
However, niacin has significant adverse effects. Hepatotoxicity is the most
important of these particularly with long-acting or sustained release niacin
preparations using doses >2000 mg daily. The extended release once-a-day
preparation of niacin (Niaspan) has been found to be effective and safe with
a low incidence of hepatotoxicity. Myopathy has been reported with the
combined use of niacin and lovastatin but has not been described in studies
of Niaspan and lovastatin in a single tablet formulation. The incidence of
myopathy associated with the combination of niacin and statins appears to be
significantly lower than with statins and gemfibrozil (100). Past use of niacin
in diabetic patients was limited because of concerns that this agent may lead
to deterioration in glucose control. Recent studies have shown only modest
increases in HbA1c values in most fairly well-controlled diabetic patients
receiving up to 3000 mg of immediate-release niacin (101) and up to 1500 mg
of Niaspan (102). Nevertheless, care should be exercised when using this agent
in diabetic subjects, and it is probably unwise to increase the niacin dose above
1000 mg daily if the HbA1c level is >8.0%. In addition to these safety concerns,
306
Goldberg
niacin may not be well-tolerated by a significant proportion of patients, particularly at higher doses, and it should be remembered that a history of gout, not
uncommon in diabetic subjects, is a relative contraindication. However, doses
as low as 1000 mg/day may have moderate HDL-C-raising effects (72).
The use of high-dose omega-3 fatty acids (38 gm/day) is another intervention that has shown to lower triglyceride levels by 1530% in diabetic
subjects in short-term studies without adverse effects on HbA1c or HDL-C and
only a slight increase in LDL-C values, and the availability of high-dose omega3 concentrates improves the tolerability of this treatment (103,104). Recently
the Japan EPA Lipid Intervention Study in a large long-term randomized
clinical trial demonstrated that 1.8 gm of esicoapentaneoic acid (EPA) added
to pravastatin therapy reduced CHD events by 19%, providing evidence that
addition of high dose EPA to statin therapy yielded further benefit. There is
in addition clinical trial evidence to show that low-dose omega-3 fat (0.31.0
g/day) reduces CVD mortality in populations with CVD, although there are no
specific data in diabetes (105).
In summary, the evidence in support of CVD benefit from niacin therapy is
somewhat more consistent than the results of fibrate therapy, there is preliminary evidence for an additive effect of niacin when added to a statin, and the
case for HDL raising is growing stronger. Limitation of niacin use because of
side effects or the presence of more severe hypertriglyceridemia might favor
addition of fibrates, and even though statinfenofibrate combinations may be
slightly safer than statingemfibrozil combinations, the clinical trial data are
more convincing with genfibrozil. High-dose omega-3 fatty acids constitute
a potentially safe hypotriglyceridemic agent for use in combination therapy,
particularly since it has been demonstrated to reduce coronary events.
IS IT TIME TO INCLUDE NEWER LIPOPROTEIN MEASURES

IN THE ASSESSMENT AND MANAGEMENT
OF DIABETIC DYSLIPIDEMIA?
A range of technologies have become available for large-scale measurement
of lipoprotein subfractions and apoproteins. These have been designated as
novel CHD risk factors by NCEP indicating that they may have added value in
predicting risk but have not yet acquired the abundance of evidence to warrant
being added to the standard lipid profile for risk assessment or management
decisions (6). These novel risk factors include apo B, apo E, apo C-III,
lipoprotein (a), lipoprotein particle size, especially LDL particle size, and HDL
subfractions. The decision to add a new measure to the standard lipid profile
would require that the method be widely available, that it demonstrate sufficient precision to be reliable over a wide range of conditions, that it have
307
independent risk-predictive value, that it adds to therapeutic decision-making

beyond what is currently available, and that the added cost be justified by the
clinical benefit it provides. From among these, measurement of total serum
apo B comes closest to meeting most of the above conditions; it is readily
available, and modern methods are sufficiently precise and inexpensive for
large-scale use (106). It has been argued that it is a more precise predictor of
outcomes (particularly when combined as a ratio with apo A-I) than LDL-C
or the LDL-C/HDL-C ratio (107,108), and although it correlates strongly with
non-HDL-C, it is not as strongly concordant (109), and several studies have
now shown it to be a better predictor of CHD than non-HDL-C (110,111). This
has been ascribed to the fact that apo B is a better measure of the number of apo
B-containing atherogenic particles than is non-HDL-C, and as it has become
clear that diabetic subjects tend to have smaller, denser LDL particles (as well
as HDL particles) and larger, lighter VLDL particles (112) and that apo B
gives a better measure of the number of particles than does non-HDL-C (113).
This assumes that the number of atherogenic particles is the most powerful
positive lipid predictor of CHD, but this remains to be proven. Certainly, in
diabetic subjects, it has been shown that in those with normal non-HDL-C
levels, apo B values may be frequently elevated (113). There is also evidence
that apo B may predict the response to statin and even fibrate therapy better
than does LDL-C (114). The Canadian Lipid Working Group has considered
these data and has adopted an apo B target of <0.90 g/l as an alternative to the
LDL-C target of <2.5 mmol/l (<100 mg/dl) in its guidelines (115), especially
in statin-treated subjects.
Although it has been difficult to prove consistently that LDL particle-size
measurements are more powerful predictors of CVD events than LDL-C or
non-HDL-C (116), the idea that LDL particle number may be a better predictor
than LDL-C, non-HDL-C or even apo B of CVD events, has been proposed
by the developers of the nuclear magnetic resonance spectroscopic method
that measures lipoprotein particle sizes and then calculates particle concentrations (117). Although this method does not produce the same particle-size
measurements as does the more traditional method of gel electrophoresis of
LDL, they do correlate well (118) although there is no available method with
which to assess and compare the particle concentration results. In a recent
analysis of the utility of measuring LDL particle number in the Framingham
Heart Study, although LDL particle number identified the metabolic syndrome
with high sensitivity, a higher small LDL particle number was not associated
with greater CVD event rates in people with the metabolic syndrome (119).
In the final analysis, the application of each of these new methodologies is
limited by what we know from therapeutic intervention trials. It is difficult
to know what further could be done in a diabetic subject with an LDL-C
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Goldberg
of 65 mg/dl, a non-HDL-C of 100 mg/dl, and an HDL-C of 44 mg/dl on a

combination of high-dose statin, ezetemibe, and extended-release niacin, who
is shown to have increased numbers of small LDL particles. Too often what
is lost in this debate is the benefit that would accrue to the patients we treat
if we were simply to adhere efficiently and rigorously to the NCEP and ADA
guidelines.
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16
Polypills for Treatment

of Type 2 Diabetes
Is the Concept of Polypharmacy Correct?
Werner Waldhusl,
MD
CONTENTS
Introduction
Characteristics of T2DM
Pathophysiology of T2DM
Risk Management and Treatment of T2DM
The Antidiabetic Polypill
References
Summary
Type 2 diabetes mellitus (T2DM) is a common disease frequently showing
complex multimorbidity in its late phase. Early stages lack clinical symptoms
and easily escape diagnosis. Once diagnosed, all treatments of T2DM are
based on adopting a healthy lifestyle and attempt to interfere with appetite,
body weight, glycemia, insulin sensitivity, blood pressure, and platelet
aggregation. But treatment regimens differ with the disease stage. Recently
polypharmacycondensed in a polypillhas been proposed as a tool of
primary and secondary prevention of cardiovascular disease and potentially
for primary and secondary prevention of T2DM. However, any antidiabetic
polypill would need to be tailored to one of the various stages of T2DM,
which differ considerably because metabolic and clinical defects evolve as the
disease progresses. Although a daily fixed-dose treatment might be helpful
from some of its aspects, any such polypill will encounter major obstacles.
These are not only due to the size and weight of its formulation but also
to the loss of therapeutic flexibility, which is mandatory to overcome acute
317
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metabolic derangements and to cope with intermittent increases in blood

pressure. Against such a background future, antidiabetic polypills will require
thorough testing not only as to their side effects but also as to their metabolic
efficacy and effect on normalization of body weight and life expectancy to
prove that they are superior to available treatment for the prevention and
treatment of T2DM.
Key Words: Depression, psychoneurohormones
INTRODUCTION
For decades, polypharmacy has been a reality for patients suffering from
fatefully progressing disorders. These include chronic cardiovascular disease
(CVD: requiring diuretics, beta-blockers, ACE-inhibitors, and aspirin), renal
disease (requiring diuretics, antihypertensives, resins, and if carrying a renal
transplant, immune suppressives), severe malign hypertension (requiring
multiple antihypertensives), or rheumatoid arthritis (requiring non-steroidal
analgetics, steroids, and immunosuppressives). Likewise in the early stages of
type 2 diabetes mellitus (T2DM), when obesity and/or hyperglycemia prevail
and treatment frequently resorts prematurely to biguanide, -glucosidase
inhibitors, and/or appetite suppressants instead of physical exercise, restriction
of calorie intake, and reduction of body weight. This is embarassing as lifestyle interventions have been shown to prevent and delay T2DM manifestation
in those prone to develop this disease (1,2).
Even more drugs are given in the late stages of T2DM when the microangiopathic sequelae of chronic hyperglycemia can result in diabetic retinopathy,
nephropathy, and neuropathy. During these stages, patients with T2DM
frequently require antihypertensives and lipid-lowering drugs, aspirin and
analgetics, in addition to antihyperglycemic agents.
Complete adherence to prescribed drugs can be as low as 20% (3). With
14% of prescriptions never taken up and 13% of prescribed drugs obtained
never ingested (4), it is no surprise that antihypertensive treatment regimens
frequently combine a diuretic and an ACE-inhibitor in a single pill to guarantee
better patient compliance. Such combipills benefit the patient as long as parallel
increases in dose do not cause any undesired side effects by overdosing one
of its components.
Wald and Law (5) conceived the idea of a polypill to more effectively
combat CVD and better protect all those at risk, that is, the entire population
above 55 years of age. The recommended contents were a statin, folic acid,
aspirin, and three antihypertensive agents each at half standard dose. Wald
and Law estimated that by this treatment, ischemic heart disease (IHD) could
Polypills for Treatment of Type 2 Diabetes
319
be reduced by 88% and stroke by 80%, a superb deal if proven correct. In

addition, one third of people taking the polypill would gain on average about
11 years of life free from events of IHD and stroke. The proposal of a polypill
to prevent and delay CVD in people above 55 years of age has provoked a
considerable debate (6,7).
The concept of combination pharmacotherapy has been extended beyond
CVD (5) to metabolic disorders and T2DM (8,9). Before embarking on any
project to design an antidiabetic polypill, (i) the characteristics of T2DM,
whose picture changes considerably during its natural course, and (ii) the
available treatment forms need to be considered. Only then can we answer the
question of whether an antidiabetic polypill might be superior to other forms
of intervention.
CHARACTERISTICS OF T2DM
Endocrinology textbooks (10) describe T2DM as a disease with a polygenic
disposition that is unveiled in response to interference by environmental factors
promoting overweight and obesity. Major players in that context include
physical inactivity, food intake in excess of energy expenditure, and a long-term
positive energy balance resulting in metabolic obesity with increased volume
of visceral fat, a predictor of T2DM (11). The prevalence of T2DM, which
accounts for 90% of all diabetes worldwide, has almost quintupled during
the second half of the twentieth century in the industrialized worldup in
Germany from only 0.71.0% shortly after World War II, at a time when food
supply was short and the burden of manual labor still considerable. Diabetes
is now the eighth leading disease in the calculated economic burden of disease
in high-income countries (12). This rising trend is set to continue with the
life-time risk of people born in the USA in the year 2000 developing T2DM
estimated to reach 32.8% for men and 38.5% for women (13). The incidence
and prevalence of T2DM depends, however, also on racial background, as
best exemplified in non-Hispanic blacks and Mexican Americans, who have a
1.6-fold and 1.9-fold greater prevalence than non-Hispanic whites (14).
In the long term, the burden of T2DM includes the sequelae of diabetic
microangiopathy, peripheral and autonomic neuropathy, and accelerated
macroangiopathy. These defects can result in manifest diabetic retinopathy
and premature cataracts, diabetic foot, and chronic renal failure, all of which
surface earlier in elderly than in young diabetic patients. Such secondary late
diabetic complications, which can become irreversible in the long run, require
thorough and specific care although they could largely be prevented by proper
and early treatment of T2DM (15,16,17). To be successful, treatment has to
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rest on a thorough knowledge of the pathophysiology of T2DM and to be

