Seminar

The metabolic syndrome

Robert H Eckel, Scott M Grundy, Paul Z Zimmet Lancet 2005; 365: 1415–28
Division of Endocrinology,
The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The Metabolism and Diabetes,
University of Colorado at
disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The
Denver and Health Sciences
pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. Center, PO Box 6511, MS 8106,
A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and Aurora, CO 80045, USA
cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight (Prof R H Eckel MD); University
of Texas Southwestern Medical
reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and
Center at Dallas, Dallas, TX,
cardiovascular disease risk reduction. USA (S M Grundy MD); and
International Diabetes
The concept of the metabolic syndrome has existed for at provide a tool for clinicians and researchers, a WHO Institute, Melbourne, Australia
(Prof P Z Zimmet MD)
least 80 years.1 This constellation of metabolic consultation proposed a set of criteria.13 Subsequently,
Correspondence to:
disturbances, all risk factors for cardiovascular disease, the National Cholesterol Education Program’s Adult
Professor Robert H Eckel
was first described in the 1920s by Kylin, a Swedish Treatment Panel III (NCEP: ATP III)14 and the European [email protected]
physician, as the clustering of hypertension, Group for the Study of Insulin Resistance15 have
hyperglycaemia, and gout.2 Later, in 1947, Vague drew formulated definitions. These definitions agree on the
attention to upper body adiposity (android or male-type essential components—glucose intolerance, obesity,
obesity) as the obesity phenotype that was commonly hypertension, and dyslipidaemia—but do differ in the
associated with metabolic abnormalities associated with detail and criteria (table 1).
type 2 diabetes and cardiovascular disease.3 The WHO definition and that of the European Group
Over the past two decades, a striking increase in the for the Study of Insulin Resistance agree in that they
number of people with the metabolic syndrome both include either glucose intolerance or insulin
worldwide has taken place. This increase is associated resistance as an essential component.13,15 However, for
with the global epidemic of obesity and diabetes.4 With the NCEP:ATP III definition,14 this criterion is not
the elevated risk not only of diabetes but also of included. Additionally, the cut-off points for criteria of
cardiovascular disease from the metabolic syndrome,5 each component of the cluster and the way of combining
there is urgent need for strategies to prevent the them to define the metabolic syndrome differ between
emerging global epidemic.4 The metabolic syndrome is a the definitions of the WHO and European Group for the
master of disguise since it can present in various ways Study of Insulin resistance and the definition of the
according to the different components that constitute NCEP:ATP III.
the syndrome. The WHO proposal was designed as a first attempt to
The metabolic syndrome is also known as syndrome define the syndrome. The report clearly stated that the
X,6 the insulin resistance syndrome,7 and the deadly definition would be modified as new information
quartet.8 The constellation of metabolic abnormalities became available about the components and their
includes glucose intolerance (type 2 diabetes, impaired predictive power.13 In retrospect, it is apparent that the
glucose tolerance, or impaired fasting glycaemia), WHO definition was better suited as a research tool
insulin resistance, central obesity, dyslipidaemia, and whereas the NCEP:ATP III definition14 was more useful
hypertension, all well documented risk factors for for clinical practice. Clinicians prefer simple tools with
cardiovascular disease. These conditions co-occur in an which to assess patients and improve their
individual more often than might be expected by chance. management, and it is generally agreed that the
When grouped together, they are associated with NCEP:ATP-III definition is simpler for practice. It
increased risk of cardiovascular disease.9,10 Lemieux and requires only a fasting assessment of blood glucose,
colleagues11 have suggested the importance of whereas the WHO definition can require an oral glucose
abdominal obesity and the so-called hypertrigly- tolerance test. Furthermore, because an accurate
ceridaemic waist phenotype as a central component.11 assessment of insulin resistance requires a more
Although some strong positions have been taken, the complicated test (eg, the hyperinsulinaemic euglycaemic
cause of the syndrome is still not settled,12 as discussed
in more detail later.
Search strategy and selection criteria
Defining the metabolic syndrome We searched PubMed with the terms “metabolic syndrome”,
While the concept of the metabolic syndrome was “insulin resistance”, “coronary heart disease”,
accepted, and even while controversies have raged about “diabetes mellitus”, “inflammation”, “hypertension”,
its cause, it was not until 1998 that there was an initiative “insulin secretion”, “CRP”, “cytokines”, and “adiponectin”.
to develop an internationally recognised definition. In an
attempt to achieve some agreement on definition, and to

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 Seminar

WHO, 1999 European Group for the Study of Insulin Resistance, 1999 ATP III, 2001
Diabetes or impaired fasting glycaemia or impaired glucose Insulin resistance—hyperinsulinaemia: top 25% of fasting insulin
tolerance or insulin resistance (hyperinsulinaemic, euglycaemic values from non-diabetic population
clamp-glucose uptake in lowest 25%)
Plus 2 or more of the following Plus 2 or more of the following 3 or more of the following
Obesity: BMI 30 or waist-to-hip ratio 0·9 (male) or Central obesity: waist circumference 94 cm (male) or 80 cm Central obesity: waist circumference 102 cm (male), 88 cm (female)
0·85 (female) (female) Hypertriglyceridaemia: triglycerides 1·7 mmol/L
Dyslipidaemia: triglycerides 1·7 mmol/L or HDL cholesterol Dyslipidaemia: triglycerides 2·0 mmol/L or HDL cholesterol 1·0 Low HDL cholesterol: 1·0 mmol/L (male), 1·3 mmol/L (female)
0·9 (male) or 1·0 (female) mmol/L Hypertension: blood pressure 140/90 mm Hg and/or medication Hypertension: blood pressure 135/85 mm Hg or medication
Hypertension: blood pressure 140/90 mm Hg Fasting plasma glucose 6·1 mmol/L Fasting plasma glucose 6·1 mmol/L
Microalbuminuria: albumin excretion 20 g/min

