The British Journal of Diabetes & Vascular

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Obesity in the pathogenesis of type 2 diabetes

Caroline Day and Clifford J Bailey
British Journal of Diabetes & Vascular Disease 2011 11: 55
DOI: 10.1177/1474651411407418
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Obesity in the pathogenesis

of type 2 diabetes
CAROLINE DAY, CLIFFORD J BAILEY
Abstract

besity, and especially visceral adiposity, escalates

the development of insulin resistance and type 2
diabetes. Excess adipose tissue contributes to a
chronic increase in circulating fatty acids reducing the
usage of glucose as a source of cellular energy. Excess
fatty acids also result in increased deposition of fat in
muscle and liver, and increased metabolites such as diacylglycerol and ceramide which activate isoforms of protein kinase C that impede cellular insulin signalling.
Chronically raised lipid levels also impair islet beta cell
function, acting in conjuction with insulin resistance to
aggravate hyperglycaemia. The detrimental effects of
several adipokines such as TNF, IL6 and RBP4, which are
produced in excess by an increased adipose mass, and
reduced production of adiponectin are further mechanisms through which obesity potentiates the development of type 2 diabetes.

Br J Diabetes Vasc Dis 2011;11:55-61.

Key words: adipokines, adipose, cytokines, insulin resistance,

obesity, type 2 diabetes

Introduction
The risk of type 2 diabetes increases exponentially as BMI
increases above about 25 kg/m2.1,2 Compared with a normal
BMI of 22kg/m2, the risk of type 2 diabetes is increased by two
to eight-fold at BMI 25, 1040-fold at BMI > 30, and > 40-fold
at BMI > 35 depending on age, gender, duration and distribution of adiposity and ethnicity. For example a BMI of 3035
increased the occurrence of type 2 diabetes by > 20 fold in
women and > 10 fold in men.3,4
In the USA, obesity is more common amongst people of
Hispanic and black ethnicities, and the increased risk of type 2
diabetes may be slightly greater than in obese people of
European origin.5,6 However in people of south Asian origin

Life and Health Sciences, Aston University, Birmingham, UK.

Correspondence to: Professor Clifford J Bailey
Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.
Tel +44 (0)121 204 3898; Fax +44 (0)121 204 4187
E-mail: c.j.bailey@aston.ac.uk

Abbreviations and acronyms

11bHSD1
ADSF
AGE
AMPK
BMI
ER
IGT
IKK
IL6
IRS
JNK
LPL
NAFLD
NF-kB
PKC
PPAR
PTP
RBP4
ROS
TNF

11b-hydroxysteriod dehydrogenase1
adipocyte-specific secretory factor
advanced glycation end product
adenosine monophosphate kinase
body mass index
endoplasmic reticulum
impaired glucose tolerance
IkB kinase
interleukin-6
insulin receptor substrate
jun N-terminal kinase/stress activated protein kinase
lipoprotein lipase
non-alcoholic fatty liver disease
nuclear factor kB
protein kinase C
peroxisome proliferator-activated receptor
protein tyrosine phosphatase
retinoid binding protein-4
reactive oxygen species
tumour necrosis factor

obesity confers a substantially higher risk of type 2 diabetes,

such that BMI 27.5 in south Asians is associated with similar
morbidity to BMI 30 in Europids, leading some authorities to
suggest that a BMI of 22 or 23 should be considered as overweight for south Asian peoples.5-9
Although excess fat in any region of the body is associated
with increased risk of type 2 diabetes and cardiovascular disease,10 it is generally held that an accumulation of abdominal
fat (central obesity), as indicated by an increased waist:hip
ratio is an independent risk for type 2 diabetes irrespective of
the extent of obesity.11 This is mainly attributed to increased
intra-abdominal (visceral) adiposity. Excessive deposition of
lipid in muscle and liver also enhances the risk of type 2 diabetes
through mechanisms of intracellular lipotoxicity.
This review offers an update on the mechanisms through
which excess adipose tissue potentiates the development of
insulin resistance and type 2 diabetes.

Lipotoxicity and type 2 diabetes

Lipotoxicity constitutes an important pathogenic link between
obesity, insulin resistance and type 2 diabetes. Lipotoxicity

THE
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Table 1. Risk factors for the development of impaired glucose tolerance

and type 2 diabetes

Overweight or obese
Other features of metabolic syndrome, especially hypertension
Family history of type 2 diabetes and/or diabetes/obesity
genes
Gestational diabetes or other previous hyperglycaemia
Ethnically predisposed
Atherothrombotic symptoms
Low birth weight, poor foetal/neonatal nutrition
High parity
Diabetogenic drugs
Microalbuminuria
Recurrent infections and persistent stress
Smoker
Elderly

describes the detrimental cellular effects of chronically elevated

concentrations of fatty acids and excess lipid accumulation in
tissues other than adipose tissue, accepting that excess adipose
tissue is often a source of increased fatty acid supply in obesity.
Excess adiposity is well known to promote the onset and
severity of insulin resistance, contributing to emergence and
progression of IGT and type 2 diabetes. Indeed, around twothirds to three-quarters of individuals who develop diabetes
have a history of significant overweight or obesity making
chronic excess adiposity the strongest risk factor for type 2
diabetes (table 1).