specific for each given state of the disease.
PATHOPHYSIOLOGY OF T2DM
Apart from hyperglycemia, key characteristics of T2DM include increased
hepatic glucose production, impaired glucose-stimulated insulin release, and
reduced insulin sensitivity of target tissues of insulin action (18), all of which
can already be seen years before the onset of the disease. These metabolic
dysregulations are aggravated in the elderly by age-associated impairments
of insulin secretion and insulin sensitivity, decreased physical activity, and
co-morbidities of all sorts as well asin partby the drugs needed for their
treatment. In addition, the aging process impairs glucose effectiveness, that
is, reduced insulin-independent glucose uptake.
Such impaired insulin action also referred to as insulin resistance not only
affects carbohydrate metabolism but also extends among others to insulins
ability to enhance blood flow, which is markedly impaired in obese insulin
insensitive elderly patients with T2DM (19).
Insulin resistance can precede overt hyperglycemia by decades in those
prone to later develop T2DM (20) but also associates with physical
inactivity, hypertension, and dyslipidemia including severe hypertriglyceridemia, ischemic cardiovascular disease (21), and polycystic ovarian
syndrome (22).
Any such loss of insulin sensitivity reduces insulin-stimulated glucose
disposal, which is accompanied by hyperinsulinemia in the obese (23) and by
impaired glucose transport/phosphorylation and glycogen synthesis in T2DM
(24) and obesity (25).
Among the factors detrimentally affecting skeletal muscle insulin sensitivity,
lipotoxicity of free fatty acids (FFA) is of considerable importance. FFA
inhibit insulin-stimulated glucose uptake at plasma concentrations within the
physiological range (26,27) and thereby promote the development of T2DM.
This is consistent with the improvement of muscle glucose disposal observed
in response to lowering plasma FFA concentration (28).
Glucose-stimulated insulin release, which depends both on glucose entry
into the beta cell and on its phosphorylation, seems in parallel to be impaired
by the same mechanism, particularly in response to long-term exposure to
elevated plasma FFA concentrations (29). Such ubiquitous reduction by FFAs
of glucose transport/phosphorylation possibly explains the inseparable coexistence of insulin insensitivity and abnormal insulin secretion in T2DM. Against
that background it would appear that chronic lipotoxicity begets hyperglycemia
and thus facilitates secondary glucotoxicity (Fig. 1) (30).
321
Fig. 1. Scheme of type 2 diabetes mellitus (T2DM) development. Based on excess supply
of fatty acids provided by both high fat/high calorie food intake and nocturnal lipolysis
reduces glucose transport/phosphorylation in skeletal muscle and potentially simultaneously
in beta cells. Such lipotoxicity impairs simultaneously glucose disposal, glucose sensing,
and insulin secretion. The resulting hyperglycemia (T2DM) is then further aggravated by
added secondary glucotoxicity. Reproduced with permission from (30).
RISK MANAGEMENT AND TREATMENT OF T2DM

Early/premature manifestation of T2DM in those prone to develop
the disease therefore largely depends on a positive energy balance due
to food intake in excess of energy expenditure resulting in obesity.
Proper risk management and prevention of T2DM thus wherever possible
have to overcome obesity by restricting food/energy intake and muscle
inactivity/atrophy through increasing physical activity. The clinical importance
of such change in life-style cannot be exaggerated, and its dominant role in
primary and secondary prevention of T2DM has been confirmed in several
major randomized clinical studies (1,2,31) in people at high risk for developing T2DM. Of note, reduction of body weight and promotion of physical
exercise reduced the cumulative incidence of T2DM by 50% over 3.2 years.
Not surprisingly, normalization of body weight and regular physical exercise
thus are the standard approach in the treatment of T2DM in its early stages.
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Waldhusl
As T2DM progresses, treatment becomes more complex, because in addition

to insulin resistance and impaired glucose-stimulated insulin release, the
disease can gradually result in a decline in basal insulin secretion and insiduously approach a state of overall insulin deficiency. Drugs have been approved
to tackle the resulting problems (Table 1) including different stages and risk
factors of T2DM. These drugs are aimed at reducing body weight (metformin,
rimonabont, orlistat; DPP IV inhibitors), insulin resistance (metformin and
glitazones), postprandial glycemia (-glucosidase inhibitors), and increasing
endogenous insulin release (insulin secretagogues: sulfonylureas, glinides;
GLP-1 mimetics, and DPP IV inhibitors).
The overall goal of any drug treatment is to improve glycemia and reduce
HbA1c, ideally to =6.5%, thereby avoiding or delaying indirectly the development of diabetes-associated microvascular complications (32). To this end,
self-monitored blood glucose values have been set as low as 70135 mg/dl by
the joint European cardiovascular prevention guidelines to account also for the
close dependence of endothelial function on blood glucose concentration (33).
The goals of treatment of T2DM, however, have to extend beyond the
control of hyperglycemia, which is critical for the prevention of microvascular lesions (32). Both dyslipidemia and hypertension have to be tackled
as well to prevent or delay macrovascular defects in the late stages of the
disease (15). The sequential use of antihyperglycemic drugs follows the natural
course of T2DM, whose phenotype is initially dominated by hyperglycemia
due to insulin resistance, overweight and obesity, and later, when weight loss
occurs spontaneously, by more markedly impaired insulin release. Rational
treatment of T2DM accommodates that pattern in its many guidelines with
attempts to reduce weight by physical exercise and cutting down food intake.
It then continues with metformin in diabetic patients still overweight, followed
by insulin secretagogues and glitazones before insulin therapy is instituted
(Fig. 2) (34).
In this context, one has to be aware that none of the drugs used for blood
glucose control directly treats established diabetes-associated eye and kidney
disease or any partialperipheral or autonomousbreakdown of the nervous
system or accelerated macroangiopathy. All these secondary defects of T2DM
may require additional and specific treatment particularly by antihypertensive
and antihyperlipidemic drugs but also local treatment once neuropathic ulcers
and proliferative diabetic retinopathy develop.
An analysis of the goals achieved controlling hyperglycemia, hyperlipidemia, and hypertension, however, gives a bleak picture. According to
NHANES III (35), 18% of all patients with diabetes surveyed had HbA1c
values above 9.5%, 34% had blood pressure greater than 140/90 mm Hg, and
58% had LDL-cholesterol above 130 mg/dl. Other data even show that only 2%
323
Table 1
Antidiabetic Drugs for the Treatment of T2DM not to be Substituted for Insulin
with Indirect (i) and Direct (d) Antihyperglycemic Action
Goal
Drug
Weight reduction
Absorption
inhibitors
Insulin sensitizer
Orlistat (i) (120 mg

t.i.d.)
Rimonabant (i)
(20 mg/day; appetite
suppressant)
(cannabinoid
receptor-1-inhibitor)
-Glucosidase
inhibitors (d)
(100 mg t.i.d.)
metformin (d)
[5002550 mg/day)
glitazones (i)
(445 mg/day)
Insulin
secretagogues
Oral
S.c. injection
As yet not approved.
Sulfonylurea (d)
(2nd generation
115 mg/day)
Meglitinides (d)
(0.5120 mg before
meals)
DPP-IV inhibitors (i)a
(LAF 237 50 mg/day)
GLP-1 mimetics (i)
(exenatide 510 g
b.i.d.)
Side effects
Fecal fat loss (soiling)
Loss of fat-soluble
vitamins
Weight loss (approximately
5 kg more than placebo)
Flatulence
Weight loss (010 kg/year)
Abdominal discomfort
Nausea
(lactic acidosis)
Weight loss (06 kg/yr)
Weight gain
(+113 kg/year)
Edema
Anemia
(hepatotoxicity)
Hypoglycemia
Weight gain (13 kg/year)
Hypoglycemia
Weight gain (13 kg/year)
Nausea
Nausea
(recovery of beta-cell
mass?)
Weight loss
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Waldhusl
Fig. 2. Rational treatment of type 2 diabetes mellitus (T2DM) accounting for the stages
of the disease, the need of lifestyle changes (diet and physical exercise), and the available
options of pharmacotherapy (metformin in those overweight, followed by insulin secretagogues and glitazones in stage II and early stage III before insulin therapy is instituted).
Reproduced with permission from (34)..
of all patients with diabetes had achieved all goals of therapy as recommended
by the American Diabetes Association (36).
Major obstacles to achieving the goals of proper diabetes care include among
others
1. partial or complete non-compliance by the patient for economic reasons, that
is, an inadequate health care system
2. non-compliance because of unrealistic polypharmacy in multimorbid patients,
that is, drugs are bought but not consumed
3. lack of patient motivation toward self-management
4. non-professionalism and/or lack of expertise on the side of the healthcare
personnel
5. environmental factors favoring obesity by promotion of excess food intake
(junk food) and avoidance of physical exercise (cars and television).
Some, but not all of these obstacles may be tackled by a polypill

that would reduce the number of pills to be swallowed by a given patient
requiring complex treatment. Before proceeding with a polypill, one has,
however, to remember that in those prone to develop T2DM removal of detrimental environmental factors, that is, of high energy food intake and physical
inactivity, could avoid manifestation of up to 80% of all T2DM, without any
pharmacotherapy (1,2,31). In the early stages of the disease, such an approach
325
can even transiently reverse hyperglycemia into a normoglycemic state. So