Table 1: Comparison of definitions of the metabolic syndrome

clamp technique), its application in an epidemiological supported by WHO (Western Pacific Region) and the
or clinical setting is impractical, although the International Obesity Task Force. They redefined
Homeostasis Model Assessment (HOMA) model could overweight as body-mass index (BMI) 23 and obesity
be used as an alternative method.16 as 25 in Asians. Central obesity was defined as 80 cm
Yet another attempt at a definition came from the for women and 90 cm in men.19
American Association of Endocrinology,17 who have More recently, a working party with representation
referred to the cluster as the insulin resistance from WHO (Geneva), the International Society for the
syndrome. They suggest that four factors should be the Study of Obesity, and the International Obesity Task
“identifying abnormalities” of the syndrome. These are Force re-emphasised the fact that obesity-associated risk
elevated triglycerides, reduced HDL cholesterol, elevated is a continuum and that there are interethnic differences
blood pressure, and elevated fasting and postload (75 g) in the relations between various obesity indices and the
glucose. Obesity is not a component of their definition. risks of cardiovascular disease.20 They noted that in
Given the mounting evidence that central obesity is a urban Asians, the BMI range of 23–24 has an equivalent
major risk factor for type 2 diabetes and cardiovascular risk of type 2 diabetes, hypertension, and dyslipidaemia
disease,11,14 this omission is rather surprising. as a BMI of 25–29·9 in white people. This finding will
Since several definitions of the syndrome are in use, it probably be taken into account when the new IDF
is difficult to compare prevalence and impact between definition is published.
countries. Fortunately, there is now a chance for a more
rational approach. In May, 2004, a group of experts was Prevalence
convened by the International Diabetes Federation (IDF) Comparisons of published prevalence for different
to attempt to establish a unified definition for the populations are difficult despite attempts to reach
metabolic syndrome and to highlight areas where more agreement on the definition of the metabolic syndrome.1
research into the syndrome is needed. A similar process Many studies compare prevalences using different
has been initiated jointly by the National Heart, Lung criteria, and perhaps their main achievement is to
and Blood Institute (NHLBI) and the American Heart reinforce the need for a standardised international
Association. Further consideration of the definition by definition. Cameron and others1 have published a
the ATP III panel is expected to follow. Ultimately, the detailed review about the prevalence of the syndrome
combined efforts of the IDF and NHLBI–American with different criteria (table 1).
Heart Association will result in a new definition(s) of the Figure 1 presents studies from various countries. They
metabolic syndrome that will be suitable for use in differ with respect to study design, sample selection,
clinical practice worldwide. year that they were undertaken, precise definition of the
A major issue for the IDF consensus consultation was metabolic syndrome used, and age and sex structure of
the fact that criteria used for obesity in Asian and other the population. Although the obesity criteria in
populations could be different from those used in the NCEP:ATP-III are not necessarily appropriate for Asian
west. The importance of obesity as a risk factor for groups,20 figure 1 only shows prevalences established
several diseases including type 2 diabetes, cardiovascular with NCEP:ATP-III criteria rather than the WHO’s.
disease, hypertension, gallstone disease, and certain Despite differences in the design of these studies and
cancers, is well documented.18 Yet, the amount of obesity other variables, certain inferences can be made. For
associated with increased risk differs between example, even for studies involving participants in the
populations. The WHO criteria that define overweight same age-groups, there is wide variation in prevalence in
and obesity in terms of comorbidities are not necessarily both sexes. In those studies that include people
appropriate for Asian populations. This issue was 20–25 years and older, the prevalence varies in urban
addressed in 2000 by a group convened by the populations from 8% (India) to 24% (USA) in men, and
International Association for the Study of Obesity and from 7% (France) to 43% (Iran) in women.

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An interesting example of the effect of ethnic origin on 60

the metabolic syndrome is a comparison of the Women
prevalence of the syndrome in the USA with lower Men
50
prevalence in non-Hispanic white people compared with
Mexican Americans, and in African American men
40
compared with non-Hispanic white and Mexican

Prevalence (%)
American men.21
30
A very consistent finding is that the prevalence of the
metabolic syndrome is highly age-dependent. This
20
pattern is clear in Iran where the prevalence is less than
10% for both men and women in the 20–29 year age-
10
group, rising to 38% and 67%, respectively, in the
60–69 year age-group.22 Similarly, in a French
0
population, the prevalence rises from 5·6% in the

20

20

20

lan –69

31

24

US 69

19

9
9
–6

–6

–6

–4

–7

–7
–7


0–


30–39 year age-group to 17·5% in the 60–64 year age-

42

50

45

30

45

30

30
30
)5
n

A
a

an

a
rke
di

Ira

ali

n)
d

Am ns)

A
d
d

n A te)
Om

ns
In

lan

e A anc
lan

US
str

ica
group.22 Additionally, the prevalence of the metabolic

Tu

ica
a

i
wh
ric
Au
Fin

ot
Ire

Fr

er
er
ilip me
Sc

m
ic
syndrome in the USA (national health and nutrition

an
a-

isp

ica
tiv

in

-H
examination survey [NHANES III]) increased from 7%

ex
a
(N

on

(M
(F

(n
A

A
A
in participants aged 20–29 years to 44% and 42% for

US

US
US

A
US
those aged 60–69 years and at least 70 years, Country/age (years)
respectively.21
Until recently, type 2 diabetes and the metabolic Figure 1: Prevalence of the metabolic syndrome from ATPIII definition
syndrome have been regarded as a disease of adults.4 Adapted from Cameron et al.1
However, with increasing rates of obesity in young
people, it is clear that the disease can begin at different 12–19 years age-group in the NHANES III study, with
ages in all ethnic groups, and that type 2 diabetes and the NCEP:ATP-III criteria modified for adolescents,
metabolic syndrome can be evident in childhood.23–26 reported that the prevalence of the metabolic syndrome
However, estimates of prevalence are difficult because of in adolescents was 4·2%.27
the problem of producing an appropriate definition of
the syndrome in children and adolescents. In the USA, Relation to predictability of diabetes and
Weiss and colleagues26 reported that the prevalence of cardiovascular disease
the metabolic syndrome increased with severity of The metabolic syndrome is associated with an increased
obesity, and reached 50% in severely obese youngsters. risk of both diabetes5 and cardiovascular disease.9,10,28,29
Each half-unit increase in BMI was associated with an Several studies have indicated that the metabolic
increase in the risk of the metabolic syndrome in syndrome predicts future diabetes.30,31 However, since
overweight and obese people (odds ratio 1·55), as was impaired fasting glucose and impaired glucose tolerance
each unit of increase in insulin resistance as assessed are components of the NCEP:ATP-III and the WHO
with the HOMA model (odds ratio 1·12 for each definitions respectively, this finding might not be a
additional unit of insulin resistance). The prevalence of surprise.
the metabolic syndrome increased significantly with In the DECODE study involving European men and
increasing insulin resistance after adjustment for ethnic women,32 non-diabetic people with the metabolic
group and degree of obesity. C-reactive protein syndrome had an increased risk of death from all causes
concentrations increased and adiponectin as well as from cardiovascular disease.32 The overall
concentrations decreased with increasing obesity. The hazard ratios for all-cause and cardiovascular disease
researchers concluded that the prevalence of the mortality in people with the metabolic syndrome
metabolic syndrome is high in obese children and compared with those without it were 1·44 and 2·26 in
adolescents, and it increases with worsening obesity. men and 1·38 and 2·78 in women after adjustment for
Biomarkers of an increased risk of adverse age, blood cholesterol concentrations, and smoking.
cardiovascular outcomes are already present in these In two other prospective European studies,9,10 the
youngsters. presence of the syndrome predicted increased
In Taiwan, a screening study of 3 million students cardiovascular disease and coronary heart disease
(aged 6–18 years)24 showed that people with type 2 mortality. Again, this finding is not unexpected since the
diabetes had higher mean BMI, cholesterol, and blood metabolic syndrome comprises established risk factors
pressure than did those with a normal fasting glucose, for cardiovascular disease. In these two studies, as well as
and, even at this young age, the metabolic syndrome was the Verona Diabetes Complications Study,33 the relative
present. Similar results have also been reported in Hong hazard ratios for cardiovascular disease outcomes ranged
Kong Chinese children.25 Finally, data from the from 2 to 5. In addition, applying the ATP III criteria to

