Obesity and Type 2 Diabetes

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Obesity and Type 2 Diabetes
Article in Journal of Diabetes Mellitus · January 2011

DOI: 10.4236/jdm.2011.14012
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Vol.1, No.4, 79-95 (2011) Journal of Diabetes Mellitus
doi:10.4236/jdm.2011.14012
Obesity and type 2 diabetes

Subhashini Yaturu
Section of Endocrinology and Metabolism, Stratton VA Medical Center, Albany, USA;
[email protected]
Received 17 August 2011; revised 20 September 2011; accepted 30 September 2011.
ABSTRACT well as waist circumference in both men and women [2].

Not all subjects with type 2 diabetes (T2DM) are obese
Obesity and type 2 diabetes (T2DM) are public
and many obese subjects do not have diabetes, but most
health problems, with health consequences and
of the subjects with T2DM are overweight or obese.
economic costs that have raised concern world-
Significant numbers of obese individuals have diabetes.
wide. The increase in the prevalence of diabetes
Overweight, obesity and T2DM are largely preventable
parallels that of obesity. Some experts call this with change in life style and avoidance of sedentary hab-
dual epidemic “diabesity”. Elevated body mass its and over-consumption of energy. Both obesity and
index (BMI) and waist circumference (WC) were T2DM, feature insulin resistance and atherogenic lipid
significantly associated T2DM. One consequen- profiles such as increased triglycerides and decreased
ce of obesity is an increased risk of developing HDL-C. The genetic basis of human obesity that predis-
T2DM. There is evidence that the prenatal, early poses to insulin resistance and T2DM is multigenic
childhood, and adolescent periods are critical in rather than monogenic. Current clinical guidelines ackn-
the development of obesity. Most obese indivi- owledge the therapeutic strength of exercise intervention
duals have elevated plasma levels of free fatty for prevention and treatment of diabetes.
acids (FFA), which are known to cause periph-
eral (muscle) insulin resistance. Weight loss ei- 2. PREVALENCE
ther with lifestyle modification, pharmacother-
apy or bariatric surgery improves glycemic con- Data from the Third National Health and Nutrition
trol and metabolic parameters that are related to Examination Survey (NHANES III) indicate that two-
cardiovascular disease. Pharmacotherapy for thirds of adults, both men and women, had BMI values >27
glycemic control with metformin or GLP-1 ago- kg/m2 [3]. The prevalence of T2DM parallels the in-
nists and DPP-4 inhibitors help in weight reduc- creasing prevalence of obesity. The World Health Orga-
tion. nization (WHO) projects that there are currently 2.3 bil-
lion overweight people aged 15 years and above, and
that there will be over 700 million obese people world-
Keywords: Diabetes; Obesity; Body Mass Index;
wide in 2015 [http://www.who.int/mediacentre/factsh-
Impaired Glucose Tolerance; Insulin Resistance
eets/fs311/en/]. The prevalence of diabetes is increasing
Syndrome
in the United States, and the diagnosed diabetes in-
creased from 0.9% in 1958 to 6.3% in 2008. In 2008,
1. INTRODUCTION
18.8 million people had diagnosed diabetes, compared to
Obesity and diabetes are emerging pandemics in the only 1.6 million in 1958 [http://www.cdc.gov/diabetes/st
21st century. Both are major public health problems thr- atistics/slides/long_term_trends.pdf.]. According to the
oughout the world and are associated with significant, International Diabetes Federation (IDF), it is estimated
potentially life-threatening co-morbidities and enormous that approximately 285 million people worldwide, or
economic costs. The prevalence of overweight (body 6.6%, in the age group 20 - 79, will have diabetes in
mass index (BMI) between 25 and 30 kg/m2) [1] and 2010 [http: //www.diabetesatlas.org/map], some 70% of
obesity (BMI of 30 kg/m2 or higher) [1] is increasing whom live in low- and middle-income countries. This
rapidly worldwide, especially in developing countries. number is expected to increase by more than 50% in the
There is a strong association between obesity and type 2 next 20 years if preventive programs are not put in place.
diabetes. Meta-analysis of studies of association of these By 2030, some 438 million people, or 7.8% of the adult
two conditions showed higher relative risk with BMI as population, are projected to have diabetes. T2DM is the
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/JDM/