why develop an antidiabetic polypill?
THE ANTIDIABETIC POLYPILL

The concept of a pill to be taken once daily for the prevention, delay,
and/or alleviation of chronic disease originates from the desire to lower cardiovascular risk in the population at large and in those over 55 years of age
in particular (5). The proposed cardiovascular polypill with its six components (three antihypertensives, a statin, aspirin, and folic acid) would serve
to reduce blood pressure, plasma LDL-cholesterol, platelet aggregation, and
plasma homocystein. Wald and Law estimate the years of life gained by taking
the polypill from age 55 years onward would be 1124 for women and 1221
for men. By adding omega-3-fatty acids, cardiac rehabilitation, and diet to
the polypill, patients with coronary heart disease, post-myocardial infarction,
or stroke are projected to respond to such polyportfolio by experiencing a
reduction in clinical events of 84, 91, and 77%, respectively (37).
Designing an antidiabetic polyportfolio might help to overcome the difficulty
of convincing people at high risk for developing T2DM that a healthy lifestyle
can reduce the incidence of the disease (1,2) and in convincing patients that
adequate clinical care including proper self-management can minimize the
risk of manifest diabetes-associated late complications due to microangiopathy
(15,16,17,32). The unwillingness of the public at large and of patients already
suffering from T2DM in particular to benefit from available knowledge might
even be outwitted. Some obstacles, however, confront that simplistic attitude.
Primary and secondary prevention of T2DM require a more complex approach
than Wald and Laws polypill (5) if fixed combinations of antidiabetic drugs
are to be used atop of necessary changes in lifestyle.
Major problems to be dealt with arise from (i) the need to adequately
address the patients actual metabolic and clinical state, which requires targeted
intervention but no polypill and (ii) the change in phenotype with progression
of T2DM. These stages of the disease could for the sake of the argument be
categorized besides prediabetes (stage 0) as reversible (stage I), improvable
(stage II), and insulin deficient (stage III) (Fig. 2).
Polypills of different content would be required to adequately deal with the
specifics of a given stage. This would lead to at least four different polypills
each embedded in a polyportfolio providing for appropriate changes in lifestyle
(Table 2) if the goals to be met are defined as prevention of T2DM and as
successful treatment of its different stages.
In this context, polypill I would have to be for the prevention of T2DM in
those at high risk of developing the disease. It would need to tame appetite
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Waldhusl
Table 2
The Antidiabetic Polypill: Goals and Requirements of Treatment for Different
Stages of T2DM (for Definition of Stages, see Fig. 2)
Stage
Stage 0
(2)
Stage I
(2)
Stage II
(6)
Stage III
(6)
Goals
Prevention
Normalization of body
weight
Appetite control
Stimulation of physical
activity
Energy wasting
Treatment
weight
Appetite control
Stimulation of physical
activity
Energy wasting
Lowering of blood glucose
weight
Insulin secretagogues
Insulin sensitizer
Normalization of blood
pressure
Normalization/reduction of
LDL-cholesterol
Insulin secretagogues
Insulin sensitizer
Insulin
Normalization of blood
pressure
Normalization/reduction of
LDL-Cholesterol
Platelet aggregation
inhibition
total number of components, n.
Polypill components
n
2
Rimonabant
? (Lifestyle intervention)
Orlistat
2
2
Rimonabant
? (Lifestyle intervention)
Orlistat and
-glucosidase inhibitor
Metformin
As in stage 1
2
2
Sulfonylurea
Metformin (if obese)
Glitazone (if non-obese)
ACE-inhibitor
Statin
Sulfonylurea or glinide
Glitazone, metformin
ACE-inhibitor
1
2
Statin
Aspirin
327
long term (e.g., by rimonabant) and provide for a negative energy balance (e.g.,
using orlistat). Wishfully, I would like to add to the mix the as yet non-existent
drug stimulating the frequently lost natural desire for physical exercise.
Polypill II should then serve for treatment of T2DM in its early phase
(stage I). It would contain metformin (maximum dose 2550 mg/day) in addition
to the contents of polypill I to overcome insulin resistance and to lower blood
glucose.
Polypill III would have to cope with T2DM stage 2. Its task would be
to restore insulin availability and action by added sulfonylurea and glitazone
compounds, respectively, and to protect with an added statin against the
sequelae of hypercholesterinemia. Possibly a DP-IV inhibitor should be
addedonce availableto stimulate insulin release, delay gastric emptying,
and reduce body weight (38).
Polypill IV would most likely omit metformin, as in stage III patients
frequently approach normal body weight. In addition, it would complement
the other ingredients of polypill III with an ACE-inhibitor to protect against
hypertension and a premature decline in renal function and aspirin to inhibit
platelet aggregation in the case of cardiovascular disease.
As the concept of the polypill rests on ingestion of a single daily pill (5) any
design of an antidiabetic polypill will encounter major obstacles due to size
and weight (up to 3 g) of its formulation and due to loss of adequate dosing
intervals (e.g., t.i.d. for orlistat and metformin and before meals for meglitinide
and -glucosidase inhibitors). Furthermore, the possibility of overdosing single
components has to be taken into account, particularly when a polypill is
erroneously taken more frequently than once daily.
Thus, antidiabetic polypills would need to be thoroughly tested to prove
their superiority over available, more flexible treatments of T2DM. To this
end, key evidence-based criteria will have to include metabolic efficacy and
normalization of body weight as well as insulin release and, additionally,
undisturbed bioavailability of the polypills single components and absence of
any interference with individual drug action.
However, even if an apparently successful antidiabetic polypill could be
designed, it remains to be seen how any such formulation can overcome
poor regional diabetes care. Such deficiencies could result from an ineffective
or individually unaffordable health care system, from inadequate patient
motivation for proper self-management, from poor training of those responsible
for adequate patient education, or from a mix of them all.
Against such a background, a polymeal could be tastier and an adequate
physical exercise program a safer alternative than any antidiabetic polypill.
Calculated from the Framingham database, the benefits of a polypill and
exercise strategy promise an increase in overall life expectancy of 6.6 years and
328
Waldhusl
in life expectancy free from cardiovascular disease of 9.0 years (39). No doubt,
such change in life-style would also benefit patients with T2DM at all stages
and thus outmaneuver any antidiabetic polypill, particularly if target-oriented
incentives were used to motivate patients to reach set therapeutic goals both
for their metabolism and body weight (40).
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17
Comorbid Depression
and Diabetes
Natural History and Clinical Aspects
Richard R. Rubin,
PhD
CONTENTS
Introduction
Why Is Depression More Common Among
People With Diabetes?
How Depression Could Increase Ones Risk
of Developing Type 2 Diabetes
Psychoneurohormonal Mechanisms
Does Treating Depression Improve
Clinical Outcomes?
Conclusions
References
Summary
Depression, the leading cause of disability in the world, is more common
in patients with diabetes, and it is associated with negative outcomes in
these patients. These negative outcomes include less adherence to treatment
recommendations, higher blood glucose levels, higher rates of microvascular
and macrovascular complications, lower rates of productivity at work, higher
health care costs, and higher mortality rates.
This chapter addresses two key issues concerning comorbid depression
and type 2 diabetes: 1) why depression is more common in patients with
type 2 diabetes, and 2) whether relieving depression in patients with diabetes
improves clinical and other outcomes. It appears that depression is a risk
factor for developing type 2 diabetes, while having type 2 diabetes does
331
332
Rubin
not seem to increase the risk of becoming depressed. Depression may

increase diabetes risk via behavioral and/or psychoneurolhormonal pathways.
Depression treatment is effective in relieving depression in patients with
diabetes, and it can improve glycemic control in those whose control is
poor. This treatment can also improve work productivity and reduce health
care costs.
Key Words: Depression, type 2 diabetes, depression treatment
INTRODUCTION
Depression is the leading cause of disability in the world and the third
most common reason for seeing a primary care physician. Most studies find
an increased risk of depression in patients with diabetes. In a nationally representative sample of adults with diabetes, the 12-month prevalence of major
depressive disorder (MDD) was about 50% greater than the rate in the general
population: 9.36.0% (1,2). A meta-analysis of 20 controlled studies also found
higher rates of clinically significant depression symptoms among patients with
diabetes (20.5%) compared with those without diabetes (11.4%) (3). Among
people with diabetes, depression is associated with a host of negative outcomes,
including less adherence to diet, exercise, medication recommendations (47),
higher blood glucose levels (7), higher rates of microvascular and macrovascular complications (4,812), lower rates of productivity at work (13), higher
mortality rates (9,14,15), and higher health care costs (4,16).
The human and economic toll of comorbid depression and diabetes has
sparked interest in two important questions:
1. Why is depression more common in people who have diabetes?
2. Does relieving depression improve clinical outcomes?
WHY IS DEPRESSION MORE COMMON AMONG

PEOPLE WITH DIABETES?
Depression could be more common in patients with diabetes for a variety
of reasons. For example, the daily demands of living with diabetes or the
challenges created by diabetes complications could increase a persons risk
for becoming depressed. Or depression could increase a persons risk for
developing diabetes. Behavioral or hormonal effects of depression could have
that effect, especially in the case of type 2 diabetes. Finally, some other
process, such as aging or an as yet undetermined genetic factor, might increase
a persons risk for both diabetes and depression.
Comorbid Depression and Diabetes
333
Could Being Depressed Increase Ones Risk of Developing Diabetes?

In 1674, Thomas Willis, the British physician who identified glycosuria as
a sign of diabetes, was the first to address the natural history of comorbid
depression and diabetes when he stated that diabetes was caused by sadness or
long sorrow and other depressions and disorders (17). No one pursued Willis
provocative hypothesis for almost 300 years; then interest in the comorbidity
of diabetes and depression was renewed with a few studies published in the
1930s through the 1960s. These researchers pursued Willis general thinking,
searching for the diabetic personality in people with type 1 diabetes (18,19).
This search proved fruitless, and researchers turned from looking for emotional
causes of diabetes to looking for emotional consequences of the disease. The
fact that diabetes can be demanding in countless ways large and small led
many to assume that diabetes increased a persons risk for depression, not the
opposite. There were a few longitudinal studies of psychological adjustment
in young people with type 1 diabetes (20,21), but until about 10 years ago, we
had essentially no data to help us understand the natural history of depression
and type 2 diabetes.
Recent Evidence Suggests it Could

In 1996, Eaton and colleagues (22) published an interesting study, suggesting
Willis might have been right after all, at least when it came to a persons risk
for developing type 2 diabetes. This study was followed in 1999 by one in
Japan conducted by Kawakami and colleagues (23) that came to similar conclusions. These studies sparked others, and between 2003 and 2005, eight more
papers were published addressing the same question. These studies varied in
important respects, including how researchers determined whether a person had
diabetes at the beginning of the study, how depression was assessed, the study
populations, and the length of follow-up. Despite these differences, the results
of all but one of these studies lent at least some support for Willis hypothesis,
even when known risk factors for developing diabetes (demographic, behavioral, and metabolic) were controlled. These studies are discussed below and
described in Table 1.
The pioneering study of Eaton et al. (22) was the only one to assess depression
using a diagnostic interview rather than a self-report questionnaire; the former is
considered a more valid method and generally yields lower estimated depression
rates. This study followed 1715 people who said they did not have type 2 diabetes
when they entered the study. After 13 years, the people who had been depressed at
baseline were about twice as likely to have developed type 2 diabetes as those who
had not been depressed, controlling for demographic, behavioral, and metabolic
risk factors. Because of the small number of people who developed diabetes during
6190 men and

women
National Health
and Nutrition
Examination
Epidemiologic
Survey Follow-Up
Survey (NHEFS)
(Carnethon et al.,
2003)
General
Well-Being
Screener
2764 male employees Zung Depression

Screener
2254 premenopausal, CES-D
middle-aged women Depression
Screener
Kawakami et al.,
1999
Study of Womens
Health Across the
Nation (SWAN)
(Everson-Rose
et al., 2003)
Diagnostic
interview (DIS)
Number of Subjects Diagnostic method
East Baltimore
1718 men and
Site of the
women
Epidemiologic
Cachment Area
Survey (Eaton et al.,
1996)
Study
>15 years
2 years
8 years
13 years
Duration of
follow-up
RR = 3.0, 95%
CI = 2.04.7 for
subjects with <HS
education
HR = 2.31, 95%
CI = 1.035.20
OR = 2.28, 95%
CI = 1.26.4 for
African Americans
RR = 2.23, 95%
CI = 0.905.55
Findings
Table 1
Effect of Depression on Subsequent Risk of Developing Type 2 Diabetes
RR is NSD for
subjects with HS
education
p < 0.30; too few

cases in other ethnic
groups for reliable
assessment
p < 0.05
p = 0.08
Comments
8870 men and