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10 537 NHANES III participants resulted in a significant through the lipolysis of triglyceride-rich lipoproteins in
association between the metabolic syndrome with tissues by the action of lipoprotein lipase.37 Insulin is
prevalent myocardial infarction and stroke.34 With a new important to both antilipolysis and the stimulation of
metabolic syndrome definition(s) imminent, it will be lipoprotein lipase. Of note, the most sensitive pathway of
important to establish whether there are differences insulin action is the inhibition of lipolysis in adipose
between ethnic groups in prediction using this new tissue.38 Thus, when insulin resistance develops, the
definition(s). From this point of view, the findings of the increased amount of lipolysis of stored triacylglycerol
INTERHEART study35 could be of great importance. This molecules in adipose tissue produces more fatty acids,
study looked at putative cardiovascular risk factors in which could further inhibit the antilipolytic effect of
nearly 30 000 people in 52 countries and from all insulin, creating additional lipolysis.
inhabited continents of the world. Abnormal lipids, Upon reaching insulin sensitive tissues, excessive fatty
smoking, hypertension, diabetes, abdominal obesity, acids create insulin resistance by the added substrate
psychosocial factors, consumption of fruits, vegetables, availability and by modifying downstream signalling
and alcohol, and regular physical activity accounted for (figure 2). In muscle, fatty acids can impair activation of
most of the risk of myocardial infarction worldwide in protein kinase C- and protein kinase C-.39 Moreover,
both sexes and at all ages in all regions. This result the generation of excess acyl CoAs or acyl-CoA
suggests that approaches to cardiovascular disease derivatives such as ceramide can diminish Akt1
prevention can be based on similar principles worldwide. activation.40 In the liver of rats fed a high-fat diet, insulin
In another study, the Diabetes Predicting Model and resistance can be attributed to a defect in insulin-
the Framingham Risk Score were used to examine the stimulated insulin receptor substrate-1 and insulin
relative value of the metabolic syndrome in predicting receptor substrate-2 tyrosine phosphorylation. These
type 2 diabetes and cardiovascular disease, respectively.36 changes were associated with activation of protein
Initially 1709 non-diabetic participants in the San kinase C- and c-Jun N-terminal kinase-1.41 However, in
Antonio Heart Study were followed up for 7·5 years, and the liver there seems to be some discrepancy in the
195 developed type 2 diabetes. Over the same interval, metabolic effects of free fatty acids on insulin-mediated
156 of 2570 participants experienced a cardiovascular glucose and lipid metabolism. While circulating free
disease event. The sensitivity for predicting diabetes fatty acids increase hepatic glucose production and
using the ATP III definition of the metabolic syndrome diminish inhibition of glucose production by insulin,42
was 66% and the false positive rate was 28%. The lipogenesis, a pathway related to both the stimulatory
sensitivity and false positive rate for the prediction of effects of such acids and insulin on sterol response
cardiovascular disease were 67% and 34%, respectively. element binding protein-1c,43 continues.
At corresponding false positive rates, the two predicting Studies of (1) insulin resistant people with obesity
models had significantly higher sensitivities, and, at and/or type 2 diabetes,44 (2) offspring of patients with
corresponding sensitivities, significantly lower false type 2 diabetes,45 and (3) the elderly46 have identified a
positive rates than the metabolic syndrome for both defect in mitochondrial oxidative phosphorylation that
outcomes. Thus, in the San Antonio Heart Study, the relates to the accumulation of triglycerides and related
metabolic syndrome proved inferior to established lipid molecules in muscle. Moreover, in murine models
predicting models for either type 2 diabetes or cardio- of obesity, another subcellular organelle could be
vascular disease. involved, the endoplasmic reticulum. In mice made
deficient in the endoplasmic reticulum X-box binding
Mechanisms underlying the metabolic protein-1, hyperactivation of c-Jun N-terminal kinase-1
syndrome increases serine phosphorylation of insulin receptor
Insulin resistance substrate-1 and insulin resistance.47 Thus, more basic
The most accepted and unifying hypothesis to describe mechanisms of insulin resistance are being discovered
the pathophysiology of the metabolic syndrome is over time. Presumably, these biochemical changes in
insulin resistance. Insulin resistance has traditionally insulin-mediated signalling pathways result in decreases
been defined with a glucocentric view—ie, when a defect in insulin-mediated glucose transport and metabolism
in insulin action results in fasting hyperinsulinaemia to in the metabolic syndrome as well.
maintain euglycaemia. Yet, even before fasting hyper-
insulinaemia develops, postprandial hyperinsulinaemia Obesity and increased waist circumference
exists. Although the first description of the metabolic
A major contributor to the development of insulin syndrome was in the early 20th century,2 the worldwide
resistance is an overabundance of circulating fatty acids. obesity epidemic has been the most important driving
Plasma albumin-bound free fatty acids are derived force in the much more recent recognition of the
mainly from adipose tissue triglyceride stores released syndrome. Despite the importance of obesity in the
through the action of the cyclic AMP-dependent enzyme model, we should remember that patients of normal
hormone sensitive lipase. Fatty acids are also derived weight can also be insulin resistant.48