80 S. Yaturu / Journal of Diabetes Mellitus 1 (2011) 79-95
predominant form of diabetes worldwide and constitutes ficantly over the last decade, the prevalence of undiag-
85% - 95% of all diabetes. Obesity and overweight cur- nosed diabetes and impaired fasting glucose (IFG) has
rently affect 15% and 20% of Spanish children [4], re- remained relatively stable [13]. More than generalized
spectively. The NHANES study noted that with increas- obesity, the risk of central obesity increases with increa-
ing overweight and obesity class, there is an increase in se in waist circumference (WC), waist-to-hip ratio, vis-
the prevalence of diabetes, from 2.4% for normal weight ceral adiposity, or abdominal obesity [14-17]. In a
to 14.2% for obesity class 3. With normal weight indi- review of 17 prospective and 35 cross-sectional studies
viduals as a reference, individuals in obesity class 3 had in adults aged 18 - 74 years, either BMI or WC predicted
an adjusted odds ratio of 5.1 (95% CI 3.7 to 7.0) for or was associated with T2DM independently [18]. Increase
diabetes [5]. in BMI is a better predictor of diabetes than increase in
weight.
Diagnostic Criteria and Definitions Prospective studies in non-diabetic overweight adults
noted a 49% increase in the incidence of diabetes in 10
WHO defines “overweight” [1] as a BMI equal to or years for every 1 kg/year increase in body weight and
more than 25, and “obesity” [1] as a BMI equal to or similarly each kg of weight lost annually over 10 years
more than 30. BMI, calculated by weight (kg)/height (m2) was associated with a 33% lower risk of diabetes in the
and adjusted for height, is used as a measure of weight subsequent 10 years. Similar studies in Pima Indians
standards. The criteria for diagnosis of diabetes mellitus reported that weight gain was significantly related to
as recommended by the American Diabetes Association7 diabetes incidence only in those who were not initially
include: 1. A1C ≥ 6.5% or fasting plasma glucose [FPG] overweight (BMI less than 27.3 kg/m2) [19,20]. Simi-
value after an 8-hour fast ≥126 mg/dL, or 2-hour post larly, in the Behavioral Risk Factor Surveillance System
load glucose (PG) ≥200 mg/dL (11.1 mmol/L) during an (BRFSS) for 1991-1998, Mokdad et al. [21] reported
OGTT, or symptoms of diabetes mellitus and a random that every 1 kg increase in average self-reported weight
plasma glucose concentration ≥200 mg/dl (11.1 mmol/ was associated with a 9% increase in the prevalence of
L). Insulin resistance [6] is defined as a failure of target diabetes [23]. Visceral fat seems to be strongly associ-
organs to respond normally to the action of insulin. Insu- ated with an abnormal metabolic profile rather than up-
lin resistance syndrome [7] (IRS) refers to the cluster of per body subcutaneous fat. The National Institutes of
abnormalities that occur more commonly in insulin re- Health uses WC to identify those at increased risk [22].
sistant individuals. Metabolic syndrome (MS), as de- Though both visceral adiposity (VAT) and subcutaneous
fined by the National Cholesterol Education Program fat are associated with adverse cardio metabolic risk
Adult Treatment Panel III (NCEP ATP III) [8], is a clus- factors, VAT remains more strongly associated with these
ter of metabolic abnormalities with insulin resistance as risk factors [23].
a major characteristic. The presence of any three of the
five components is sufficient for diagnosis. The compo- 3.1. Impact of Childhood Obesity on T2DM
nents of metabolic syndrome include: 1) abdominal obe-
sity (waist circumference > 102 cm [40] in men, >88 cm Obesity now affects 15% of children and adolescents
[35] in women); 2) hypertriglyceridemia (≥150 mg/dL); in the United States. BMI in childhood changes sub-
3) low HDL-C (<40 mg/dL in men, <50 mg/dL in stantially with age and is not applicable when defining
women); 4) high blood pressure (≥130/85 mm Hg); and childhood obesity [24-26]. In the United States, the 85th
5) high fasting glucose. and 95th percentiles of body mass index for age and sex
based on nationally representative survey data have been
3. Impact of Obesity on Type 2 Diabetes recommended as cut off points to identify overweight
and obesity [27]. T2DM in children and adolescents is
The relative risk of T2DM increases as BMI increases
above 23 [9], and the association was found to be an important public health problem directly related to the
stronger in younger age groups in this study from the epidemic of childhood obesity. The increasing rates of
Asia-Pacific region [10]. Weight gain in early adulthood youth T2DM parallel the escalating rates of obesity,
is related to a higher risk and earlier onset of type 2 which is the major risk factor affecting insulin sensitivity
diabetes than is weight gain between 40 and 55 years of [28]. Altered glucose metabolism, manifested as im-
age [11]. The risk of diabetes increases linearly with paired glucose tolerance (IGT), appears early in obese
BMI; the prevalence of diabetes increased from 2% in children and adolescents. Obese young people with IGT
those with a BMI of 25 to 29.9 kg/m2, to 8% in those are characterized by marked peripheral insulin resistance
with a BMI of 30 to 34.9 kg/m2 , and finally to 13% in and a relative beta-cell failure [29]. The prevalence of
those with a BMI greater than 35 kg/m2 [12]. Although the metabolic syndrome is considerable among obese
the prevalence of diagnosed diabetes has increased signi- adolescents [30,31] and the diseases that are associated

S. Yaturu / Journal of Diabetes Mellitus 1 (2011) 79-95 81
81
with obesity in children include T2DM, hypertension, verted to the visceral fat depot as well as to ectopic sites.
hyperlipidemia, gallbladder disease, nonalcoholic stea- This leads to a substantial rise in insulin resistance and
tohepatitis [32,33] sleep apnea, and orthopedic compli- the prevalence of its associated disorders. Evidence sup-
cations [34,35]. porting this hypothesis includes studies showing that in
lean subjects the prime determinant of insulin resistance
3.2. Neonatal Size and Impact of Catch-Up is BMI, that is, subcutaneous fat, whilst in overweight
Growth and obese subjects, it is waist circumference and visceral
adiposity. It has also been shown that the metabolic syn-
Low birth weight predicts central obesity. High BMI
drome suddenly increases in prevalence at high levels of
at birth and low socio-economic status were shown to be
insulin resistance and it is suggested that this is due to
independent determinants for overweight [36]. Prema-
the diversion of lipids from the subcutaneous to the vis-
ture infants are at increased risk for persistent growth
ceral depot [48]. Accumulation of fat in abdomen re-
failure, hypertension, and diabetes [37]. The risk of
gions has major implications for metabolism and parti-
T2DM is high among adults with low birth weight
cularly for insulin sensitivity [49-51]. This high preva-
(small for gestational age) [38] and is further increased
lence of co-morbidities relates more to waist circumfe-
by high growth rates after 7 years of age [39]. Acce-
rence than to BMI.
lerated childhood growth is another risk factor for adi-
Many studies have pointed to an association between
posity and insulin resistance, especially in children with
insulin resistance and intra-abdominal fat accumulation
low birth weight [40]. These children with low birth
(visceral obesity) [52]. The look AHEAD (Action for
weight and catch up growth are at risk for diabetes, obe-
Health in Diabetes) Trial of patients with T2DM demon-
sity, and cardiovascular disease [41]. Prevention of early
strated adipose tissue distribution that was significantly
catch-up growth reversed the development of glucose
altered, with more visceral adipose tissue and intermu-
intolerance and obesity was shown in a mouse model of
scular adipose tissue, depots known to exacerbate insulin
low birth weight associated diabetes [42]. Crossing into
resistance, and less subcutaneous adipose tissue in peo-
higher categories of BMI after the age of two years is
ple with diabetes than in healthy control subjects [53]. A
also associated with these disorders [42].
high prevalence of obesity and abdominal obesity in
Mexicans is associated with a markedly increased inci-
4. PATHOPHYSIOLOGY dence of diabetes and hypertension [54]. Visceral adipo-
sity is considered a risk factor for insulin resistance me-
4.1. Insulin Resistance in T2DM and Obesity tabolic syndrome [55] and T2DM in adults [56], as well
Normal glucose homeostasis is maintained by a deli- as in first degree relatives of patients with T2DM with
cate balance between insulin secretion by the pancreatic normal glucose levels [57]. Adipocytokines, hormones
β-cells and insulin sensitivity of the peripheral tissues secreted by the visceral adipocytes, generate the insulin
(muscle, liver and adipose tissue). Insulin resistance is a resistant state and the chronic inflammatory profile that
key feature of the metabolic syndrome and often pro- frequently goes along with visceral obesity [58].
gresses to T2DM. Decreased insulin sensitivity and im-
paired β-cell function are the two key components in 4.3. Visceral Adiposity and Children
T2DM pathogenesis based on long-term experience in
As defined by a BMI greater than the 95th percentile
adults [43-46]. The major link between obesity and T2DM
for age and gender from the revised National Center for
is insulin resistance. In the natural history of diabetes,
Health Statistics growth charts, 10% - 15% of 6- to 17-
obesity and insulin resistance precede abnormal glucose.
year-old children and adolescents are overweight in the
Insulin resistance in both of these conditions is mani-
United States [3] and worldwide [59]. Visceral adiposity
fested by decreased insulin-stimulated glucose tran-
is considered a risk factor for insulin resistance in chil-
sport and metabolism in adipocytes and skeletal muscle
dren [29,60-65]. Children with central adiposity can de-
and by impaired suppression of hepatic glucose output
velop the metabolic syndrome with insulin resistance,
[47].
hypertension, and dyslipidemia [66]. The dynamics of
glucose tolerance status in these youngsters seems to be
4.2. Visceral Adiposity, Obesity, Insulin more rapid than in adults, thus representing a narrow
Resistance, T2DM window of opportunity for successful intervention to
In obesity the initial deposition of triglycerides occurs prevent diabetes [67]. White adolescent subjects with
in subcutaneous adipose tissue and as this increases in obesity without DM were noted to have approximately
size insulin resistance will rise and limit further subcu- 50% lower levels of adiponectin [68,69]. In addition, the
taneous lipid accumulation. Triglycerides will then be di- study noted that hypoadiponectinemia was a strong and