women
72,178 female
nurses
11,615 men and

women
971 men and

women
10,308 civil
servants
1622 men and

women with
diabetes; 2279
without diabetes
NHEFS (Sadyah
et al 2003)
Nurses Health
Study (Arroyo,
2004)
Atherosclerosis
Risks in
Communities
(ARIC) Study
(Golden et al.,
2004)
Rancho Bernardo
Study (Palinkas
et al., 2004)
Whitehall II Study
(Kumari et al.,
2004)
Brown et al., 2005
Population-based,
case-controlled
administrative
database
General Health
Questionnaire
Depression
Screener
Beck Depression
Screener
Vital Exhaustion
Screener
Mental Health
Index Screener
CES-D
Depression
Screener
History of
depression in
previous 3
years
12 years
8 years
6 years
4 years
9 years
OR = 1.23, 95%
CI = 1.101.37 for
those 2050 years
of age
OR (men) = 1.17,
95% CI = 0.8-1.7;
OR (women)
= 1.08, 95%
CI = 0.61.9
OR = 2.50, 95%
CI = 1.294.87
Highest quartile
versus lowest
RH = 1.38, 95%
CI: 1.10-1.73
RR = 1.2, 95%
CI = 1.01.5
RH = 1.11, 95%
CI = 0.791.56
OR = 0.92, 95%
CI = 0.841.00 for
those 51 years of
age
OR for diabetes or
IGT significant for
both genders
Type 2 diabetes at
baseline not
associated with later
depression
p = .05
RH = 1.27 (95%
CI = 0.931.73) not
adjusting for BMI
and physical activity
336
Rubin
the study, this difference in diabetes rates between depressed and non-depressed
subjects was not statistically significant. Kawakami et al. (23) published a study
several years later on 2764 Japanese men whose diabetes status at baseline was
determined by self-report and medical records and reported findings similar to
those of Eaton et al. After 8 years, study participants who had been moderately or
severely depressed at baseline according to a validated self-report screener were
significantly more likely to have developed diabetes, controlling for other risk
factors. Those who had been identified as only mildly depressed at baseline did
not have an increased risk of developing diabetes during the study. In a result
similar to that of Kawakami et al., Golden et al. (24) found an increased risk of
developing diabetes over 6 years only among those in the highest quartile of vital
exhaustion, a proxy for depression symptoms. The study population was 11,615
adults participating in the Atherosclerosis Risk in Communities (ARIC) study.
Other researchers have reported that the effects of depression on diabetes
risk vary by demographic factors, including education, age, and race/ethnicity.
Carnethon assessed depression symptoms in 6190 adults who participated
in the National Health and Nutrition Examination Epidemiologic Follow-Up
Study and found a significant association with the risk of developing type 2
diabetes after a 15 year follow-up only in those with less than a high-school
education (25). In a retrospective database study, Brown et al. compared earlier
depression markers (diagnosis of depression or antidepressant medication use)
in a group of patients recently diagnosed with type 2 diabetes and a matched
sample that had not been diagnosed with diabetes. Among patients 2050
years old, prior depression markers were more common in those recently
diagnosed with diabetes, but this was not true for those over the age of 50 (26).
Everson-Rose et al. (28), following 2662 women in the Study of Womens
Health Across the Nation (SWAN) study, reported that depression screener
scores were significantly associated with 3-year risk of developing type 2
diabetes in African-American participants but not in Whites (27).
The findings of Arroyo et al. (28) were consistent with Willis hypothesis:
among 72,178 participants in the Nurses Health Study, those who had higher
depression screener scores were significantly more likely to develop type 2
diabetes over 4 years than participants with lower MHI-5 scores. Kumari et al.
(29) reported that depression was associated with higher blood glucose levels
in people who have normal glucose tolerance (NGT), leading to an increase
in the number of people developing impaired glucose tolerance (IGT). In this
report on 10,308 civil servants participating in the Whitehall II study, scores
on a depression screener predicted a composite measure of type 2 diabetes +
new IGT 12 years later, but these scores did not predict developing type 2
diabetes alone.
337
In a study that included some patients who already had diabetes, Palinkas
et al. (30) demonstrated not only that depression symptoms at baseline predicted
diabetes risk but also that study participants who had type 2 diabetes at baseline
were no more likely to be depressed at follow-up than those who did not
have diabetes when they entered the study. This is the only study that directly
assessed both causal possibilities.
Only Saydah et al. reported findings that provided no support for the
hypothesis that depression increases a persons risk for developing type 2
diabetes (31). In this study of 8870 adults who completed a depression screener
as part of the National Health and Nutrition Examination Epidemiologic
Follow-Up Study, there was no statistically increased incidence of diabetes
at 9-year follow-up for those with high or moderate baseline depression
screener scores compared with those with no depression symptoms. In this
study, reported depression rates were very high (15.9%), and diabetes status
at baseline was determined solely by self-report, which might account for the
lack of positive findings.
Overall, these studies suggest that depression could well be a risk factor
for developing type 2 diabetes, though this effect may vary according to
characteristics of the population (i.e., by. age, education, or race/ethnicity), and
it might not be present for patients with low levels of depression symptoms.
The possibility that depression could increase a persons risk for developing
type 2 diabetes appears more likely if one considers risk factors such as BMI
and physical activity as mediators of depressions effect on diabetes risk (i.e. as
mechanisms by which depression affects diabetes risk) rather than considering
these risk factors as confounders of depressions effect (i.e., as factors to be
eliminated in an effort to generate the most accurate estimate of depressions
true effect on diabetes risk). If we consider BMI and physical activity to be
mechanisms by which depression exerts its effect on diabetes risk, published
estimates that control for those factors underestimate depressions true effect.
If depression does increase a persons risk for developing type 2 diabetes,
the mechanism for this effect could be behavioral, psychoneurohormonal,
or both.
HOW DEPRESSION COULD INCREASE ONES RISK

OF DEVELOPING TYPE 2 DIABETES
Behavioral Mechanisms
Depression is associated with behaviors that increase a persons risk of
developing type 2 diabetes. For example, depression is associated with physical
inactivity (3235) and higher BMI (3640), and in the Womens Health
Study (WHS), BMI and physical inactivity were each independent risk factors
338
Rubin
for developing diabetes during the 7-year study (41). Physical inactivity can
increase diabetes risk indirectly by contributing to weight gain and directly
by decreasing insulin sensitivity and impairing glucose metabolism through
insulin receptor down-regulation in muscle and inhibited glucose delivery to
muscle. Several large randomized controlled trials (RCT) including the Da
Qing IGT and Diabetes Study, the Finnish Diabetes Study and the Diabetes
Prevention Program, have shown that decreasing BMI and increasing physical
activity can reduce the risk of developing type 2 diabetes in those at high risk
for the disease (4244).
Depression is associated with increased smoking, and smoking appears to
be associated with an increased risk of developing type 2 diabetes. Most
researchers have found higher levels of depression among smokers (4548). In
a 40-year study, the association between smoking and depression was assessed
in 1952, 1970, and 1992. In 1992, a smoker was three times more likely
to be depressed than a non-smoker (45). Smoking at baseline in this study
did not predict the onset of depression, but subjects who became depressed
during the 40-year study were more likely to start smoking and less likely
to quit than those who had never been depressed. Several studies have found
an association between smoking and the risk of developing type 2 diabetes
(4952). In one of the strongest studies that included standardized measures of
glucose tolerance to determine incident diabetes, current smokers in the Insulin
Resistance Atherosclerosis Study (IRAS) were almost three times as likely to
develop type 2 diabetes over 5 years as participants who had never smoked
(after multivariate adjustment for other diabetes risk factors) (49). For some
reason, this finding did not apply to subjects who entered the study with IGT.
Mechanisms by which smoking could increase diabetes risk include inducing
hyperglycemia and hyperinsulinemia (53), impaired insulin sensitivity through
impaired endothelial function (54), and the effects of cadmium on glucose
metabolism (55).
Depression is also associated with sleep disturbances (5659), but it is
unclear whether sleep disturbances are a risk factor for type 2 diabetes. Three
studies found that those who slept less (fewer than 5 or 6 h) or more (longer
than 9 h) than average (seven or eight hours) had an increased risk of later
developing diabetes (6062); in one of these studies (61), the association
remained significant only for long sleep durations after adjustment for BMI
and a variety of confounders and was no longer significant for short sleep
durations. Other researchers (63), found no association between sleep duration
or sleep complaints and diabetes risk in a 32-year follow-up of 1077 women.
IGT during sleep deprivation has been demonstrated (64); this could be the
mechanism by which sleep problems increase a persons risk for developing
diabetes, if these problems have that effect.
339
PSYCHONEUROHORMONAL MECHANISMS
Depression could also increase a persons risk for developing diabetes
through psychoneurohormonal mechanisms. Depression has been called a
stress response gone awry. Stress triggers the release of catecholamines,
growth hormone, and glucagon, all of which affect blood glucose levels.
In depression, this release is abnormally prolonged. People suffering from
depression also experience prolonged elevations in cortisol levels; chronically
elevated cortisol levels can contribute to hyperglycemia through a variety
of mechanisms, including synergy with other counter-regulatory hormones
to stimulate glycogenolysis, gluconeogenesis, lipolysis, and inhibition of
peripheral glucose transport and utilization (65). Michelson et al. established
that cortisol hypersecretion has clinical consequences when they demonstrated
that women who were depressed developed premature osteoporosis, a recognized side effect of elevated cortisol (66). Chronic hypersecretion of cortisol
and counter-regulatory hormones could contribute to insulin resistance in
patients with major depression (6770). Winokur et al. (71) demonstrated
that during oral glucose tolerance test (OGTT), depressed patients without
any diabetes risk factors had a greater increase in plasma glucose levels
and a greater decrease in plasma glucagon concentrations than non-depressed
individuals.
It is interesting to note that depression is also associated with hypersecretion
of proinflammatatory cytokines, including IL-1, IL-6, and tumor necrosis
factor-alpha (72), and with the expression of adhesion molecules. Elevated
proinflammatory cytokine levels in patients with diabetes are due to increased
production by adipose tissue (73) and to age-related increased secretion by
monocytes and macrophages (74,75). Cytokine hypersecretion may not only
interfere with insulin action and increase diabetes risk but also contribute to
increased risk for cardiovascular disease, the leading cause of death in patients
with type 2 diabetes.
Conclusions Regarding the Natural History of Depression

and Type 2 Diabetes
The current literature provides substantial evidence for the hypothesis that
depression increases the risk of developing type 2 diabetes and some evidence
for behavioral and psychoneurohormonal mechanisms that might account for
this effect. On the other hand, there is evidence that type 2 diabetes does not
increase the risk of becoming depressed (30) and that the initial onset of MDD
typically precedes the diagnosis of type 2 diabetes by many years (30,76).
This does not preclude the possibility that diabetes-related distress contributes
to the increased prevalence of depression among people with diabetes (77).
340
Rubin
Diabetes-related distress could partially explain the higher recurrence rates

and longer duration of MDD and depressive symptoms among those with
diabetes (78).
It is possible that the effects of depression on risk for diabetes are appreciable only for those who are already at high risk for diabetes. Depression
may worsen glycemic control only among those who already have impair-
Type 1 (14);
type 2 (14)
Type 1 (26);
type 2 (34)
Type 2 (51)
Type 2 (315);
type 1(14)
Type not
specified (417)
Lustman et al., 1997
Katon et al., 2004
Cognitive behavioral therapy.

Diabetes education.
c
Depression case management.
d
Usual care.
Williams et al., 2004
Subjects (n)
Study
DCMc versus UCd (12

months)
DCMc versus UCd (12
months)
CBTa + DEb versus

DE alone (10 weeks)
Fluoxetine versus
placebo (8 weeks)
Nortripyline versus
placebo (8 weeks)
Treatment
n > p: reduction in
depression screener
scores, proportion with
depression remission
F > p: reduction in
depression screener
scores, proportion with
significant improvement
CBT + DE > DE alone:
proportion with
depression remission
DCM > UC: reduction in
depression severity
DCM > UC: reduction in
depression severity
Effect on depression
Table 2
Effect of Depression Treatment on Clinical Outcomes
A1c levels
decreased in CBT
+ DE > DE alone
NSD A1c levels
DCM versus UC
NSD A1c levels
DCM versus UC
Trend (p = 0.13):
A1c levels
decreased in F > p
A1c levels
increased in n > p
Effect on clinical
outcomes
342
Rubin
CBT is designed to help patients identify mistaken and maladaptive thoughts