Onset of obesity
A variable mix of inherited susceptibilities and environmental
(lifestyle) factors conspire to create a positive energy balance
and generate excess adipose tissue. Several rare monogenic
forms of severe obesity are recognised, such as mutations of
genes in the leptin and pro-opiomelanocortin pathways and
melanocortin-4 receptors. However, genetic susceptibility to
obesity is probably commonly due to the small influences of a
wide selection of genes such as those encoding the beta3 adrenoceptor, PPARg and its co-activator-1, adiponectin, FTO (fat
mass and obesity associated gene), and a selection of genes
that could potentially influence behaviour and hypothalamic
hungersatiety mechanisms have been implicated.12,13

Glucosefatty acid cycle

One of the main routes though which excess adiposity impedes
glucose metabolism is an increased supply of fatty acids into
the circulation.14-16 Persistent positive energy balance is associated with increased storage of triglyceride. This expands the
adipose depots and increases the proportion of hypertrophied
adipocytes (figure 1). Under conditions of normal insulin

Figure 1. Factors affecting adipose depots

 Glucose
utilisation

Chylomicrons
VLDL-TG
LPL

Energy for
glucose
production

FA

FA

HSL

TG

Insulin

Circulating triglycerides (TG), principally from dietary triglycerides as

chylomicrons and hepatically synthesised very-low-density lipoprotein
(VLDL) are partially degraded by lipoprotein lipase (LPL) produced by
adipose tissue. Many of the released fatty acids are incorporated into
adipocyte TG. Subsequent lipolysis involving hormone-sensitive lipase
(HSL) releases fatty acids into the circulation. These are taken up by
muscle and liver.

sensitivity, insulin suppresses the activity of hormone-sensitive

lipase and thereby reduces lipolysis, which in turn limits the
supply of fatty acids into the circulation. However, enlarged
adipocytes become less sensitive to the antilipolytic action of
insulin, causing an increase in the liberation and turnover of
fatty acids. The fatty acids can be taken up by liver and muscle
where they are used in competition with glucose as a source of
energy. Thus the imbalance to the glucosefatty acid (Randle)
cycle increases the availability of fatty acids and their oxidation,
and reduces the utilisation of glucose. Fatty acid metabolites
are also produced which impair the post-receptor pathway of
intracellular insulin signalling and decrease insulin-stimulated
glucose transport in muscle. Energy generated by fatty acid
oxidation can be utilised by the liver in the production of glucose by gluconeogenesis, and fatty acid metabolites that
impede insulin action that will inhibit the normal suppression of
gluconeogenesis by insulin. Thus disturbances of the glucose
fatty acid cycle enable increased fatty acids to exacerbate insulin resistance and hyperglycaemia.

Ectopic fat
Excess circulating fatty acids that are taken up by muscle (intramyocellular fat) are often stored as triglyceride in this tissue or
used for extra b-oxidation. However, type 2 diabetes is associated with a reduction in mitochondrial mass, requiring excess
fatty acids to be diverted into non-oxidative pathways such as
the production of diacylglycerol and the production of ceramide.
Both of these metabolites of fatty acids activate isoforms of
PKC that promote serine phophorylation of insulin signalling
proteins such as insulin receptor substrates (e.g. IRS-1, IRS-2),

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Deposition of excess fat in the liver (hepatic steatosis) or

NAFLD also impairs insulin signalling. This may also involve a
similar interruption to early insulin signalling as noted with
intramyocellular lipid, but resulting principally in failure to
inhibit excessive glucose production (figure 2) as well as
causing lipotoxic hepatocyte cell death.22