independent correlate of insulin resistance, β-cell dys- and mesenteric fat may play a special role in delivering
function, and increased abdominal adiposity [69]. It is both excess FFA and IL-6 to the liver [91]. Atherogenic
hypothesized that abdominal obesity leads to insulin lipid abnormalities with lower levels of high-density
resistance partly through decreased adiponectin [70]. liporotein (HDL) and overproduction of large very low-
FFA, Free Fatty Acids density lipoprotein (VLDL) particles precede the diag-
Visceral fat exhibits accelerated lipolytic activity with nosis of T2DM by several years [92]. In obesity and
increased release of free fatty acids (FFA), which can T2DM, the altered communication between adipose tis-
adversely affect insulin action and glucose disposal in sue and the liver results in the altered regulation of
several tissues [71-75]. Conversely, declines in visceral VLDL production. A number of studies indicate that adi-
adiposity and reduced FFA levels following weight-loss pocytokines, in particular adiponectin, may be seminal
diets have been associated with enhanced insulin sensi- players in the regulation of fat metabolism in the liver
tivity [76,77]. A strong correlation between intramyo- [93]. VLDL assembly in the liver is catalyzed by micro-
cellular triacylglycerol concentrations and the severity of somal triglyceride transfer protein (MTP). A study by
insulin resistance has been found, which led to the assu- Wolfrum and Stoffel [94] showed that the forkhead pro-
mption that lipid oversupply to skeletal muscle contrib- tein Foxa2 stimulates hepatic VLDL production in con-
utes to reduced insulin action [71,78]. These increases in cert with the coactivator PGC-1beta and that insulin in-
circulating FFA levels may also result in the develop- hibits this process by inactivating Foxa2. It appears that
ment of triglyceride reservoirs in both muscle and liver, excessive VLDL production associated with insulin re-
depressing the actions of insulin and increasing hepatic sistance is caused by the inability of insulin to regulate
very-low-density lipoprotein output [79-81]. In most FoxO1 transcriptional activation of MTP [95,96].
obese subjects, plasma FFA levels are increased. FFAs
have been shown to have an important contributing role 4.4. Visceral Fat Tissue as a
in the pathogenesis of insulin resistance in human obe- Pro-Inflammatory Tissue
sity [82]. The mechanism involves intramyocellular ac-
Adipose tissue is a highly active metabolic and endo-
cumulation of diacylglycerol and activation of protein
crine organ. During the progression from normal weight
kinase C. FFAs cause hepatic insulin resistance by inhib-
to obesity and then to overt diabetes, adipocyte-derived
iting insulin-mediated suppression of glycolgenolysis
factors contribute to the occurrence and development of
[82-85]. Physiologic increases in plasma FFA levels
cause insulin resistance in both diabetic and nondiabetic β-cell dysfunction and type 2 diabetes [97]. Adipocytes
subjects by producing several metabolic defects: 1) FF- secrete a variety of products known as “adipokines”,
As inhibit insulin-stimulated glucose uptake at the level including leptin, adiponectin, resistin and visfatin, as we-
of glucose transport or phosphorylation (or both); 2) ll as cytokines and chemokines such as TNF-α, IL-6, and
FFAs inhibit insulin-stimulated glycogen synthesis; and monocyte chemoattractant protein-1 [98] all of which
3) FFAs inhibit insulin-stimulated glucose oxidation also play important roles in the pathogenesis of diabetes,
(this last-mentioned defect probably does not contribute dyslipidemia, inflammation, and atherosclerosis [98-100].
to insulin resistance). Studies have shown that both obe- The release of adipokines by either adipocytes or adi-
sity and T2DM impair insulin-induced suppression of pose tissue-infiltrated macrophages leads to a chronic sub
glycogenolysis and gluconeogenesis, and that the degree inflammatory state that could play a central role in the
of impairment correlates with plasma FFA concentrations development of insulin resistance and T2DM, and the
[86,87]. The stimulatory effect of FFAs on hepatic glu- increased risk of cardiovascular disease associated with
cose production (HGP) would then become unchecked, obesity [98].
resulting in hyperglycemia. Hence, continuously ele- In addition to inducing insulin resistance in insulin-
vated levels of plasma FFAs may play a key role in the responsive tissues, adipocyte-derived factors play an im-
pathogenesis of T2DM in predisposed individuals by portant role in the pathogenesis of β-cell dysfunction.
impairing peripheral glucose utilization and by promot- Leptin, free fatty acids, adiponectin, TNF-α and IL-6 are
ing hepatic glucose overproduction [86-90]. Potential all produced and secreted by adipocytes, and may dir-
mechanisms of this increased risk with VAT may include ectly influence aspects of β-cell function, including in-
increased free fatty acid release and alterations in adi- sulin synthesis and secretion, insulin cell survival and
pokines. Evidence from studies that manipulate FFA apoptosis [97]. Leptin is almost exclusively expressed
concentrations suggests that a number of these metabolic and produced by white adipose tissue—specifically, by
abnormalities are caused by elevated FFAs, because the differentiated adipocytes. Subcutaneous fat is respon-
most consistent abnormality in FFA metabolism is failure sible for 80% of total leptin production. This was shown
to normally suppress FFA in response to insulin/meal in cultures ex vivo where the production of leptin was
ingestion [91]. In people with visceral obesity, omental higher in subcutaneous adipocytes than in those of