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For several definitions of the metabolic syndrome, operational in the setting of systemic insulin resistance
waist circumference is included.13–15 Mechanistically, a has not been completely addressed. Additionally, insulin
distinction between a large waist due to increases in resistance could also reduce the concentrations of
subcutaneous adipose tissue versus visceral fat is lipoprotein lipase in peripheral tissues (ie, in adipose
debated. This distinction can be made with computed tissue more than muscle).62 This alteration in lipoprotein
tomography or magnetic resonance imaging.49 With lipase, however, seems to contribute less to the
increases in intra-abdominal or visceral adipose tissue, a hypertriglyceridaemia than does the overproduction of
higher rate of flux of adipose tissue-derived free fatty VLDL. Nevertheless, hypertriglyceridaemia is an
acids to the liver through the splanchnic circulation excellent reflection of the insulin resistant condition and
would be expected, whereas increases in abdominal is one of the important criteria for diagnosis of the
subcutaneous fat would release lipolysis products into metabolic syndrome.
the systemic circulation and avoid more direct effects on The other major lipoprotein disturbance in the
hepatic metabolism (ie, glucose production, lipid metabolic syndrome is a reduction in HDL cholesterol.
synthesis, and secretion of prothrombotic proteins such This reduction is a consequence of changes in HDL
as fibrinogen and plasminogen activator inhibitor 1).50 composition and metabolism. In the presence of
Despite these potential differences in mechanisms hypertriglyceridaemia, a decrease in the cholesterol
related to excessive abdominal adipose tissue content of HDL results from decreases in the cholesteryl
distribution, the clinical diagnosis of the metabolic ester content of the lipoprotein core with variable
syndrome does not distinguish between increases in increases in triglyceride making the particle small and
subcutaneous and visceral fat. Yet, perhaps by a dense, a function in part of cholesteryl ester transfer
mechanism related to free fatty acid flux and protein.63 This change in lipoprotein composition also
metabolism, the relative predominance of visceral rather results in an increased clearance of HDL from the
than subcutaneous adipose tissue with increasing waist circulation.64 The relation of these changes in HDL to
circumference in Asians and Asian Indians51 renders the insulin resistance are probably indirect, arising in
relative prevalence of the syndrome higher than in concert with the changes in triglyceride-rich lipoprotein
African-American men in whom subcutaneous fat metabolism.
predominates.52 However, there is evidence that the In addition to HDL, the composition of LDL is also
elevated postprandial free fatty acid release in upper modified in a similar way. In fact, with fasting serum
body obese women originates from the non-splanchnic triglycerides 2·0 mmol/L, almost all patients have a
upper body fat, and not from the visceral depot.53 These predominance of small dense LDL.65,66 This change in
results suggest that visceral fat might be a marker for, LDL composition is attributable to relative depletion of
but not the source of, excess postprandial free fatty acids unesterified cholesterol, esterified cholesterol, and
in obesity. phospholipid with either no change or an increase in
In the setting of partial or complete lipoatrophy, LDL triglyceride.67,68 Small dense LDL might be more
insulin resistance and the metabolic syndrome typically atherogenic than buoyant LDL because (1) it is more
coexist.54 Evidence from these less common disorders toxic to the endothelium; (2) it is more able to transit
does support a genetic basis of the syndrome including through the endothelial basement membrane; (3) it
single gene defects in peroxisome-proliferator activated adheres well to glycosaminoglycans; (4) it has increased
receptor-, lamin A/C, 1-acylglycerol-3-phosphate, susceptibility to oxidation; and/or (5) it is more
O-acyltransferase, seipin,55 the -2 adrenergic receptor,56 selectively bound to scavenger receptors on monocyte-
and adiponectin.57 derived macrophages;69,70 however, this contention is not
entirely accepted.71 In some studies, this alteration in
Dyslipidaemia LDL composition is an independent risk factor for
In general, with increases in free fatty acid flux to the cardiovascular disease.72 However, more often this
liver, increased production of apo B-containing association is not independent, but related to the
triglyceride-rich very low-density lipoproteins (VLDL) concomitant changes in other lipoproteins and other
occurs.58 The effect of insulin on this process is risk factors.73
somewhat complex. In the setting of insulin resistance,
increased flux of free fatty acids to the liver increases Glucose intolerance
hepatic triglyceride synthesis; however, under The defects in insulin action in glucose metabolism
physiological conditions, insulin inhibits rather than include deficiencies in the ability of the hormone to
increases the secretion of VLDL into the systemic suppress glucose production by the liver and kidney, and
circulation.59 This response in part is an effect of insulin to mediate glucose uptake and metabolism in insulin
on the degradation of apo B.60 Yet, insulin is also sensitive tissues (ie, muscle and adipose tissue). The
lipogenic, increasing the transcription and enzyme relation between impaired fasting glucose or impaired
activity of many genes that relate to triglyceride glucose tolerance and insulin resistance is well
biosynthesis.61 Whether or not this pathway remains supported by human, non-human primate, and rodent