and to replace these thoughts with more accurate and adaptive ones. CBT
is also designed to increase patients engagement in enjoyable activities, and
it has been shown to improve depression in the general population (8789).
In the cognitive therapy study (86), the control treatment was an educational
intervention combined with supportive counseling, provided by nurses and
diabetes educators. The actively treated group received both the CBT and the
education/support intervention; the control group received only the latter.
In each study, patients receiving depression treatment (nortripyline, fluoxetine, or CBT) had a significantly higher rate of depression remission compared
with the control group (nortriptyline, 57% vs. 35%; fluoxetine, 62% vs. 31%;
and cognitive therapy, 85% vs. 27%).
Effects of depression treatment on A1C were mixed in these studies. Nortritpyline had a hyperglycemic effect; fluoxetine use was associated with a trend
toward lower A1c levels; and CBT was associated with significantly lower A1C
levels compared with control treatments. Nortriptyline improved depression,
but A1c levels rose during the 8-week study in the nortriptyline group while
they remained stable in the control patients. Path analysis that included all
subjects revealed a substantial (0.81.2%) reduction in A1C level attributable
to depression remission that was offset by an increase of similar magnitude in
A1C attributable to nortriptyline treatment. In the fluoxetine study there was a
trend (p = .13) toward greater A1C reduction among actively treated patients
compared with controls. In the CBT + DE study those in the active treatment
arm had a greater reduction in A1C levels compared with controls 6 months
after the intervention ended (0.9 vs +0.7%; p = 0.04).
Although these studies were well controlled, the number of patients involved
was small, so statistical power was limited. Very recently, other researchers have
studied the benefits of depression treatment in RCT that included more patients
with diabetes; their findings confirm the effectiveness of depression treatment
while providing little support for the hypothesis that this treatment lowers A1C
levels. In the Pathways Study, 329 patients with diabetes and depression were
randomized to a depression case management intervention or to usual care (90).
The case management intervention was an individualized treatment program run
by specially trained nurses who were supervised by psychiatrists and psychologists. Patients began treatment by choosing either short-term counseling with the
nurse (following a structured intervention protocol) or antidepressant medication;
the treatment was adjusted as needed. Depression symptom and A1C levels were
assessed at baseline and 3, 6, and 12 months later. Patients receiving the depression
intervention reported less depression severity over time than patients receiving
usual care, but both groups had identical reductions in A1C levels during the
343
study (baseline 7.99 1.55%; 6-month assessment 7.58 1.47%; and 12-month
assessment 7.64 1.57%).
The Improving Mood-Promoting Access to Collaborative Treatment
(IMPACT) Study included 417 people with diabetes and used a design nearly
identical to that used in the Pathways Study (91). The results of this study
were also very similarpatients assigned to the active intervention had less
severe depression at 12-month follow-up than those receiving usual care, but
HA1C levels declined to the same small degree in both groups (baseline 7.28
1.43% and 12-month assessment 7.11 1.38%).
Only one of the five studies described above found that depression treatment
lowered A1C levels. In that study, the only one that used counseling as the
exclusive intervention, mean baseline A1C level was 10.2% in the CBT group
and 10.4% in the control group, much higher levels than are seen in most
patients today. By contrast, the A1C levels of patients in the more recent larger
trials were lower (7.38.0%) than seen in many settings. Taken together, these
studies do not provide much support for the idea that depression treatment,
especially medication, will improve A1C levels for most patients, especially
those in reasonably good glycemic control.
Although these findings might be considered discouraging, it should be noted
that earlier small RCT found that fluoxetine treatment lowered A1C (9294) or
increased insulin sensitivity (95). It is also worth noting that in the Pathways
study, where A1c levels went down about 0.35% in both groups, about half
of the patients in the usual care arm were taking antidepressants as part of
their usual care. In addition, 45% of the patients in the intervention group still
had significant depression symptoms at 12-month follow-up, so more intensive
antidepressant treatment might have yielded additional glycemic benefits. This
suggests that study findings might underestimate the true effect of depression
treatment. Even if this is true, it is clear in patients with good glucose control
that it almost certainly requires enhanced diabetes self-management training
as well optimal depression treatment to lower A1C levels.
We should also keep in mind that depression could affect outcomes other
than A1C levels. We know, for example, that cardiovascular disease is
expressed earlier in the course of diabetes in patients who are also depressed
(96); would treating depression protect patients from this process? Studies to
address this question would be ambitious undertakings, given the length of
time (and the very large number of patients) required to answer questions about
long-term cardiovascular outcomes.
Depression treatment might also improve work productivity, another
important outcome. Depression has a negative impact on work productivity
in people with diabetes (97), and primary care-based depression management
incorporating a nurse case manager resulted in an annual improvement in
344
Rubin
productivity and reduced absenteeism of $2601 in a group of patients not

selected for having diabetes (98). The costs of the intervention were not
specified, but studies like this one have encouraged a few large health
insurance companies to begin paying for depression management programs,
including paying primary care physicians additional fees to screen patients for
depression and to provide follow-up consultation to patients who are prescribed
antidepressant medication or in more severe cases referred to a psychiatrist
or psychologist. One large insurer eventually plans to offer this program
nationwide (99).
CONCLUSIONS
Depression appears to be a likely risk factor for developing type 2 diabetes,
though many important questions about this relationship remain unanswered,
including the level of depression symptoms required to increase diabetes risk
(some have suggested that mild depression does not have an effect), the
magnitude of the depression-related risk (some found only statistically nonsignificant effects), whether depression elevates diabetes risk only in certain
demographic populations (some found depression effects risk only in African
Americans, younger patients, or those with less education), and the degree to
which behavioral and psychoneurohormonal factors mediate the relationship
between depression and diabetes risk.
Studies designed to answer these questions should include a population
sufficiently large and diverse to allow assessment of demographic variation
in depression-related diabetes risk. Participants ought to have an oral glucose
tolerance test to objectively determine their precise metabolic status at baseline
and during follow-up (a procedure not used in some previous studies). In
addition, the severity of depressive symptoms should be assessed, by means
of diagnostic interview if possible. Depression has cognitive, emotional, and
vegetative symptoms. Future research should determine whether each type of
symptom has the same association with diabetes risk.
Studies should also assess mechanisms that might explain the relationship
between diabetes and depression, should one be observed. For example, one
could test the theory that chronic mild cortisol excess causes the deterioration of glucose tolerance leading to type 2 diabetes. At least in the early
stages of progressive glucose intolerance, agents that block cortisol secretion
or cortisol action should ameliorate glucose metabolism in some depressed
patients. In patients with abnormal cortisol function, blocking cortisol should
improve glucose tolerance; in patients with normal cortisol function it should
have no effect on glucose tolerance. This approach could help determine
whether cortisol hypersecretion causes both depression and glucose intolerance
345
or depression leads to cortisol hypersecretion, which leads to glucose intolerance (and perhaps worsened depression as well) Answering these questions
could lead to new treatments for preventing type 2 diabetes.
Depression in patients with diabetes can be treated effectively with
medication or counseling (8485,9091). To date most randomized clinical
trials found that depression treatment was not associated with a greater
reduction in A1C levels than usual care (8485,9091), though the populations
in recent large trials had rather low A1C levels at baseline, and many patients
in the usual care groups received depression treatment. Future studies should
address important unanswered questions, including the effect of depression
treatment on outcomes other than A1C level (e.g., level of functioning, complications, health care utilization, and mortality), the effects of treatment rather
than treatment arm (to deal with the fact that in RCT many usual care patients
receive treatment), the efficacy of therapy rather than its effectiveness (to
deal with the fact that treatment in treatment arms of studies is often suboptimal), and the effects of combined antidepressant treatment and diabetes
self-management training on clinical outcomes.
This review has clinical implications. It indicates the potential benefits of
depression screening in those at high risk for developing type 2 diabetes,
because in this case, depression may well represent an additional diabetes
risk factor. Depression treatment should always be provided to patients who
need it, and it could prevent or delay the development of diabetes in some
individuals. Recognizing depression as an additional diabetes risk factor should
also heighten the clinicians attention to reducing other risk factors.
The association between depression and bad outcomes in those who already
have diabetes means clinicians should regularly screen patients for depression.
The clinician can identify patients likely to be depressed by asking two
questions about mood and anhedonia (the diagnostic and statistical manual
(DSM) -IV cardinal diagnostic criteria): During the past 2 weeks, have you
felt down, depressed, or hopeless? and During the past 2 weeks, have you
felt little interest or pleasure in doing things? Positive responses to one or
both questions should trigger questions about the remaining seven DSM-IV
symptoms, verifying the severity, frequency, and duration of any symptoms
that are present. Screening questionnaires may also be used before seeing the
patient to guide the discussion or determine whether the issue needs discussion
or after seeing the patient to confirm or document impressions.
Clinicians can choose from a variety of validated self-report questionnaires
for depression screening. Most patients can complete one of these questionnaires in <5 min; scoring takes <2 minutes, so results are available to discuss at
the same visit. One of the most widely used of these, especially in recent years,
346
Rubin
is the Patient Health Questionnaire-9 (PHQ-9) (100), which has questions that
match the DSM-IV diagnostic criteria for depression.
Patients identified as depressed should be treated or referred for treatment.
In 1994, 60% of patients being treated for depression received antidepressant
medication; 10 years later, the figure was over 80%. All commonly prescribed
antidepressant agents seem to be similarly effective when it comes to relieving
depression, so prescription decisions should be based on the patients prior
experience with these agents, cost, and likely side-effects. Tricyclic antidepressants and similar agents are more likely to contribute to sleepiness and weight
gain, and more likely to be associated with cardiac toxicity than bupropion
or the SSRIs and related agents (SSNRI and SSRIB), though some of the
latter agents also cause weight gain. Some SSRI and related agents have also
been associated with sexual problems in both men and women (101,102).
Effective treatment is more likely when (i) the dose is titrated (patients are
often exquisitely sensitive to side-effects and may stop treatment as a result);
(ii) patients understand that side-effects will diminish (and that full therapeutic
effect will not be felt for a few weeks); and (iii) insomnia is treated proactively (begin a sleep normalizing agent along with the antidepressant). As
noted, counseling, especially CBT, is also a proven treatment for depression
in patients with diabetes (86).
In summary, depression appears to be a risk factor for diabetes, depression
can be treated effectively in people with diabetes, and this treatment could help
reduce the great and growing human and economic toll of comorbid depression
and diabetes.
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J Clin Psychopharmacol 1999, 21:241242.
102. Rudkin L, Taylor MJ, Hawton K. Strategies for managing sexual dysfunction induced by
antidepressant medication. Cochran Database Syst Rev 2004, 18(4):CD003382.
Index
A1C level, 342343

see also Comorbid depression
Acarbose for metabolic syndrome, 42
ACCORD Trial
cardioprotection and earlier insulin therapy trials,
7980
diabetic retinopathy and, 102
HDL-C lowering study, 304
intensive therapy, 6465
see also Clinical trials
ACE
ACE/ARBs
for CVD, 43
for metabolic syndrome, 43
for type 2 diabetes, 43
metabolic syndrome, 3537
Acute sensory neuropathy (ASN), 113
see also Distal polyneuropathies
ADA guidelines, HDL-C lowering and, 300302
A-delta fiber pain, 124
see also Diabetic neuropathies (DN)
Adiponectin, 43
ADP-ribose polymerase, 241242
see also Hyperglycemia induced mitochondrial
superoxide production
AGEs (advanced glycosylation endproducts),
57, 235
Aldose reductase, 234, 235
Aldose reductase inhibitors (ARIs), 121
Alpha-lipoic acid, 121
Amino acid fragment of BSA (ABBOS), 185
Anticonvulsants, 124125
Antidepressants
comorbid depression treatment, 340
diabetic neuropathies (DN) treatment, 124
Antidiabetic polypill, 325328
polypill I, 325, 327
polypill II, 327
polypill III, 327
polypill IV, 327
Antioxidants, catalytic, 245
Antiplatelet treatment, diabetic retinopathy