83
deeper origin [101]. Leptin improves insulin sensitivity tance, ultimately resulting in a progression of metabolic
through activation of AMP protein kinase (AMPK), syndrome to prediabetes and then to T2DM [109,110].
which controls cellular concentrations of malonyl-CoA, Adiponectin is a protein highly expressed in adipose
thereby inhibiting acetyl-CoA carboxy-lase (the enzyme tissue. Like leptin, adiponectin enhances insulin sensi-
involved in malonyl-CoA transformation) [102]. While a tivity through activation of AMPK [111]. Functional
deficiency of leptin is very likely to contribute to in- analyses including generation of adiponectin transgenic
sulin resistance when adipose tissue is lacking and leptin or knockout mice have revealed that adiponectin serves as
resistance is considered as a main feature of human an insulin-sensitizing adipokine. Obesity-linked down-
obesity. regulation of adiponectin is a mechanism that explains
TNF-α and IL-6 are expressed in adipose tissues, with how obesity could cause insulin resistance and diabetes
visceral fat responsible for more TNF-α production than [112]. Adiponectin also affects hepatic glucose produc-
subcutaneous fat. These cytokines inhibit insulin signa- tion by decreasing the mRNA expression of two es-
ling and TNF-α may play a crucial role in the systemic sential gluconeogenesis enzymes: phosphoenolpyruv-
insulin resistance of T2DM [103,104]. Interleukin-6 (IL- ate carboxykinase and glucose-6-phosphatase. It appears
6), one of the adipokines, has emerged as one of the po- that high-molecular-weight adiponectin may be the most
tential mediators linking obesity-derived chronic infla- insulin-sensitizing [112]. Adiponectin correlates with
mmation with insulin resistance. Adipose tissue contri- blood concentrations of free fatty acids and reduced bo-
butes to up to 35% of circulating IL-6, the systemic eff- dy mass index or body weight, and may be the molecular
ects of which have been best demonstrated in the liver, link between obesity and insulin resistance, and may
where a STAT3-SOCS-3 pathway mediates IL-6 impair- serve as a biomarker for the metabolic syndrome [113].
ment of insulin actions. In contrast to its role in liver, IL- Interventions to reduce insulin resistance by increasing
6 is believed to be beneficial for insulin-regulated glu- adiponectin concentrations may be effective particularly
cose metabolism in muscle [105]. in obese, insulin-resistant individuals [113]. Plum treat-
TNF-α is a pro-inflammatory cytokine produced by ment (plum juice) significantly increased plasma adi-
numerous cells, but adipocytes also produce TNF-α. TNF- ponectin concentrations and PPAR-γ mRNA expression
α is overexpressed in adipose tissue from obese animals in adipose tissue from Wistar fatty rats [114]. Decreased
and humans, and obese mice lacking either TNF-α or its plasma adiponectin and insulin resistance coexist in
receptor show protection against developing insulin re- subjects with prediabetes, diabetes and atherosclerosis
sistance. TNF-α induces a state of insulin resistance in [115].
terms of glucose uptake in myocytes and adipocytes that Visfatin (also known as pre-B cell colony-enhancing
impair insulin signalling at the level of the insulin rece- factor or PBEF) is a newly discovered adipocyte hor-
ptor substrate (IRS) proteins. The mechanism involves mone, highly expressed in visceral fat, with a direct rela-
Ser phosphorylation of IRS-2 mediated by TNF-α acti- tionship existing between plasma visfatin levels and T2-
vation of MAPKs [106]. TNF-α inhibits tyrosine kinase DM. Visfatin binds to the insulin receptor at a site dis-
phosphorylation of the insulin receptor, resulting in tinct from that of insulin and causes hypoglycemia by
defects in insulin signaling and ultimately leading to reducing glucose release from liver cells and stimulating
insulin resistance and impaired glucose transport [107, glucose utilization in adipocytes and myocytes [116].
108]. An imbalance in favor of pro-inflammatory cytokin- Serum visfatin levels were reported to be elevated in ty-
es from adipose tissue (hypoadiponectinemia and increas- pe 2 diabetes independent of insulin resistance [117].
ed levels of IL-6) and other sources may trigger CRP Increased visfatin levels have been shown to be asso-
secretion. CRP levels are related strongly to insulin resis- ciated with BMI and insulin resistance in obese child-
tance and adiposity, and elevated levels correlate with ren [118]. Visfatin is not related to insulin resistance
impaired endothelial dysfunction (ED) and CAD. This in either as assessed by a homeostasis model assessment or
turn can exacerbate mild insulin resistance and accentu- during lipid infusion [119].
ate other metabolic abnormalities that together constitute Lipocalin (LCN) 2 belongs to the lipocalin subfamily
metabolic syndrome. Thus, insulin resistance, itself, app- of low-molecular mass-secreted proteins that bind small
ears to be an endothelial dysfunction risk equivalent. The hydrophobic molecules. LCN2 has been characterized
pathways are clearly intertwined with and sparked by recently as an adipose-derived cytokine, and its expres-
obesity, in large part by excess adipokine production. sion is upregulated in adipose tissue. LCN2 has been
The association of endothelial dysfunction with insulin shown to play a critical role in the regulation of body fat
resistance in the absence of overt diabetes or metabolic mass, lipid metabolism, and insulin resistance, especially
syndrome provides evidence that the atherosclerosis may as it attenuates diet-induced insulin resistance [120].
actually begin earlier in the spectrum of insulin resis- LCN2 is associated with MMP-2 and MMP-9 activities