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studies. To compensate for defects in insulin action, disease and/or non-alcoholic steatohepatitis, obstructive
insulin secretion and/or clearance must be modified to sleep apnoea, and polycystic ovarian disease are all
sustain euglycaemia. If this compensation fails, defects associated with insulin resistance.
in insulin secretion predominate. Non-alcoholic fatty liver disease (fatty liver) is
Insulin resistance in pancreatic islet cells implies common; however, in non-alcoholic steatohepatitis both
that signals that generate glucose-dependent insulin triglyceride accumulation and inflammation coexist.90
secretion have been adversely modified, and fatty acids Non-alcoholic steatohepatitis in particular is becoming
are prime candidates. Although free fatty acids can an important health problem that is present in 2–3% of
stimulate insulin secretion, increasing and prolonged individuals in the USA and other western countries.91 As
exposure to excessive concentrations results in falls in the incidence of overweight/obesity and the metabolic
insulin secretion.74 The mechanism for this alteration syndrome increases, this disease could become one of
has been attributed to lipotoxicity through several the more frequent causes of end stage liver disease and
potential different mechanisms.75–77 hepatocellular carcinoma.
Insulin also can feedback on its own secretion. The Cigarette smoking92 and sedentary lifestyle93 can also
importance of this system comes from experiments in produce many of the major criteria of the syndrome and
rodents in which the insulin receptor is tissue- beyond. Increases in apo B and C-III,94 and non-
specifically deleted. When the insulin receptor is deleted alcoholic steatohepatitis95 are tied to the effects of fatty
in skeletal muscle, hyperglycaemia does not result;78 acids on VLDL production by the liver, and in the case
however, the -cell specific knockout of the insulin of apo B and C-III provide evidence of an increased
receptor produces progressive glucose intolerance and number
diabetes.79 In people with genetic predispositions to of proatherogenic particles in the circulation.
development of diabetes, the presumed stress of the Hyperuricaemia results from defects in insulin action
insulin resistant environment on -cell function causes
glucose intolerance and ultimately higher risk of
diabetes. Panel: Changes associated with insulin resistance
Lifestyle
Hypertension Cigarette smoking
The relation between insulin resistance and Sedentary behaviour
hypertension is well established,80 and relates to several
different mechanisms. First, it is important to note that Lipoproteins
insulin is a vasodilator when given intravenously to Increased apo B
people of normal weight,81 with secondary effects on Decreased apo A-1
sodium reabsorption in the kidney.82 Evidence indicates Small dense LDL and HDL
that sodium reabsorption is increased in white people Increased apo C-III
but not Africans or Asians with the metabolic Prothrombotic
syndrome.83 In the setting of insulin resistance, the Increased fibrinogen
vasodilatory effect of insulin can be lost,84 but the renal Increased plasminogen activator inhibitor 1
effect on sodium reabsorption preserved.85 Fatty acids Increased viscosity
themselves can mediate relative vasoconstriction.86
Insulin also increases the activity of the sympathetic Inflammatory markers
nervous system,87, an effect that might also be preserved Increased white blood cell count
in the setting of the insulin resistance.88 However, when Increased interleukin 6
assessed by concentrations of fasting insulin, HOMA or Increased tumour necrosis factor

the HOMA insulin resistance index (HOMA-IR),16 Increased resistin

insulin resistance contributes only modestly to the Increased C-reactive protein
increased prevalence of hypertension in the metabolic Decreased adiponectin
syndrome.89 Vascular
Microalbuminuria
Other manifestations Increased asymmetric dimethylarginine
Insulin resistance is accompanied by many other
alterations that are not included in the diagnostic criteria Other
for the metabolic syndrome (panel). Increases in apo B Increased uric acid
and C-III, uric acid, prothrombotic factors (fibrinogen, Increased homocysteine
plasminogen activator inhibitor 1), serum viscosity, Non-alcoholic steatohepatitis
asymmetric dimethylarginine, homocysteine, white Polycystic ovaries syndrome
blood cell count, pro-inflammatory cytokines, the Obstructive sleep apnoea
presence of microalbuminuria, non-alcoholic fatty liver

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on the renal tubular reabsorption of uric acid,96 whereas

the increase in asymmetric dimethylarginine, an A
endogenous inhibitor of nitric oxide synthase, relates to Hypertension
endothelial dysfunction.88 An extended form of C-II

endothelial pathophysiology in insulin resistant states C-III HDL cholesterol

B-100 and
Triglyceride Small dense LDL Sympathetic nervous
could be microalbuminuria.97 FFA Insulin
system
VLDL
Glucose
Proinflammatory cytokines
The association of the metabolic syndrome with Insulin
inflammation is well documented.98 The increases in
proinflammatory cytokines including interleukin 6, _
Glycogen
resistin, tumour necrosis factor
(TNF
) and _ _

C-reactive protein99 reflect overproduction by the

FFA _ CO2
expanded adipose tissue mass (figure 2).100 Evidence
FFA
suggests that monocyte-derived macrophages reside in
adipose tissue and might be at least in part the source of
the generation of proinflammatory cytokines locally and
in the systemic circulation.101,102 There is increasing
evidence that insulin resistance in the liver, muscle, and Triglyceride
(intramuscular droplet)
adipose tissue is not only associated with the abundance
of proinflammatory cytokines (and relative deficiency of B
the anti-inflammatory cytokine adiponectin), but is a Hypertension
direct result of this burden.91 It remains unclear, C-II
C-III HDL cholesterol
however, how much of the insulin resistance related to Triglyceride
B-100 and
Small dense LDL Interleukin 6
FFA Insulin Sympathetic nervous
the adipose tissue content of macrophages is paracrine VLDL system
versus endocrine. Glucose
As a general index of inflammation, C-reactive protein
TNF
_
concentrations vary by ethnic origin and within ethnic Interleukin 6 Insulin
C-reactive
groups by fitness.103,104 For instance, concentrations of protein _
C-reactive protein were higher in healthy Indian Asians Glycogen
_ _
than in European white people and were related to
greater central obesity and insulin resistance in Indian FFA CO2
_
Asians.104 At present it remains unclear whether these FFA
differences when adjusted for other covariates will relate
to different rates of development of diabetes and/or Fibrinogen
_
PAI-1 Adiponectin
cardiovascular disease.
Prothrombic Triglyceride
Adiponectin state (intramuscular droplet)
Adiponectin is an anti-inflammatory cytokine that is
produced exclusively by adipocytes. Adiponectin both
enhances insulin sensitivity and inhibits many steps in Figure 2: Pathophysiology of the metabolic syndrome (insulin resistance)
the inflammatory process.105 In the liver, it inhibits both A: Free fatty acids (FFA) are released in abundance from an expanded adipose tissue mass. In the liver, FFA produce
the expression of hepatic gluconeogenic enzymes and an increased production of glucose, triglycerides and secretion of very low density lipoproteins (VLDL). Associated
lipid/lipoprotein abnormalities include reductions in high density lipoprotein (HDL) cholesterol and an increased
the rate of endogenous glucose production.106 In muscle, density of low density lipoproteins (LDL). FFA also reduce insulin sensitivity in muscle by inhibiting insulin-
it increases glucose transport and enhances fatty acid mediated glucose uptake. Associated defects include a reduction in glucose partitioning to glycogen and increased
oxidation, effects that are partly due to the activation of lipid accumulation in triglyceride (TG). Increases in circulating glucose and to some extent FFA increase pancreatic
AMP-kinase.102 In mice, decreased circulating insulin secretion resulting in hyperinsulinemia. Hyperinsulinaemia may result in enhanced sodium reabsorption
and increased sympathetic nervous system (SNS) activity and contribute to the hypertension as might increased
concentrations of adiponectin could be important in levels of circulating FFA.
producing changes in metabolism consistent with the B: Superimposed and contributory to the insulin resistance produced by excessive FFA is the paracrine and
metabolic syndrome,107,95 with reductions in adiponectin endocrine effect of the proinflammatory state. Produced by a variety of cells in adipose tissue including adipocytes
also apparent in people with the syndrome.108,96 The and monocyte-derived macrophages, the enhanced secretion of interleukin-6 (IL-6) and tumor necrosis factor
alpha (TNF-
) among others results in more insulin resistance and lipolysis of adipose tissue triglyceride stores to
relative contribution of the deficiency in this cytokine circulating FFA. IL-6 and other cytokines also are increased in the circulation and may enhance hepatic glucose
versus the overabundance of the proinflammatory production, the production of VLDL by the liver and insulin resistance in muscle. Cytokines and FFA also increase
cytokines remains unclear. Some reports link low the production of fibrinogen and plasminogen activator inhibitor-1 (PAI-1) by the liver that complements the
overproduction of PAI-1 by adipose tissue. This results in a pro-thrombotic state. Reductions in the production of
concentrations of adiponectin to myocardial infarction109
the anti-inflammatory and insulin sensitizing cytokine adiponectin are also associated with the metabolic
and to the progression of subclinical coronary heart syndrome and may contribute to the pathophysiology of the syndrome. PAI1=plasminogen activator inhibitor 1.
disease.110 FFA=free fatty acids.