and, 103
Apoproteins
for dyslipidemia, 306307
LDL-C level, 307
non-HDL-C level, 307
Appetite, GLP-1 effects on, 274
ARBITER study (HDL-C lowering), 302, 305
ARBs (angiotensin receptor-blockers)
for CVD, 43
ARIC study (comorbid depression), 336
Aspirin
CVD and, 103
ATP III, 300301
HDL-C lowering, 300
LDL-C lowering, 297
metabolic syndrome and, 3538
Autoimmunity, childhood type 1 diabetes and,
183186
Autonomic neuropathy see Diabetic autonomic
neuropathy (DAN)
Azathioprine, 17
Bariatric surgery, 294296
see also Obesity; Weight loss
Basal bolus approach, 63
Basal insulin
earlier insulin replacement initiation and,
8286
type 2 treatment using insulin, 7071
see also Prandial insulin
Behavioral mechanisms
comorbid depression, 337338
see also type 2 diabetes (T2DM)
-cell
autoimmunity, type 1 childhood diabetes
and, 184
endogenous, 2526
regeneration, 2526
353
354
replacement, 2325
see also Islet cell transplantation
-cell preservation and earlier insulin therapy, 73
insulin initiation timing (window of opportunity
concept), 7477
-cell dysfuntion, 7377
-cell loss, 7377
-cell rest hypothesis, 76
see also Cardioprotection and earlier insulin
therapy
Biguanides
metformin, 60
thiazolidinediones (TZD), 60
see also Intensive therapy
Binge eating disorder (BED), 206
see also Weight loss
Blood glucose control
with intensive insulin, 162165
see also Intensive insulin therapy for critically ill
(CI) patients
Blood pressure
lowering therapy, 64
see also Biguanides; Intensive therapy; Lipid
management; Thiazolidinediones (TZD)
B-mode ultrasound, 62
Bovine serum albumin (BSA), 185
see also Childhood diabetes
Breast-feeding, 184185
Bulimia nervosa, 206
Byetta, 277
see also Incretin effect
C fiber pain, 122123
Calcineurin inhibitors, 17
Calorie-restricted diet, 212
see also Diet strategies for weight loss
Cannabinoid CB-1 receptor blocker, 42
Carbamazepine
see also Anticonvulsants
Carbohydrate diets, low see Low carbohydrate diets
Cardioprotection and earlier insulin therapy
completed trials
Steno-2 study, 78
UKPDS, 77
ongoing trials, 78
ACCORD, 79, 80
ORIGIN, 80
Veterans Affairs Diabetes Trial (VADT), 79
see also -cell preservation and earlier insulin
therapy
Index
Cardiovascular autonomic neuropathy (CAN), 117
quantitative autonomic function tests
(symptomatic therapy aspects), 145
see also Diabetic autonomic neuropathy (DAN)
Cardiovascular disease (CVD), 52
ACCORD study, 64, 65
aspirin for, 103
complications
CAD, 52
DAD, 52
drug therapies
ACE/ARBs, 43
metformin, 41
Orlistat, 42
pioglitazone, 42
Rimonabant, 4243
thiazolidinediones (TZDs), 4142
HDL-C lowering, 303306
insulin, oral, 63
life style change aspects
CVD prevention, 3940
intensive, 5859
lipid disorders and, 292294
LDL-C lowering with statin, 297300
metabolic syndrome as risk factor for, 34,
3839
multiple risk factor approach and, 57
ORIGIN study, 65
thiazolidinediones (TZD) for, 60, 62
weight loss in type 2 diabetes and, 204206
CARE studyLDL-C lowering with statin), 299
Catalytic antioxidants, 245
CD26 marker, 282
Cell-based transplantation, 12
Charcot neuroarthropathy (CN), 260262
CHD see Coronary heart disease
Childhood diabetes, 179
comparison of type 1 and type 2 diabetes, 180
type 1, 180182
problem tackling, 190191
reaching epidemic levels, 182187
type 2, 180182
problem tackling, 191194
reaching epidemic levels, 187189
Cholesterol concentrations
lipid management aspects, 64
see also HDL (high density lipoprotein); LDL
(low density lipoprotein)
Chronic inflammatory demyelinating
polyneuropathy (CIDP), 113
immune therapy for, 122
see also Somatic diabetic neuropathies
355
Index
Clinical islet transplantation, 1617
immunosuppression aspects of, 16
Clinical outcomes, depression treatment effect on,
340344
Clinical trials
cardioprotection and earlier insulin therapy, 77
ACCORD, 7980
ORIGIN, 80
Steno-2 study, 78
UKPDS, 77
VADT, 79
intensive therapy
ACCORD, 6465
ORIGIN, 65
Cognitive behavior therapy (CBT), 340, 342
Collagenase, 1213
Comorbid depression, 331344
A1C level, 342343
cognitive behavior therapy (CBT) for, 340
depression treatment and clinical outcomes
improvement, 340344
diabetes risk and, 332337
fluoxetine for, 342
nortriptyline for, 342
selective serotonin reuptake inhibitors (SSRIs)
for, 340
tricyclic antidepressants for, 340
type 2 diabetes and, 331340
behavioral mechanisms, 337338
natural history of depression, 339340
psychoneurohormonal mechanisms, 339
Composite autonomic severity score (CASS), 146
Coronary artery disease (CAD), 52
Coronary heart disease (CHD), 293294
HDL-C lowering and, 302305
LDL-C lowering and, 297298
see also Cardiovascular disease (CVD); Lipid
disorders
Cows milk exposure, 184185
C-reactive protein (CRP)
insulin resistance aspects, 62
intensive insulin therapy for critically ill (CI)
patients and, 170171
CREATE ECLA study
patients and, 171
Critically ill (CI) patients
clinical complications, 158160
hyperglycemia in CI, 160
hyperglycemia and outcome of CI

patients, 161
hyperglycemia development, 160161
intensive insulin therapy, 157
blood glucose control, 162165
glucose toxicity aspects, 166170
hypoglycemia risk, 163164
improved outcome explaining
mechanisms, 166
non-glycemic metabolic effects, 170
non-metabolic effects, 170171
CVD see Cardiovascular disease
Da Quing Study, 203
Daclizumab, 18
DAIS study, HDL-C lowering and, 304
DAISY (Diabetes Autoimmunity Study in the
Young) study, 185186
DASH diet (metabolic syndrome), 40
DAWN (Diabetes Attitude, Wishes and Needs)
study, 81
DCCT (Diabetes Control and Complications
Trial), 21
diabetic retinopathy and
glycemic control, 96
pregnancy and, 104
serum lipids and, 102
see also Clinical trials; Diabetic complications
Deceased donor (DD) kidney
graft survival rate, 6
transplant
KTA, 3
PAK, 34
PTA, 4
SPK, 23, 8
see also Living donor (LD) kidney
DECODE Study (metabolic syndrome), 38
Depression see Comorbid depression
Diabetes
biguanides for, 60
blood pressure lowering therapy, 64
cardiovascular disease and, 52
childhood see Childhood diabetes
comorbid depression and, 332344
complications see Diabetic complications
DPP (Diabetes Prevention Program), 40,
202203
insulin, oral, 5963
356
lipid disorders in, 291
CHD aspects, 293294
CVD, 292297
dyslipidemia, 292, 296307
hypertriglyceridemia, 300306
low carbohydrate diets versus low fat diets,
294296
metformin for, 60
multiple risk factor approach for, 57
oral insulin therapy, 5963
pioglitazone for, 6062
pregnancy and, 103104
rosiglitazone for, 60, 62
thiazolidinediones for, 6062
treatment, 52
troglitazone for, 61
type 2 treatment see Type 2 diabetes treatment
using insulin
see also DCCT (Diabetes Control and
Complications Trial); Weight loss
Diabetes mellitus (DM), 51, 110
insulin resistance and, 52
see also diabetic neuropathies (DN)
Diabetes Prevention Program (DPP), 40
weight loss and, 202203
Diabetic autonomic neuropathy (DAN), 117119
quantitative autonomic function tests
(symptomatic therapy aspects), 144145
see also Distal symmetric polyneuropathy (DPN)
Diabetic complications, 233
advanced glycation endproducts (AGEs), 235
increased flux through polyol pathway, 234235
increased hexosamine pathway activity, 236238
protein kinase C activation, 236
therapeutic approaches
PARP inhibitors, 244245
transketolase activators, 244
unified mechanism and
diabetic macrovascular disease, 243244
hyperglycemia induced mitochondrial
superoxide production, 238242
see also DCCT (Diabetes Control and
Complications Trial)
Diabetic foot, 251
adjunctive therapies
hyperbaric oxygen (HBO), 263264
negative pressure wound therapy
(NPWT), 263
at-risk foot screening, 253255
charcot neuroarthropathy (CN), 260262
footwear role, 264
Index
future aspects, 265
infection, 259260
methicillin-resistant staphylococcus Aureus
(MRSA), 260
offloading, 258259
osteomyelitis, 260262
screening suggestions
examination, 255
history, 255
neurological assessment, 256
QST, 257, 258
vascular assessment, 257
ulceration pathway, 253255
Diabetic macular edema, 96, 100
see also Diabetic retinopathy
Diabetic neuropathies (DN), 109135
autonomic, 117119
classification, 111
defined, 111
diabetic peripheral neuropathy (DPN), 136138
nerve conduction studies (NCS), 141142
QOL aspects, 140141
quantitative electrophysiology, 141142
quantitative sensory tests, 143
SNAP tools for, 149150
VDT tools for, 149150
small fiber neuropathies, 125
somatic
acute sensory neuropathy (ASN), 113
chronic inflammatory demyelinating
polyneuropathy (CIDP), 113
diabetic truncal radiculoneuropathy, 112
distal, 113
distal symmetric polyneuropathy (DPN),
114116
focal and multifocal neuropathies, 112
proximal, 112
rapidly reversible hyperglycemic
neuropathy, 113
symptomatic therapy (symptoms as endpoint in
clinical studies), 136
candidates identification for participation in
research studies, 149150
cardiovascular autonomic neuropathy
(CAN), 145
composite autonomic severity score
(CASS), 146
diabetic autonomic neuropathy (DAN),
144145
electrophysiology, 141, 142
heart rate variability (HRV), 145
Index
minimally clinically important differences
(MCID), 138
nerve conduction studies (NCS), 141142
nerve symptom change (NSC), 138
Neurologic Impairment Score (NIS), 140
Neurologic Symptom Score (NSS), 136
neurological examination, 139140
Neuropathy Symptoms and Change (NSC)
score, 138
Neuropathy Total symptom Score-6
(NTSS-6), 138
neurovascular function, 147149
quality of life (QOL aspects), 137, 140141
quantitative autonomic function tests, 144146
quantitative sensory tests (QST), 140144
Total Neuropathy Score (TNS), 140
Total Symptom Score, 138
treatment
A-delta fiber pain, 124
adjunctive management and complications
treatment, 125
anticonvulsants for, 124125
antidepressants for, 124
C fiber pain, 122123
electrical cord stimulation, 126
frequency-modulated electromagnetic neural
stimulation (FREMS), 126
glycemic and metabolic control, 120
immune therapy, 122
infrared light therapy, 126
magnetic field therapy, 126
mechanical measures, 126
neurotrophic factors, 121
of specific underlying pathogenic
mechanisms, 120122
of symptoms and improvement in quality of
life, 122124
oxidative stress, 120121
PKC-beta inhibitors, 121
surgery for, 127129
transcutaneous nerve stimulation
(electrotherapy), 126
see also Diabetes mellitus (DM); Diabetic
complications; Diabetic foot; Diabetic
retineopathy
Diabetic peripheral neuropathy (DPN) see under
Diabetic neuropathies (DN)
Diabetic retinopathy, 95104
antiplatelet treatment, 103
aspirin treatment, 103
glycemic control and, 9697
hypertension and, 99100
pregnancy and, 103104
357
Diabetic truncal radiculoneuropathy, 112
Diabetic vascular disease, 53
Diet strategies for weight loss, 210215
dietary adherence in weight loss programs,
214215
dietary intake in registry members, 210211
Exchange Diet Plan, 215
low-fat versus low-carbohydrate diets,
211213
MRs, 214215
physical activity combined with diet more
effective for weight loss?, 217219
sibutramine use, 215
standard behavioral treatment (SBT), 214
see also Physical activity strategies for
weight loss
Dietary treatment (metabolic syndrome), 40
DIGAMI study
patients and, 171
Dipeptidyl peptidase IV (DPP-IV), 269282
FE 999011, 279
LAF237, 280
NVP-DPP728, 280
see also Glucagon-like peptide-1 (GLP-1)
Dipyridamole Aspirin Microangiopathy of Diabetes
(DAMAD) study, 103
Distal polyneuropathies
acute sensory neuropathy (ASN), 113
neuropathy, 113
Distal symmetric polyneuropathy
clinical presentation, 114
diagnosis, 114116
nerve conduction studies, 115
quality of life (QOL), 116
quantitative sensory testing, 115
skin biopsy and quantification of
intraepidermal nerve fibers, 116
DPP-IV see Dipeptidyl peptidase IV
Dyslipidemia
antidylipidemic agents added to statin treatment,
300306
apoproteins for, 306307
aspirin use, 96
lipid disorder, 292
358
low carbohydrate diets versus low fat diets,
294296
newer lipoprotein measures, 306307
see also Diabetic complications
Dysmetabolic syndrome, 147
Earlier insulin replacement
complexity barriers overcoming, 8090
basal insulin, 8286
inhaled insulin, 8790
NPH insulin, 8283
prandial insulin, 8690
need, 72
earlier insulin therapy and cardioprotection,
7780
earlier insulin therapy and -cell preservation,
7377
Early Treatment Diabetic Retinopathy Study
(ETDRS), 99
Eating disorders
binge eating disorder (BED), 206207
Edema, diabetic macular, 96, 100
EDIC study
diabetic retinopathy
Edmonton protocol (islet cell transplantation),
1720
EGIR criteria (metabolic syndrome), 3538
Electrical cord stimulation
diabetic neuropathies (DN)
symptomatic therapy aspects, 142
treatment, 126
see also Infrared light
Electrophysiology
diabetic foot screening, 258
diabetic neuropathies (DN), symptomatic therapy
aspects, 141142
Electrotherapy, 126
Encapsulation (islet cell transplantation),
12, 2325
Endogenous beta-cell regeneration, 2526
Endothelial NO synthase (eNOS), 63
Energy-restricted diet, 212213
Enteroviral infection, 183184
ETDRS study (diabetic retinopathy)
aspirin and antiplatelet treatments, 103
Index
EURODIAB study
glycemic and metabolic control, 120
Exchange Diet Plan, 215
Exenatide (incretin effect), 277279
Exercise, 219220
weight loss
Exubera (earlier insulin replacement aspects), 87
Fat diets, low see Low fat diets
Fat-restricted diet, 212
FE 999011, 279
Fibrate therapy, HDL-C lowering and, 304
Fibrinolytic activity, TZD and, 62
FIELD study (HDL-C lowering), 303304
Fluoxetine, 340, 342
Focal neuropathies, 112
Food intake, GLP-1 effects on, 274
Foot, diabetic see Diabetic foot
Framingham Studymetabolic syndrome), 38
Free fatty acid (FFA), 243244, 320
FREMS (frequency-modulated electromagnetic
neural stimulation), 126
Gabapentin
Gamma-linolenic acid, 121
GAPDH see Glyceraldehyde-3-phosphate
dehydrogenase
Gastrointestinal tract, GLP-1 effects on, 274
Gemfibrozil, HDL-C lowering and, 304
GIP see Glucose-dependent insulinotropic
polypeptide
Glargine (earlier insulin replacement aspects), 83
Glucagon-like peptide-1 (GLP-1), 269279
analogs (incretin mimetics), 277279
in type 2 diabetes, 273276
effects on appetite and food intake, 274
effects on gastrointestinal tract, 274
effects on islets, 273274
see also Dipeptidyl peptidase IV (DPP-IV)
Glucose control
blood glucose, 162165
see also Glycemic control; Intensive insulin
therapy for critically ill (CI) patients
Glucose-dependent insulinotropic polypeptide
(GIP), 269273
Glucose toxicity (intensive insulin therapy for CI
patients), 166170
Index
GLUT-1/2/3/4, 167
GLUT-4 controls, 165
Glycemia, 96
Glycemic control
intensive insulin therapy and, 162
weight loss in type 2 diabetes and, 204205
see also Glucose control
Glyceraldehyde-3-phosphate dehydrogenase
(GAPDH)
damaging pathways activation aspects, 240241
inhibition by activating poly(ADP-ribose)
polymerase, 241242
see also Hyperglycemia induced mitochondrial
Graft survival rate, 1
DD, 6
PAK, 46
PTA, 37
SPK, 37
HATS study, HDL-C lowering and, 305
HbA1c reduction, 5556
HBO see Hyperbaric oxygen (HBO)
HDL (high density lipoprotein)
diet strategies for weight loss, 213
dietary weight loss approaches and, 295
patients and, 170
thiazolidinediones (TZD) effect on, 61
see also LDL (low density lipoprotein)
HDL-C lowering
ACCORD study, 304
ADA guidelines, 300302
ARBITER study, 302, 305
ATP-III recommendations, 300
CHD and, 302305
CVD, 303304, 306
DAIS study, 304
dyslipidemia pharmacotherapy and, 300306
fibrate therapy, 304
FIELD study, 303304
gemfibrozil for, 304
HATS study, 305
NCEP criteria, 301
niacin for, 304305
pioglitazone for, 301
rosiglitazone for, 301
359
simvastatin therapy, 305
UKPDS study, 300
VA HIT, 303
with statin, 300306
see also LDL-C lowering; non-HDL-C lowering
Heart Outcomes Prevention Evaluation (HOPE)
study (intensive therapy), 64
Heart Protection Study (HPS)
intensive therapy and, 64
LDL-C lowering , 297298
Heart rate variability (HRV), 145
Hexosamine pathway activity
increased, 236238
Hyperbaric oxygen (HBO), 263264
see also Diabetic foot
Hyperglycemia, 53
in critically ill (CI) patients
hyperglycemia and outcome of CI
patients, 161
hyperglycemia development, 160161
see also Diabetic complications; Hypoglycemia
Hyperglycemia induced mitochondrial superoxide
production
four damaging pathways activation by GAPDH
inhibition, 240241
GAPDH inhibition by activating
poly(ADP-ribose) polymerase, 241242
production increase, 238240
Hypertension
Hypertriglyceridemia
antidylipidemic agents for, 300306
see also Statin
Hypoglycemia
in CI patients, 163164
see also Hyperglycemia
IDF criteria (metabolic syndrome), 3537
IENF, 148
IEQ number (islet cell transplantation), 15
Immune therapy for diabetic neuropathies (DN)
treatment, 122
Immunosuppression
aspects of transplantation, 3
clinical islet transplantation and, 16
islet cell transplantation and, 12, 17
T1DM and, 17
Incretin effect, 270282
DPP-IV inhibitors, 279282
exenatide, 277
360
GLP-1
analogs (incretin mimetics), 277279
in diabetes, 273276
insulin resistance and, 271
type 2 diabetes, 271276
Incretin hormones
GIP, 269273
GLP-1, 269273
Infection, diabetic foot, 259260
Inflammatory syndrome, 147
Infrared light, 126
Inhaled insulin
earlier insulin replacement initiation and, 8790
see also Oral agents
Instant total contact cast (iTCC), 259
Insulin
independence, pancreas transplantation and, 12
inhaled, 8790
oral, 62
basal-bolus approach, 63
for CVD, 63
replacement
earlier, 7190
resistance, 52
incretin effect and, 271
nitric oxide production and, 53
T2DM and, 320
Insulin resistance syndrome (IRS), 59
Insulin therapy
intensive, 56, 58, 6263
see also Biguanides; Insulin therapy for critically
ill patients; Thiazolidinediones (TZD)
Intensive insulin therapy for critically ill (CI)
patients, 157171
blood glucose control aspects, 162165
clinical complications associated with CI,
158160
glucose toxicity and, 166170
hyperglycemia in CI, 160161
hypoglycemia risk, 163164
improved outcome explaining mechanisms, 166
non-glycemic metabolic effects, 170
non-metabolic effects, 170171
Intensive life style change, 5859
Intensive therapy
advantages, 5457
benefits mechanisms, 5758
blood pressure and, 64
Index
clinical trials
ACCORD, 6465
ORIGIN, 65
complications preventing approaches, 58
CREATE ECLA, 56
DCCT study, 5456
DIGAMI study, 56
EDIC study, 5455
for diabetes, 5457
intensive life style change aspects, 58, 59
multiple risk factor approach, 57
pharmacological therapy with oral agents,
5963
biguanides, 60
insulin, 6263
metformin, 60
pioglitazone, 6062
rosiglitazone, 6062
thiazolidinediones, 6062
troglitazone, 61
UKPDS study, 55
see also Intensive insulin therapy for critically ill
(CI) patients
Intraepidermal nerve fibers quantification, 116
Islet cell transplantation, 11
benefits, risks, and limitations, 2023
beta-cell replacement, 2325
clinical, 1617
DCCT trial, 21
Edmonton protocol, 1720
encapsulation aspects, 2325
endogenous beta-cell regeneration, 2526
history, 12
immunosuppression aspects, 17
islet isolation technique, 1316
outcome follow-up, 1820
T1DM, 16
Islets, GLP-1 effects on, 273274
Isolation, islet cell transplantation and, 1216
JUPITER trial, LDL-C lowering and, 299
Kidney transplant alone (KTA), 2
DD kidney transplant, 3
LD kidney transplant, 23
LADA see latent autoimmune diabetes of adults
LAF237, 280
LANMET study, 8485
Latent autoimmune diabetes of adults (LADA), 183
LD kidney see Living donor (LD) kidney
Index
LDL (low density lipoprotein)
dietary weight loss approaches and,
213, 295
patients and, 170
lipid disorders and, 293
see also HDL (high density lipoprotein)
LDL-C (LDL cholesterol)
apoproteins and, 307
dyslipidemia pharmacotherapy and, 296300
lowering with statin, 296300
thiazolidinediones (TZD) effect on, 61
LDL-C lowering
ATP III, 297
CARDS study, 298
CARE study, 299
Heart Protection Study (HPS), 297, 298
JUPITER trial, 299
MIRACL study, 299
MRFIT study, 297
361
362
Index
hypertension, 36
obesity and, 36
risk factor, 34
triglycerides and, 36
type 2 diabetes and, 34, 3840
prevention (therapeutic lifestyle change
aspects), 3940
risk factor and, 3839
Metformin, 277
earlier insulin replacement initiation
and, 86
for CVD, 41
incretin effect and, 277278
see also Biguanides
Methicillin-resistant staphylococcus Aureus
(MRSA), 260
Microalbuminuria
thiazolidinediones (TZD) for, 62
see also Cardiovascular disease (CVD)
Minimally clinically important differences
(MCID), 138
Mitochondrial electron transport see
Hyperglycemia induced mitochondrial
MnSOD see Manganese SOD
Mortality, weight loss in type 2 diabetes and,
205206
MRFIT study (LDL-C lowering), 297
MRs see Meal replacement products
Multifocal neuropathies, 112
Multiple motor polyneuropathy (MMP), immune
therapy for, 122
Multiple risk factor approach, 57
Nerve fiber morphology