as well as with pro-inflammatory markers, suggesting its and mortality rates. The current data support a continued
potential involvement in the low-grade chronic inflame- focus on weight loss, including moderate weight loss, as
mation accompanying obesity [121]. a key component of good care for overweight patients
with type 2 diabetes [127]. The list of benefits is shown
4.5. Non-Alcoholic Fatty Liver Disease in Table 1. The most effective interventions include
comprehensive behavioral management, dietary modify-
Non-alcoholic fatty liver disease (NAFLD) is chara- cation, exercise, pharmacotherapy and bariatric surgery.
cterized by hepatic steatosis in the absence of a history The most widely investigated drugs, sibutramine and
of significant alcohol use or other known liver diseases. orlistat, result in modest weight loss with demonstrable
Primary NAFLD emerges due to the metabolic syn- improvements in co-morbidities, among which is type 2
diabetes.
drome. Compared with healthy controls, risk for stea-
Nutrition in the management of obesity and type 2
tosis is increased 4.6-fold in obese subjects. Subjects
diabetes: Observational and interventional studies have
with NAFLD have a 2-fold greater risk of diabetes [122].
clearly shown that type 2 diabetes can be prevented by
Free fatty acids (FFAs) play a pivotal role in the deve-
lifestyle measures, including reduced energy intake to
lopment of simple hepatic steatosis. The development of
induce a modest but sustained weight reduction, together
NAFLD is closely linked to an excess flow of FFAs
with changes in diet composition [128]. Even in elderly
arising from visceral adipose tissue. Multiple mechan-
individuals, diet induced weight loss results in improved
isms including pro-inflammatory cytokines and pathways insulin sensitivity and improved β-cell function [129]. In
have been implicated in the pathogenesis of NAFLD. short-term [130] as well as long-term studies [131], use
Understanding the role of obesity and lipotoxicity in of a low carbohydrate diet in obese subjects with type 2
patients with liver disease as part of a broader metabolic diabetes has improved glucose profiles, insulin sensitive-
disorder is likely to improve the management of these ity and decreased plasma triglyceride and cholesterol
challenging diseases. In a 11 year follow-up study, NAF- levels.
LD with elevated aminotransaminase (ALT) levels was a
risk factor for incident diabetes or the metabolic syn- 5.1. Prevention of Type 2 Diabetes by
drome (MS) [123]. Insulin resistance is the basis of both Weight Reduction
NAFLD and metabolic syndrome [124,125]. Obesity
results in marked enlargement of the intra-abdominal Several interventional studies have demonstrated that
significant weight reduction could lead to a decreased
visceral fat depots. The development of insulin resist-
incidence of progression to type 2 diabetes.
ance leads to continuous lipolysis within these depots,
Finnish study [132]: This study from Finland included
releasing fatty acids into the portal circulation, where
middle-aged obese subjects with impaired glucose tol-
they are rapidly translocated to the liver and reassembled
erance (IGT) who were randomized to receive either
into triglycerides. Reactive oxygen species, generated in
the liver from oxidation of fatty acids, are precipitating Table 1. Benefits of weight loss in type 2 diabetes.
factors in the cascade of events leading from simple
steatosis to NASH [32]. Circulating free fatty acids may 1 Improved glucose levels
be cytotoxic by inducing lipid peroxidation and hepato-
2 Improved glycemic control
cyte apoptosis. Insulin resistance is often associated with
chronic low-grade inflammation, and numerous media- 3 Reduced fasting insulin
tors released from immune cells and adipocytes may
contribute liver damage and liver disease progression 4 Increased insulin sensitivity
[125].
5 Reduced upper body adiposity
5. BENEFITS OF WEIGHT LOSS IN TYPE 6 Less atherogenic lipid profile

2 DIABETES AND OBESITY
7 Decreased triglycerides
Weight loss of 5% to 10% can significantly improve
risk factors for obesity-related diseases [126]. Weight 8 Increased high-density lipoprotein (HDL) cholesterol
loss has been shown to improve glycemic control and Larger, less small, dense low-density lipoprotein (LDL)
cardio-vascular risk factors in obese individuals with 9
cholesterol particles
type 2 diabetes. Clinical studies demonstrate that the
10 Reduced blood pressure
therapeutic benefit rises with increasing weight loss, but
that losses as low as 0.45 - 4 kg (1 - 9 lb) have positive 11 Improved mortality
effects on metabolic control, cardiovascular risk factors