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Beyond insulin resistance no increase in power of prediction; 119,122 however, in the

Despite the substantial amount of evidence in support of Quebec Cardiovascular Study concentrations of fasting
the notion that the metabolic syndrome is an insulin insulin, triglycerides, apo B, small dense LDL, and waist
resistance syndrome, quantification of insulin action in circumference all proved important determinants.11,123
vivo is not always strongly related to the presence of the The PROCAM risk algorithm124 also includes
syndrome.111 Several key questions are raised. First, if the triglycerides and a family history of premature coronary
metabolic syndrome is a consequence of only insulin heart disease.124 Whether adding further factors—
resistance, is the definition appropriately constructed? abdominal obesity, apo B, small LDL, C-reactive protein,
Second, is it possible that the current components and and insulin and glucose concentrations—to the current
their relation to the metabolic syndrome exist as three- definition of the metabolic syndrome will enhance risk
factor or four-factor aggregates—eg, insulin or glucose, prediction for cardiovascular disease has not been
lipids or lipoproteins, blood pressure, and obesity rigorously tested, but elevated C-reactive protein seems
assessments (BMI, waist circumference)?112 Third, do to carry increased risk for coronary heart disease beyond
other mechanisms remain to be discovered? And fourth, standard criteria.125,126
if other mechanisms exist, do some components of the The finding of IFG or IGT nonetheless signifies a
syndrome need to be grouped with insulin resistance higher risk for type 2 diabetes.127 It is noteworthy that
and the others separately? when the NCEP:ATP-III and WHO criteria for the
An alternative concept suggested by Unger113 to explain metabolic syndrome were compared in subjects with or
the metabolic syndrome is leptin resistance.113 In without a history of cardiovascular disease, the age-
general, conditions in which leptin deficiency or adjusted prevalence was 23·9% according to the ATP III
resistance are present are associated with triglyceride definition and 25·1% according to the WHO
accumulation in non-adipose organs (eg, liver, muscle, definition.128 Estimates differed substantially for some
and the islets).113 This pathophysiology could relate to the subgroups—in African-American men, the WHO
absence of down regulation of sterol response element estimate was 24·9%, compared with the ATP III
binding protein 1c by leptin114 and/or the inability of estimate of 16·5%. Yet, NCEP:ATP-III and WHO
leptin to activate AMP-kinase in muscle.115 Leptin also criteria were similar at identifying the relative risk for
seems to lower insulin secretion,116 but leptin resistance cardiovascular disease in the presence and absence of
could relate to the hyperinsulinaemia that develops in the metabolic syndrome.
the setting of the metabolic syndrome before defects in The incidence of cardiovascular disease in Asian
insulin secretion lead to the development of diabetes.117 people is much less than in white people,129 and the
Framingham risk algorithm reportedly overestimates
Management of metabolic syndrome the risk of coronary heart disease in Asians.130 This
The presence of the metabolic syndrome carries finding suggests that evaluation of cardiovascular
increased risk for cardiovascular disease10,118 and type 2 disease risk based on a database of mainly white people
diabetes.117 Some affected people are at high or could be inappropriate for Asians. This possibility
moderately high risk for major cardiovascular disease certainly needs to be considered seriously in the
events in the short term (10 years); others are at less diagnosis and approach to prevention and treatment of
risk in the short term, but carry a fairly high long-term cardiovascular disease in these populations with the
risk.119 In the latter group, therapeutic lifestyle metabolic syndrome.
modification is first-line therapy, but if 10-year risk is
high, drug therapy to modify cardiovascular disease risk Management of underlying risk factors
factors might be required as well.120 For this reason, a Although the metabolic syndrome appears to be more
10-year risk assessment is needed in all those who have a common in people who are genetically susceptible,
diagnosis of the metabolic syndrome. acquired underlying risk factors—being overweight or
obese, physical inactivity, and an atherogenic diet—
Risk assessment commonly elicit clinical manifestations. Clinical
Several approaches are available to estimate 10-year management should first focus on management of these
risk for cardiovascular disease (or coronary heart underlying risk factor independent of an individual’s
disease).120,121 These risk engines incorporate the major risk status (table 2).
risk factors for cardiovascular disease: cigarette
smoking, blood pressure, total cholesterol, HDL Obesity
cholesterol, age, sex, and sometimes other risk factors Abdominal obesity is the body fat parameter most
such as diabetes. In some guidelines,120 diabetes counts closely associated with the metabolic syndrome.120,131 As
as a high-risk condition independent of other risk noted previously, definitions of abdominal obesity vary
factors. According to the Framingham Heart Study, according to population. Clinical management of obesity
adding abdominal obesity, triglycerides, and fasting should adhere to several well-established principles.5
glucose to the Framingham risk algorithm yields little or Effective weight reduction improves all risk factors