diabetic neuropathies, symptomatic therapy
aspects, 147, 148
intraepidermal, 116
Nerve growth factor (NGF), 121122
Nerve symptom change (NSC), 138
Neuroarthropathy, charcot, 260262
Neurologic Impairment Score (NIS), 140,
148149
Neurologic Symptom Score (NSS), 136
Neuropathy see diabetic neuropathies (DN)
Neuropathy Symptoms and Change (NSC)
score, 138
Neuropathy Total symptom Score-6 (NTSS-6), 138
Neurotrophic factors, 121
Neurovascular function, diabetic neuropathies
symptomatic therapy aspects, 147149
NHANES study
type 2 childhood diabetes study, 192
Niacin
non-HDL-C lowering, 304
NIS-LL score, 148149
Nitric oxide (NO), 53
see also Cardiovascular disease (CVD)
NO synthase (eNOS) gene expression, 63
see also Insulin
Non-HDL-C lowering
apoproteins and, 307
niacin for, 304
statins for, 301302
see also HDL-C lowering; LDL-C lowering
Nortriptyline, 340, 342
NPH insulin, 8283, 86
NPWT see Negative pressure wound therapy
(NPWT)
NVP-DPP728, 280
NWCR see National Weight Control Registry
National Weight Control Registry (NWCR),

208209
NCEP ATP III
LDL-C lowering and, 298299
HDL-C lowering and, 300301
NCV abnormalities, 115
Negative pressure wound therapy (NPWT), 263
Nerve conduction studies (NCS)
diabetic neuropathies (DN), symptomatic therapy
aspects, 141142
distal symmetric polyneuropathy, 115
Obesity
bariatric surgery and, 294, 296
intensive life style change aspects, 58
type 2 childhood diabetes and, 188189, 192
Offloading
importance and application, 258259
instant total contact cast (iTCC), 259
removable cast walker (RCW), 258259
total contact cast (TCC), 258259
Index
Oral agents, 8790
for intensive therapy
biguanides, 60
insulin, 6263
metformin, 60
pioglitazone, 6062
rosiglitazone, 60, 62
thiazolidinediones, 6062
troglitazone, 61
see also Blood pressure; Inhaled insulin;
Lipid
ORIGIN trial
cardioprotection and earlier insulin therapy
trials, 80
Orlistat
for CVD, 42
for weight loss, 204
Osteomyelitis, diabetic foot, 260262
Overweight
see also Obesity; Weight loss
Oxidative stress, 120121
Pancreas after kidney (PAK) transplants,