85
brief diet and exercise counseling (control group) or in- without IGT. After 4 years of treatment, the effect of
tensive individualized instruction on weight reduction, orlistat addition corresponded to a 45% reduction in risk
food intake, and guidance on increasing physical activity factors in the IGT group, with no effect observed in
(intervention group). After an average follow-up of 3.2 those without IGT [137].
years, there was a 58% relative reduction in the inci- Look AHEAD (Action for Health in Diabetes) [138]:
dence of diabetes in members of the intervention group This was a multicenter randomized study of 5145 parti-
compared with the control subjects. cipants randomized between 2001 and 2004, whose eth-
Diabetes Prevention Program (DPP) [133]: This mul- nicities paralleled the ethnic distribution of DM in the
ticenter study enrolled subjects with impaired glucose National Health and Nutrition Examination Survey
tolerance who were slightly younger and more obese. (NHANES) 1999-2000 survey, with a mean age of 59
Approximately 45% of study subjects were recruited +/– 6.8 years (mean +/– SD), and of whom 60% were
from minority groups (e.g., African American, Hispanic) women. Furthermore, 65.0% of participants had a first-
and 20% of subjects were aged ≥ 60 years. Subjects were degree relative with diabetes. Overall, BMI averaged 36
randomized to one of three intervention groups: the in- +/– 5.9 kg/m2 at baseline, with 83.6% of the men and
tensive nutrition and exercise counseling (“lifestyle”) 86.1% of women having a BMI > 30 kg/m2 and 17.9%
group, or either of two masked medication treatment of men and 25.4% of women having a BMI > 40 kg/m2.
groups, the metformin group or the placebo group. Par- Intensive lifestyle intervention (ILI) participants had a
tipants in both the placebo group and the metformin gr- greater percentage of sustained weight loss (–6.15% vs.
oup received standard diet and exercise recommenda- –0.88%; P < 0.001) and improvements in fitness, glyce-
tions. After an average follow-up of 2.8 years, compared mic control, and CVD risk factors in individuals with
with the control group, a 58% relative reduction in the type 2 diabetes [139].
progression to diabetes was observed in the lifestyle gr- In a recent Japanese randomized control trial to test
oup and a 31% relative reduction in the metformin group. the feasibility and effectiveness of a lifestyle intervene-
On an average, 50% of the subjects in the lifestyle group tion program in the primary care setting, in 30-60-year
achieved the goal of ≥7% weight reduction and about old subjects and BMI > 22.5 kg/m2, a significant impro-
74% maintained at least 150 min/week of moderately vement in insulin sensitivity was observed representing a
intense activity. During follow-up after DPP at 10 years, significant reduction in the cumulative incidence of pro-
incidences in placebo and metformin groups fell to equal gression to diabetes [140].
those in the former lifestyle group, but the cumulative
incidence of diabetes remained lowest in the lifestyle 5.2. Pharmacotherapy for Obesity and
group, indicating that prevention or delay of diabetes Improvement in Metabolic Risk Factors
with lifestyle intervention or metformin can persist for at and Diabetes
least 10 years [134]. Progression to diabetes is more
common in women with a history of gestational diabetes Orlistat, a gastrointestinal lipase inhibitor drug, has
(GDM) compared with those without a history of GDM, been used effectively and safely in the treatment of obe-
despite equivalent degrees of impaired glucose tolerance sity [141]. Orlistat significantly reduces body weight,
(IGT) at baseline. Both intensive lifestyle changes and and improves glycemic control and several cardiovascu-
metformin use are highly effective in delaying or pre- lar risk factors in overweight and obese subjects with
venting diabetes in women with IGT and a history of type 2 diabetes [142,143]. In type 2 diabetic patients,
GDM [135]. orlistat also attenuates postprandial increases in triglyc-
Da Qing study [136]: this study from China included erides, remnant-like particles, cholesterol, and free fatty
subjects with IGT determined by oral glucose tolerance acids [144]. The anti-hyperglycemic effect of orlistat has
tests, who were randomized by clinic to a control group been attributed to a weight loss-associated decrease in
or to one of three active treatment groups: diet only, ex- insulin resistance [145] and augmentation of the post-
ercise only, or diet plus exercise. Subjects were followed prandial increases in plasma levels of glucagon-like pep-
biannually. After an average of 6 years’ follow-up, the tide 1 (GLP-1) [146].
diet, exercise, and diet plus exercise interventions were RIO-Europe study [147]: rimonabant is a selective
associated with 31%, 46% and 42% reductions in risk of cannabinoid-1 receptor blocker with both central and pe-
developing type 2 diabetes, respectively. ripheral actions [148]. A 20 mg/day dose of rimonabant,
Xenical in the prevention of Diabetes in Obese Sub- along with a low calorie diet, resulted in significant wei-
jects (XENDOS) study [137]: this study addressed the ght reduction and improvement in cardiovascular risk
benefit of weight reduction achieved by the addition of factors such as waist circumference, HDL cholesterol, tri-
orlistat to lifestyle change, to delay the progression of glycerides, insulin resistance and the incidences of meta-
type 2 diabetes in a group with BMI ≥ 30 kg/m2 with or bolic syndrome.

Rimonabant in obesity-lipids study [149]: it has thesis.