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 Seminar

associated with the metabolic syndrome,132 and it will severely abnormal, drug therapy may be necessary.
further reduce the risk for type 2 diabetes.133,134 Approaches to each risk factor can be considered briefly.
Weight reduction is best achieved by behavioural
change to reduce energy intake and by physical activity Atherogenic dyslipidaemia
to enhance energy expenditure.132 Caloric intake should This condition consists of elevations of triglycerides and
be reduced by 500–1000 calories per day to produce a apo B, small LDL particles, and low HDL cholesterol.
weight loss of 0·5–1·0 kg per week. The goal is to reduce 3-hydroxy-3-methylglutaryl-coenzyme A reductase
bodyweight by about 7–10% over 6–12 months, followed inhibitors (statins) reduce risk for major cardiovascular
by long-term behaviour modification and maintenance disease events in high risk patients with the metabolic
of increased physical activity. To date, weight reduction syndrome by reducing all apo B containing lipo-
drugs have not been particularly effective for treatment proteins.141,142 Fibrates mitigate atherogenic dyslipi-
of obesity; on the other hand, in the USA, bariatric daemia and appear to reduce the risk for cardiovascular
surgery has been used increasingly to treat patients with disease in patients with the metabolic syndrome.143 Their
morbid obesity.135 The effectiveness and safety of use in combination with statins is particularly attractive,
bariatric surgery in patients with the metabolic but carries some increased risk for myopathy. This
syndrome has been quite encouraging with 95% of increase in risk with a statin plus fibrate has been
patients free of the syndrome 1 year after the particularly noted for the fibrate gemfibrozil.144 A higher
operation.136 Longer periods of observation after weight risk from the combination could result from pharmaco-
stabilisation are, however, needed. logical interaction of gemfibrozil with the statin to
produce higher concentrations of the statin in the
Physical inactivity
Current guidelines137 recommend practical, regular, and Therapeutic goals and recommendations
moderate regimens of physical activity (eg, 30 min Abdominal obesity Goal: 10% weight loss first year, thereafter continued weight loss or maintain weight
moderate-intensity exercise daily). Regular and Recommendation: caloric restriction; regular exercise; behaviour modification
Physical inactivity Goal: regular moderate-intensity physical activity
sustained physical activity will improve all risk factors of
Recommendation: 30–60 min moderate-intensity exercise daily
the metabolic syndrome.27,93 Sedentary activities in Atherogenic diet Goals: reduced intakes of saturated fats, trans fats and cholesterol
leisure time should be replaced by more active behaviour Recommendations: saturated fat ,7% of total calories; reduce trans fat; dietary cholesterol
such as brisk walking, jogging, swimming, biking, 200 mg daily; total fat 25–35% of total calories
Cigarette smoking Goal and recommendation: complete smoking cessation
golfing, and team sports. Combination of weight loss
LDL-C Goals: High-risk patients*—LDL cholesterol 1 g/L (2·6 mmol/L)
and exercise to reduce the incidence of type 2 diabetes in Therapeutic option—LDL cholesterol 0·7 g/l (1·8 mmol/L)
patients with glucose intolerance should not be Moderately high-risk patients†—LDL cholesterol 1·3 g/L (3·4 mmol/L)
dismissed.138 Therapeutic option—LDL cholesterol 1 g/L (2·6 mmol/L)
Moderate-risk patients‡—LDL cholesterol 1·3 g/L (3·4 mmol/L)
Recommendations: high-risk patients—lifestyle therapies§ and LDL-cholesterol lowering
Atherogenic and diabetogenic diets drug to achieve recommended goal
There is general agreement that persons with the Moderately high-risk patients—lifestyle therapies; add LDL-cholesterol lowering drug if
metabolic syndrome should adhere to a set of dietary necessary to achieve recommended goal when baseline LDL cholesterol 1·3 g/L
(3·4 mmol/L)
principles: low intakes of saturated fats, trans fats, and Moderate risk patients—lifestyle therapies; add LDL-cholesterol lowering drug if necessary
cholesterol, reduced consumption of simple sugars, and to achieve recommended goal when baseline LDL cholesterol 1·6 g/L (4·1 mmol/L)
increased intakes of fruits, vegetables, and whole High triglyceride or Goal: insufficient data to establish goal
grains.120 More controversial is the relative amounts of low HDL-C Recommendation: High-risk patients—consider adding fibrate (preferably fenofibrate) or
nicotinic acid to LDL-lowering drug therapy
carbohydrate and unsaturated fats. Some investigators
Elevated blood pressure Goals: blood pressure 135/85 mm Hg. For diabetes or chronic
favour lower fat intakes, whereas others recommend kidney disease: blood pressure 130/80 mm Hg
higher fat diets.139 Low-fat diets have been advocated to Recommendation: lifestyle therapies; add antihypertensive drug(s) when necessary to
promote weight reduction,140 whereas higher achieve goals of therapy
Elevated glucose Goal: maintenance or reduction in fasting glucose if 1 g/L (5·5 mmol/L). Haemoglobin
monounsaturated fat intakes diminish postprandial A1C 7·0% for diabetes
glycaemia, reduce serum triglycerides, and raise Recommendation: lifestyle therapies; add hypoglycaemic agents as necessary to achieve
concentrations of HDL-cholesterol.139 goal fasting glucose or haemoglobin A1C
Prothrombotic state Goal: reduction of prothrombotic state
Recommendation: High-risk patients—initiate low-dose aspirin therapy; consider
Management of metabolic risk factors clopidogrel if aspirin is contraindicated
The metabolic risk factors that are part of the definition Moderately high-risk patients—consider low-dose aspirin therapy
of the syndrome include atherogenic dyslipidaemia, Proinflammatory state Recommendations: no specific therapies
elevated blood pressure, and elevated plasma glucose;
*High-risk patients: those with established atherosclerotic cardiovascular disease, diabetes, or 10-year risk for coronary heart
however, we will also consider the prothrombotic state disease 20%. ‡Moderately high-risk patients: those with 10-year risk for coronary heart disease 10–20%. ‡Moderate risk
and a proinflammatory state. Effective treatment of the patients: those with metabolic syndrome but 10-year risk for coronary heart disease 10%. §Lifestyle therapies include weight
reduction, regular exercise, and antiatherogenic diet.
underlying risk factors will reduce the severity of all of
the metabolic risk factors. However, if people are found Table 2: Targets, goals, and recommendations for clinical management of metabolic syndrome
to be at particularly high risk or if a given risk factor is