18
survival rates, 38
see also Pancreas transplants alone (PTA);
Simultaneous pancreas and kidney (SPK)
transplants
Pancreas transplantation, 1
PAK, 2
PTA, 2
SPK, 2
Pancreas transplants alone (PTA), 17
see also Pancreas after kidney (PAK)
transplants; Simultaneous pancreas and
kidney (SPK) transplants
PARP see poly(ADP-ribose) polymerase
Peripheral arterial disease (PAD), 52
Photocoagulation
aspirin use and, 103
diabetic retinopathy and, 99, 103
363
Physical activity strategies for weight loss,
203, 216
exercise, 219220
physical activity alone effective for weight loss?,
216217
physical activity combined with diet more
effective for weight loss?, 217219
physical activity done all at once effective for
weight loss, 220221
walking, 220
Pioglitazone
for CVD, 42
for HDL-C lowering, 301
see also Thiazolidinediones (TZD)
Poly(ADP-ribose) polymerase (PARP)
hyperglycemia induced mitochondrial superoxide
production, 241, 242
inhibitors, 244245
Polyneuropathy, 113
Polyol pathway, increased flux through, 234235
Polypharmacy see Polypills
Polypills
antidiabetic polypill, 325328
polypill I, 325, 327
polypill II, 327
polypill III, 327
polypill IV, 327
characteristics, 319
pathophysiology, 320
risk management and treatment, 321324
PPAR- agonists
PPAR- agonists, 42
PPAR- agonists, 4142, 6062
Prandial insulin
earlier insulin replacement initiation and,
8690
see also Basal insulin
Pregabalin
Pregnancy
DCCT study and, 104
364
PROACTIVE trial
pioglitazone use and, 42
Progenitors, islet cell transplantation and, 12
Protein intake, 213
Protein kinase C (PKC)
activation, diabetic complications and, 236
beta inhibition, diabetic neuropathies (DN)
treatment and, 121
PROVE-IT study
Proximal neuropathies, 112
Psychoneurohormonal mechanisms
comorbid depression, 339
see also Type 2 diabetes
PTA see Pancreas transplants alone
QST see Quantitative sensory tests
Quality of life (QOL)
distal symmetric polyneuropathy (DPN) and, 116
in diabetic neuropathies (DN), 137, 140141
Quantitative autonomic function tests
CAN, 145
composite autonomic severity score (CASS), 146
DAN, 144, 145
diabetic neuropathies (symptomatic therapy),
144146
heart rate variability (HRV), 145
Quantitative sensory tests (QST)
diabetic foot screening , 257258
diabetic neuropathies (DN), 140
diabetic neuropathies (symptomatic therapy),
142144
Radiculoneuropathy, diabetic truncal, 112
Rapidly reversible hyperglycemic neuropathy, 113
Reactive oxygen species (ROS), 238244
regeneration, islet cell transplantation and, 12
Removable cast walker (RCW), 258259
Retinopathy see Diabetic retinopathy
Ricordi chamber, 13
Rimonabant
for CVD, 42, 43
for metabolic syndrome, 42, 43
for type 2 diabetes, 42, 43
RIO-Europe trials, 43
RIO-Lipid trials, 43
Index
Rosiglitazone (RSG)
earlier insulin replacement aspects, 8384
HDL-C lowering, 301
intensive therapy, 60, 62
Rubella infection, 184
Screening, diabetic foot
foot ulceration, 253255
suggestions, 255258
Selective serotonin reuptake inhibitors
(SSRIs), 340
Semmes Weinstein monofilament (SWM),
126127
Sensory nerve action potentials (SNAP),
121, 142
for neuropathy detection, 149150
Serum lipids
ACCORD study and, 102
DCCT/EDIC study and, 102
ETDRS study and, 100102
HDL levels, 101102
LDL levels, 101102
Sibutramine
diet strategies for weight loss and, 215
Simultaneous pancreas and kidney (SPK)
transplants, 18
DD kidney transplant, 23, 8
LD kidney transplant, 23, 78
uremic candidates, 3
see also Pancreas after kidney (PAK) transplants;
Pancreas transplants alone (PTA)
Simvastatin, HDL-C lowering and, 305
Skin biopsy
diabetic neuropathies, symptomatic therapy
aspects, 147148
distal symmetric polyneuropathy (DPN) and, 116
Small fiber neuropathies, 125
SNAP see Sensory nerve action potential
Solitary pancreas transplants
Pancreas after kidney (PAK) transplants, 18
Pancreas transplants alone (PTA), 17
see also Simultaneous pancreas and kidney
(SPK) transplants
Somatic diabetic neuropathies
CIDP, 113
diabetic truncal radiculoneuropathy, 112
365
Index
distal
ASN, 113
neuropathy, 113
distal symmetric polyneuropathy, 114116
focal and multifocal neuropathies, 112
proximal, 112
see also Diabetic autonomic neuropathy (DAN)
SPK see Simultaneous pancreas and kidney (SPK)
transplants
Standard behavioral treatment (SBT), 214
Statin
antidylipidemic agents addition to, 300306
LDL-C lowering with, 296300
non-HDL-C lowering, 301302
see also Dyslipidemia
Steno-2 study (earlier insulin therapy trials), 78
STOPP study (type 2 childhood diabetes
study), 193
Sulfonylureas, 277
earlier insulin replacement initiation and, 86
incretin effect, 277
Superoxide dismutase (SOD), 239
Superoxide production see Hyperglycemia induced
mitochondrial superoxide production
Surgery for diabetic neuropathies (DN) treatment,
127129
SWAN study (comorbid depression), 336
Symptomatic therapy see under Diabetic
neuropathies (DN)
Tacrolimus, 18
Tarsal tunnel entrapment syndrome (TTS), 127
TEDDY study (childhood diabetes), 190
Therapeutic lifestyle change (TLC)
for CVD prevention, 3940
for metabolic syndrome prevention, 3940
for type 2 diabetes prevention, 3940
see also Lifestyle intervention
Thiazolidinediones (TZD)
effect on HDL cholesterol, 61
effect on LDL cholesterol, 61
fibrinolytic activity and, 62
for CVD, 4142, 60, 62
PPAR- agonists, 42
PPAR- agonists, 42
PPAR- agonists, 4142
for microalbuminuria, 62
insulin resistance aspects of, 6062
pioglitazone, 6062
PROACTIVE study, 61
rosiglitazone, 60, 62
troglitazone, 61
see also Biguanides
Thioctic acid, 121
Ticlopidine Microangiopathy of Diabetes
Study, 103
TLC see Therapeutic lifestyle change
Topiramate
Total contact cast (TCC), 258259
Total Neuropathy Score (TNS), 140
Total Symptom Score, 138
Transcutaneous nerve stimulation
(electrotherapy), 126
Transketolase activators, 244
Treatment to New Targets (TNT) study, 298
Treat-to-target concept, 72
Tricyclic antidepressants, 340
Triglycerides, 36
Troglitazone
Truncal radiculoneuropathy, diabetic, 112
Type 1 diabetes
childhood, 180191
Type 1 diabetes mellitus (T1DM)
beta-cell regeneration aspects, 2526
immunosuppression aspects, 17
islet cell transplantation
clinical islet transplantation and, 16
risks, benefits, and limitations, 2022
Type 2 diabetes
ACCORD study, 6465
CAD with, 52
childhood, 180194
comorbid depression and, 331340
behavioral mechanisms, 337338
natural history of depression, 339340
psychoneurohormonal mechanisms, 339
drug therapies
ACE/ARBs, 43
metformin, 41
Orlistat, 42
pioglitazone, 42
366
Rimonabant, 4243
thiazolidinediones (TZDs), 4142
incretin effect, 271282
DPP-IV inhibitors, 279282
GLP-1, 273276
GLP-1 analogs (incretin mimetics),
277279
insulin for, oral, 6263 see also Type 2 diabetes
treatment using insulin
metabolic syndrome and, 34, 3839
ORIGIN study, 65
polypills for, 317328
prevention (therapeutic lifestyle change aspects),
3940
weight loss in, 201223
Type 2 diabetes treatment using insulin,
6990
basal insulin, 7071
earlier insulin replacement and complexity
barriers overcoming aspects, 8081
basal insulin, 8286
inhaled insulin, 8790
NPH insulin, 8283
prandial insulin, 8690
earlier insulin replacement need, 72
earlier insulin therapy and cardioprotection,
7780
earlier insulin therapy and -cell preservation,
7377
insulin replacement aspects, 71
NHANES study, 6970
treat-to-target concept, 72
UKPDS trial
cardioprotection and earlier insulin therapy
trials, 77
diabetic retinopathy
hypertension and, 99100
glycemic control and, 96, 120
HDL-C lowering, 300
LDL-C lowering with statin and, 297
metabolic control, 120
Ulceration, foot, 253255
Index
Unified mechanism and diabetic complications,
238245
diabetic macrovascular disease, 243244
hyperglycemia induced mitochondrial superoxide
production
four damaging pathways activation by
GAPDH inhibition, 240241
GAPDH inhibition by activating
poly(ADP-ribose) polymerase, 241242
production increase aspects, 238240
therapeutic approaches, 244245
Uremic candidates
DD KTA and, 3
SPK, 3
LD kidney transplant and, 4
VA HIT study
Vascular disease, diabetic, 53
Vasodilatation, NO-mediated, 53
VDT see Vibration detection threshold
VEGF, diabetic neuropathies (DN) treatment, 122
Very-low-density lipoprotein (VLDL), 53
see also HDL (high-density lipoprotein); LDL
(low-density lipoprotein)
Veterans Affairs Diabetes Trial (VADT), 79
Vibration detection threshold (VDT), 143
for neuropathy detection, 149150
see also Quantitative sensory tests (QST)
Vibration perception threshold (VPT)
diabetic foot screening and, 257
Vitamin D (childhood diabetes aspects), 186187
Walking, 220
weight loss
Weight loss, 59
adverse psychological effects
binge eating disorder (BED), 206207
bulimia nervosa, 206
CVD risk and, 204206
diabetes prevention and, 202203
Diabetes Prevention Program (DPP) and,
202203
diet strategies, 210215
effective strategies dissemination aspects,
221223
in type 2 diabetic patients, 201221
mortality in T2D patients, 205206
long-term weight loss aspects, 207210
Index
life style intervention and, 202204
long-term
National Weight Control Registry (NWCR),
208, 209
successful weight loss in individuals with
diabetes, 209, 210
weight loss maintenance aspects, 207, 208
metformin for, 203204
mortality in T2D patients, 205206
obese diabetic subjects, 294, 296
367
physical activity strategies, 203, 216221
see also Obesity
Weight loss maintenance
diet strategies for, 210215
effective strategies dissemination aspects, 223
long-term weight loss, 207208
physical activity strategies for, 216221
WHO criteria for metabolic syndrome, 3538
Window of opportunity concept, 7477
see also Earlier insulin replacement

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CONTROVERSIES IN TREATING DIABETES

The Metabolic Syndrome: Epidemiology,

Hypertension and Hormone Mechanisms,

Androgen Excess Disorders in Women:

Evidence-Based Endocrinology, edited by

Male Hypogonadism: Basic, Clinical, and

Endocrine Replacement Therapy in Clinical

Assisted Fertilization and Nuclear Transfer in

Derek LeRoith, md, phd

Aaron I. Vinik, md, phd,

Library of Congress Control Number: 2007933146

in the absence of a need for renal transplantation; this is a controversial issue

1 Pancreas Transplantation: Should They be Reserved for

2 Islet Cell Transplantation: How Effective Is It? .............. 11

11 Weight Loss in Type 2 Diabetic Patients:

Heather M. Niemeier, phd Brown Medical School, The Miriam Hospital,

David E. R. Sutherland, MD, PHD

Sutherland and Gruessner

PANCREAS TRANSPLANTATION: SHOULD THEY BE

Sutherland and Gruessner

Fig. 1. Annual number of US pancreas transplants by category, 19882005.

Sutherland and Gruessner

dying after a pancreas transplant is less by 2 months in SPK, 3 months in PAK,

Sutherland and Gruessner

Relative Hazard Ratio

100 150 200 250 300

patients who receive a preemptive kidney transplant. If allocation favors SPK

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Islet Cell Transplantation

Liu and Harlan

Cell-based transplantation has long held great promise as a diabetes

Islet Cell Transplantation

Liu and Harlan

LIMITS OF THE PROCEDURE

Islet Cell Transplantation

Liu and Harlan

CLINICAL ISLET TRANSPLANTATION

Islet Cell Transplantation

THE EDMONTON ADVANCE

Liu and Harlan

Widespread experience since that publication now suggests that of the

ISLET TRANSPLANTATION OUTCOME FOLLOW-UP

Islet Cell Transplantation

that if a cell transplant was rejected because an experimental therapy failed,

Liu and Harlan

BENEFITS, RISKS, AND LIMITATIONS

Islet Cell Transplantation

Liu and Harlan

Islet Cell Transplantation

NOVEL METHODS OF -CELL REPLACEMENT

Liu and Harlan

Islet Cell Transplantation

ambient glucose levels and secrete insulin with near-physiological kinetics,

ENDOGENOUS -CELL REGENERATION?

Liu and Harlan

biopsied 2 years after the pancreas transplant, many insulin-immunostaining

Islet Cell Transplantation

Liu and Harlan

Islet Cell Transplantation

Liu and Harlan