shown to reduce body weight and improve cardiovascu-
lar risk factors in obese patients, such as a reduction in 6. PHARMACOGENETICS: POTENTIAL
waist circumference, increase in HDL cholesterol and ROLE IN THE TREATMENT OF
reduction in triglycerides. In addition, rimonabant use at DIABETES AND OBESITY
a daily dose of 20 mg also resulted in an increase in
The prevalence of obesity and diabetes, which are
plasma adiponectin levels that was partly independent of
heritable traits that arise from the interactions of multiple
weight loss alone.
genes and lifestyle factors, continues to rise worldwide.
Sibutramine: sibutramine is an anti-obesity drug that
Until recently, candidate gene and genome-wide linkage
induces satiety and thermogenesis [150]. Sibutramine
studies have been the main genetic epidemiological ap-
use has been shown to reduce weight, lower the levels of
proaches to identify genetic loci for obesity and diabetes,
nonesterified fatty acids, decrease hyperinsulinemia, and
yet progress has been slow, with limited success. Recent
reduce insulin resistance. It has been used as an effective
advances have transformed the situation and there has
adjunct to oral hypoglycemic therapy in obese subjects
been progress in understanding how genetic variation
with type 2 diabetes [151]. However, the magnitude of
predisposes individuals to diabetes and obesity, and how
weight loss was modest, and the long-term health bene-
candidate genes may alter drug response. The discovery
fits and safety remain unclear [152].
of causal genes includes family-based linkage analyses
Pharmacotherapy for diabetes and weight reduction:
and focused candidate-gene studies; among them, large-
Weight loss is an important therapeutic objective for
scale surveys of association between common DNA se-
individuals with type 2 diabetes [153]. Both short [154]
quence variants and disease were most successful. The
and long-term [155] weight loss in overweight or obese
current total of approximately 40 confirmed type 2 dia-
type 2 diabetic subjects on very low calorie diets was
betes loci includes variants in or near WFS1 (wolframin)
shown to decrease insulin resistance, improve measures
and the hepatocyte nuclear factors HNF1A and HNF1B
of glycemic control, improve lipid abnormalities and
(genes that also harbor rare mutations responsible for
lower blood pressure [154,156]. Metformin, an oral hy-
monogenic forms of diabetes) [165-168]; the melatonin-
poglycemic agent, decreases calorie intake in a dose-
receptor gene MTNR1B (which highlights the link be-
dependent manner and leads to a reduction in body
tween circadian and metabolic regulation) [169-171];
weight in subjects with type 2 diabetes and obesity [157-
and IRS1 (encoding insulin-receptor substrate 1), one of
159]. Exenatide: exenatide is a member of a new class of
a limited number of type 2 diabetes loci with a primary
agents known as incretin mimetics currently in deve-
effect on insulin action rather than on secretion [172].
lopment for the treatment of type 2 diabetes. In short-
Genetic discoveries have provided a molecular basis for
term studies, Exenatide improved glycemic control and
the clinically useful classification of monogenic forms of
helped to reduce body weight over 28 days in patients
diabetes and obesity [173,174]. Genomewide association
with type 2 diabetes treated with diet/exercise or metfor-
studies of population-based samples undertaken to ex-
min [160].
amine the full range of BMI values have identified ap-
Bariatric surgery for obesity and effect on type 2 dia-
proximately 30 loci influencing BMI and the risk of ob-
betes: bariatric surgery for severe obesity results in
esity. The strongest signal remains the association with
long-term weight loss, which leads to an improved life-
variants within FTO (the fat-mass and obesity–related
style and recovery from diabetes [161,162], hypertrigly-
gene) [171,175-177]. Other signals near BDNF, SH2B1,
ceridemia, low levels of high-density lipoprotein choles-
and NEGR1 (all implicated in aspects of neuronal func-
terol, hypertension, and hyperuricemia [162-164].
tion) reinforce the view of obesity as a disorder of hypo-
thalamic function [178-181]. There are insufficient gene-
5.3. Potential Role of Adiponectin in the
tic data to support management decisions for common
Treatment of Obesity, Diabetes and
forms of type 2 diabetes and obesity [182]. Although the
Insulin Resistance
TCF7L2 genotype variants influence therapeutic respon-
Studies have shown that adiponectin administration in se to sulfonylureas but not metformin [183], the effect is
rodents has insulin-sensitizing, anti-atherogenic and anti- too modest to guide the care of individual patients. Three
inflammatory effects and under certain settings also de- large genome-wide association studies on obesity, toge-
creases body weight. Therefore, adiponectin replacement ther involving more than 150,000 individuals, were pub-
in humans may represent a promising approach to pre- lished in Nature Genetics last year. The results suggested
vent and/or treat obesity, insulin resistance and type 2 the involvement of a large number of genetic variants in
diabetes; however, clinical studies with adiponectin ad- disease susceptibility and have identified 19 loci for
ministration need to be conducted to confirm this hypo- common obesity and 18 for common type 2 diabetes.

87
The combined contribution of these loci to the variation improvement of type 2 diabetes mellitus ([T2DM]
in obesity and diabetes risk is small and their predictive  60%), hypertension (  43%), and dyslipidemia
value is typically low. One of these loci, variants in the (  70%). One meta-analysis study reported that surgery
fat-mass and obesity-associated gene (FTO), influences was found to be superior to medical therapy in resolving
susceptibility to type 2 diabetes via an effect on adipos- T2DM, hypertension, and dyslipidemia. Sleep apnea was
ity/obesity [184]. The EPIC-Norfolk study is a popula- significantly resolved/improved in  85% across pro-
tion-based, ethnically homogeneous, white European cedures in the one meta-analysis that addressed this
cohort study of 25,631 residents living in the city of co-morbidity [188]. Studies have shown that those who
Norwich, United Kingdom, and its surrounding area. Of undergo bariatric surgery for obese diabetic patients ex-
these, 12,201 had complete genotype data for all 12 sin- perience complete remission of diabetes, maintaining
gle nucleotide polymorphisms (SNPs). The FTO locus euglycemia without medications for more than 10 years
represented the largest [185]. Variants that predispose to [189]. Additionally, following some gastrointestinal (GI)
common obesity also result in altered susceptibility to procedures, T2DM resolves within days to weeks, long
PCOS, probably mediated through adiposity [200]. One before the occurrence of major weight loss. T2DM reso-
single-nucleotide polymorphism (SNP) associated with lution or remission has usually been defined as HbA1C
weight is located close to monoacylglycerol acyltrans- values ranging from <6% to <7% in the absence of
ferase 1 (MGAT1), the MGAT enzyme family known to antidiabetic medications. Meta-analysis of bariatric sur-
be involved in dietary fat absorption [186]. Genetic gery by Buchwald et al. [190] included 136 studies for a
studies offer two main avenues for clinical translation. total of 22,094 patients; mean baseline BMI was 46.9
First, the identification of new pathways involved in kg/m2 (32.3 - 68.8). The studies that reported resolution
disease predisposition-for example, those influencing of T2DM included a total of 1846 patients. Diabetes
zinc transport and pancreatic islet regeneration in the resolution rates were 98.9% after biliopancreatic diver-
case of type 2 diabetes-offers opportunities for devel- sion (BPD), 83.7% after RYGB and 47.9% after AGB.
opment of novel therapeutic and preventive approaches. Another systematic review by Levy et al. [191]. con-
Second, with continuing efforts to identify additional firmed that bariatric surgery was highly effective in ob-
genetic variants, it may become possible to use patterns taining weight reduction in morbidly obese patients with
of predisposition to tailor individual management of losses of up to 60% of the excess weight, along with re-
these conditions. solution of preoperative diabetes in more than 75% of
the cases.
7. BARIATRIC SURGERY FOR OBESITY
AND IMPROVEMENT IN DIABETES Pharmacotherapy for Diabetes that Helps
CONTROL Weight Reduction
Bariatric surgery as a modality to treat obesity in the Pramlintide is an analog of amylin, a naturally occur-
US is reserved for patients with BMI ≥ 35 kg/m2 and the ring hormone produced by pancreatic β-cells. The major
presence of serious co-morbidities (T2DM, moderate or mechanism of action appears to be inhibition of gastric
severe obstructive sleep apnea (OSA), pseudotumor ce- emptying and suppression of glucagon release. Clinically,
rebri, and severe steatohepatitis), or BMI > 40 kg/m2 and it also suppresses appetite in patients who receive it.
minor comorbidities (mild OSA, hypertension (HTN), Glucagon-like peptide-1 (GLP-1) is recognized as an
insulin resistance, glucose intolerance, dyslipidemia, im- important regulator of glucose homeostasis. Exenatide
paired quality of life, or activities of daily living). Gas- and liraglutide are analogs of GLP-1, a naturally occur-
tric bypass surgery appears to have significant increased ring incretin produced by the L-cells of the distal ileum.
therapeutic potential for treating obesity and Type 2 dia- GLP-1 stimulates insulin release from the pancreatic β-
betes. In view of the growing enthusiasm for surgical cells, suppresses glucagon release from the pancreatic α-
interventions to treat T2DM, the first diabetes surgery cells, slows gastric emptying, and acts on the brain to
summit (DSS) was held in Rome in March 2007. Trends increase satiety. Increases in GLP-1 may be responsible
in mortality in bariatric surgery were reported by Buch- for some of the weight loss following roux-en-Y gastric
wald et al. in 2007 [187] in a systemic review that in- bypass surgery in patients with type 2 diabetes [192].
cluded meta-analysis of 361 studies and a total of 85,048 The improvement in overall glucose control has been
patients with a mean BMI of 47.4 kg/m2. The early and modest in clinical trials, at around 0.3%. However, those
late mortality rates after bariatric surgery were reported using the medication have also experienced weight re-
as low. duction of ~1 - 1.5 kg in patients with type 1 diabetes
A review by Cunneen reported that all studies report- and ~2.0 - 2.5 kg in patients with type 2 diabetes. Ad-
ing on co-morbidities showed significant resolution or ministration of exenatide in patients with type 2 diabetes