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 Seminar

blood.145 Recent studies suggest that fenofibrate hypoglycaemia. With the exception of nicotinic acid,
combined with a statin is less likely to cause myopathy lipid-altering drugs do not affect insulin sensitivity or
than is gemfibrozil.146 The combination of a statin with a weight, whereas the effect of antihypertensive drugs is
low dose of nicotinic acid is an alternative to a statin plus more complex. -adrenergic blockers and thiazide
fibrate.147 Although low doses of nicotinic acid can be diuretics might decrease insulin sensitivity but less so at
tolerated by most patients with the metabolic syndrome, low doses, whereas ACE inhibitors and angiotensin II
some patients might find it difficult to take on a long- receptor antagonists have variable effects.151 By uncertain
term basis. For patients with diabetes, nicotinic acid can mechanisms, ACE inhibitors and angiotensin II
raise glucose concentrations, but as long as the dose is receptor antagonists seem to decrease the incidence of
kept relatively low, it does not produce substantial type 2 diabetes.158
deterioration of glycaemic control in most patients.148
Prothrombotic state
Blood pressure This risk factor is characterised by elevations of
Mild elevations of blood pressure can often be controlled fibrinogen, plasminogen activator inhibitor 1, and
with lifestyle changes, but if hypertension persists possibly other coagulation factors. The only available
despite such therapies, antihypertensive drugs are clinical approach to an increased risk for arterial
usually required.149 The benefits of blood pressure thrombosis in patients with diabetes is low-dose aspirin
reduction for reducing major cardiovascular disease has or other antiplatelet drugs.159 These drugs are universally
been well established through many clinical trials,149 recommended unless contraindicated in patients with
including those in patients with type 2 diabetes.150 Some established cardiovascular disease. Their efficacy in
investigators believe that angiotensin-converting patients with type 2 diabetes in the absence of
enzyme (ACE) inhibitors or angiotension receptor cardiovascular disease has not been established through
blockers are better first-line therapy for metabolic clinical trials, although they are widely recommended.
syndrome patients, especially when type 2 diabetes is In other people with the metabolic syndrome, aspirin
present,151 but the issue of the most effective drug has prophylaxis is a therapeutic option when the risk for
not been entirely resolved.152 cardiovascular disease events is judged to be relatively
high.160
Insulin resistance and hyperglycaemia
Lifestyle intervention can reduce the risk for conversion Proinflammatory state
of IFG/IGT to type 2 diabetes.133,134,138 Preliminary reports This condition can be identified by elevated cytokines
indicate that metformin or thiazolidinediones also (eg, TNF
and interleukin 6) as well as by elevations in
reduce risk for type 2 diabetes in people with IFG or acute phase reactants (C-reactive protein and
IGT.133,153 On the other hand, no clinical trial evidence fibrinogen). An elevated concentration of C-reactive
indicates that these drugs will reduce risk for protein is widely thought to be an indicator of a
cardiovascular disease events in patients with the proinflammatory state and to be associated with higher
metabolic syndrome. Currently, metformin or risk for both cardiovascular disease and diabetes.161
thiazolidinediones are not recommended solely for the Lifestyle therapies, especially weight reduction, will
prevention of diabetes. The cost-effectiveness of this reduce concentrations of this cytokine and thus can
approach has not been established. mitigate an underlying inflammatory state.162 No specific
When patients with type 2 diabetes concomitantly anti-inflammatory drugs are available to treat the
exhibit other features of the metabolic syndrome they proinflammatory state. However, several drugs used to
are at particularly high risk for cardiovascular disease. treat other metabolic risk factors—statins, fibrates, and
Clinical trials show that high priority should be given to thiazolidinediones—have been reported to reduce
treatment of dyslipidaemia154 and hypertension.149 concentrations of C-reactive proteins.163,164 The drugs,
Glycaemic control to a haemoglobin A1c of less than 7% however, cannot be recommended specifically to reduce
will reduce microvascular complications and could a proinflammatory state independent of other risk
decrease risk for macrovascular disease as well.155 factors.
The use of lipid-altering, antihypertensive and Conflict of interest statement
hypoglycaemic drugs can modify insulin sensitivity and R H Eckel has a Merck grant, “The Impact of HMG Co-A Reductase
bodyweight. Metformin and thiazolidinediones improve Inhibitors on C-reactive Protein in Patients with Type 2 Diabetes”.
P Z Zimmet is a consultant for Novartis, GlaxoSmithKline, Bristol-
insulin sensitivity but have discrepant effects on Myers Squibb, Abbott, and Merck, and has received payment for
bodyweight: metformin reduces weight whereas speaking for E Merck, Bayer, Sanofi, AstraZeneca, and Kissei. In the
thiazolidinediones increase it.156,157 The increase in past 5 years, S M Grundy has been an investigator on research grants
weight in patients treated with insulin secretagogues awarded to the University of Texas Southwestern Medical Center (UT
Southwestern), Dallas, Texas, for the study of statins (Merck),
(sulfonylureas and repaglinide or nateglinide) and fenofibrate (Abbott), and nicotinic acid (Kos). Additionally, during this
insulin results mostly from improved glycaemic control period, he has given lectures approved by UT Southwestern to health
and increases in caloric intake as a result of professionals on cholesterol management, in which cholesterol-

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 Seminar

lowering drugs were discussed and for which he received honoraria that 20 Appropriate body-mass index for Asian populations and its
were funded either directly or indirectly (through continuing medical implications for policy and intervention strategies. Lancet 2004;
education programmes) from the following companies: Merck (statins), 363: 157–63.
Pfizer (statins), Sankyo (colesevelam), Schering Plough (ezetimibe), Kos 21 Ford ES, Giles WH, Dietz WH. Prevalence of the metabolic
(nicotinic acid), Abbott (fenofibrate), Fournier (fenofibrate), Bristol- syndrome among US adults: findings from the third National
Myers Squibb (statins), and AstraZeneca (statins). Health and Nutrition Examination Survey. JAMA 2002; 287:
356–59.
Acknowledgments 22 Azizi F, Salehi P, Etemadi A, Zahedi-Asl S. Prevalence of metabolic
We thank Dalan Jensen and Julie Morris for their assistance in syndrome in an urban population: Tehran Lipid and Glucose
producing this Seminar. No funding was received except for a small Study. Diabetes Res Clin Pract 2003; 61: 29–37.
payment from The Lancet. 23 Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose
tolerance among children and adolescents with marked obesity.
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