has similar effects. Clinically, the result is an A1C reduce- them. The risk of CVD mortality in type 2 diabetic pa-
tion of ~1%. Preliminary studies suggest that a signify- tients is more than double compared with that in age-
cant proportion of insulin-treated patients with type 2 matched subjects [199]. The risk of coronary artery dis-
diabetes may be successfully transitioned from insulin to ease (CAD) in subjects with type 2 diabetes is consid-
Exenatide in addition to their oral agents. Most patients ered equivalent to that of nondiabetic subjects who have
experience significant weight loss of ~2.5 kg when Ex- CAD [200,201], especially women [202]. The associa-
enatide is used in addition to metformin and ~1 kg when tion of obesity with clinically significant coronary artery
it is added to a sulfonylurea [193,194]. Exenatide was disease is blatant in two classical prospective studies
associated with a significant reduction in mean (SD) highly consulted: the Framingham Heart Study [203]
body weight from baseline (–2.1 [0.2] kg), with pro- and the Nurses Health Study [204]. Elevated pro-in-
gressive reductions after 2 years (–4.7 [0.3] kg; P < flammatory cytokine levels found in obese patients re-
0.001 vs baseline) [195]. late mainly to obesity rather than to T2DM. Moreover,
Liraglutide works in a manner similar to that of Exen- surgery-induced weight loss reduces circulating concen-
atide but has a longer half-life, which allows for once trations of key pro-inflammatory factors, which contri-
daily (rather than twice daily) dosing. Some studies, ute to the improvement in the cardiovascular co-mor-
including one meta-analysis, suggest that it may have a bidity following excess weight loss [205]. Obesity and
slightly greater A1C-lowering effect than Exenatide, alth- overweight are often defined by WHO (World Health
ough more investigation is warranted to substantiate Organization) in terms of excess weight for a given hei-
such findings. In a meta-analysis, it is noted that exena- ght [1206] Overweight was defined as a body mass in-
tide and liraglutide resulted in greater weight loss (from dex (BMI) of 25.0 to 29.9 and obesity as a BMI of >30.0.
2.3 to 5.5 kg) with improvements in HbA1C similar to BMI, calculated by weight (kg)/height (m2) and adjusted
that obtained with sufonylureas [196]. Neither exenatide for height is used as a measure of weight standards.
nor liraglutide are indicated for simple weight loss.
9. CONCLUSIONS
8. MULTIPLE RISK FACTORS FOR
Obesity has become an epidemic worldwide. The de-
CARDIOVASCULAR DISEASE AND
velopment of obesity and diabetes involves complex ge-
DIABETES MELLITUS
netic and environmental factors. Diabetes is fastest grow-
The metabolic syndrome is a constellation of central ing disease in the world. The health consequences and
adiposity, impaired fasting glucose, elevated blood pres- economic costs of the overweight, obesity and type 2
sure, and dyslipidemia (high triglyceride and low HDL diabetes epidemics are enormous. Behavioral changes
cholesterol). When three of these five criteria are present, leading to increased body weight is a major contributing
the risk of cardiovascular disease and diabetes is in- factor to the rising incidence of diabetes.
creased 1.5- to 2-fold [197,198].
10. ACKNOWLEDGEMENTS
8.1. Obesity and Co-Morbidities
Dr. Yaturu receives salary support from Veterans Health Administra-
Obesity is becoming a major public health problem tion.
throughout the world and is associated with significant,
potentially life-threatening co-morbidities. Either obesity
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Obesity and Type 2 Diabetes

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Obesity and type 2 diabetes

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ABSTRACT well as waist circumference in both men and women [2].

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5. BENEFITS OF WEIGHT LOSS IN TYPE 6 Less atherogenic lipid profile

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Rimonabant in obesity-lipids study [149]: it has thesis.

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SESPAS Report 2010. Gaceta Sanitaria, 24, 49-55. doi:10.1038/ejcn.2009.93

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Cell Biology, 38, 804-819. doi:10.2220/biomedres.26.193

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tion in older men. The Journal of Clinical Endocrinology doi:10.1111/j.1464-5491.2005.01723.x

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[158] Genuth, S. (2000) Implications of the United Kingdom doi:10.1080/07853890701670421

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