Figure 2. Cellular sites at which genetic and environmental factors

impact on insulin resistance

Insulin

Hyperinsulinaemia

Receptor
Hyperglycaemia
FFAs, TNF,
adipokines

Insulin receptor substrates

e.g. IRS 1, IRS 2
PI3-kinase
PDK, PKB

Ras complex
Raf, MEK, MAPK

PEPCK
Gluconeogenesis

GLUT 4
Glucose
transport

Although the distribution of fat between visceral and subcutaneous compartments varies widely subcutaneous adipose tissue typically accounts for over 80% of body fat. Women have
proportionally more subcutaneous fat than men, but men
appear to be more susceptible to the accumulation of excess
visceral fat. Since most studies indicate that excess visceral fat
carries a much higher risk of type 2 diabetes and vascular disease than excess subcutaneous fat,11 visceral fat cells appear to
be a more important source of agents to cause insulin resistance. The increased release of fatty acids into the portal vein
will have a direct impact on hepatic energy metabolism and
hepatic lipotoxicity, and are regarded as an important culprit
for hepatic insulin resistance.23

Inherited
(genetic)
levels of
expression
of signalling
intermediates,
enzymes and
transporters

Enzyme activities

Gene expression

Adipose tissue depots

GS
Glycogenesis

Key: FFAs = free fatty acids; GLUT = glucose transporter;

GS = glycogen synthase; IRS = insulin receptor substrate;
MAPK=mitogen-activated protein kinase; MEK = mitogen-activated
protein kinase kinase; PEPCK = phosphoenolpyruvatecarboxy kinase;
PDK = phosphoinositide dependent kinase; PI3 =phosphatidylinositol 3;
PKB = protein kinase B; TNFa = tumour necrosis factor alpha

Adipokines

thereby reducing their signalling activity.17-19 This accounts in

part for the effect of lipotoxicity to impede the translocation of
GLUT4 glucose transporters into the plasma membrane, reducing glucose transport (figure 2). Since skeletal muscle accounts
for >70% of glucose disposal compared with about 10% into
adipose tissue, the development of insulin resistance in muscle
is a major feature of obesity-induced insulin resistance.20,21

There is increasing acceptance that endocrine and locally acting

(paracrine and autocrine) adipokines can modify insulin sensitivity, and many will contribute to the development and maintenance of insulin resistance in overweight patients with insulin
resistance (figure 3).24

TNFa and IL6

The pro-inflammatory cytokines TNFa and IL6 are produced in
increasing amounts by expanding adipose depots. Although

Figure 3. Adipokines and other adipocyte products that affect insulin action, nutrient homeostasis and cardiovascular function

Adipose
tissue

Lipid metab Ins action

LPL
FFA

Ins action

Adiponectin

TNFa

Leptin
Visfatin
Vaspin ?

PAI-1

IL6

Angiotensinogen

RBP4

Apelin

Resistin ?

*(Omentin)

Vascular

Cortisol
FFA

* From stromal vascular cells in visceral adipose depots

Inflammation
MCP1
TNF
IL6
Various
cytokines
CRP and
other acute
phase proteins

Immune Prostaglandins
Adipsin
(comple
ment D)

PGE2

Other
complement
factors

Key: CRP = C reactive protein; FFA = free fatty acid; IL6 = interleukin 6; Ins = insulin; LPL = lipoprotein lipase; MCP1 = monocyte chemoattractant protein;
PAI-1 = plasminogen activator inhibitor-1; PGE2 = prostaglandin E2; RBP4 = retinol binding protein; TNFa = tumour necrosis factor a

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these cytokines are produced by adipocytes, within adipose

tissue there are large numbers of macrophages which may also
be a source of these adipokines. Animal studies have shown
that insulin sensitivity improves after TNF knockout whereas
raising TNF levels accentuates insulin resistance. TNF impedes
insulin receptor phosphorylation and also impedes some postreceptor insulin signalling reactions. Both TNFa and IL6 reduce
the activity of LPL and increase intracellular lipolysis, raising
circulating fatty acid concentrations.25 Since circulating concentrations of these pro-inflammatory cytokines are relatively low
it is possible that their main effects on insulin resistance and
lipid metabolism are mediated locally in a paracrine manner. A
further mechanism is through serine phosphorylation of IRS-1
and IRS-2 and reduced tyrosine phosphorylation of IRS-1
through TNFa-induced activation of PTP-1b.

concentrations are reduced in obese diabetic states. Thus a

reduction of adiponectin appears to contribute to the development of insulin resistance in obesity and type 2 diabetes.

Leptin
The adipocyte hormone leptin acts mainly via central mechanisms to reduce food intake and increase metabolic energy
expenditure. Although leptin concentrations may increase in
obesity this tends to be associated with the development of
leptin resistance which appears to reduce its effectiveness.
Leptin may act on skeletal muscle to improve insulin action possibly via activation of AMPK and increased fatty acid oxidation
suggesting that it probably does not play a significant role in
insulin resistance.25

Other adipokines
Retinol binding protein
RBP4 is produced and secreted by adipocytes and transports
retinol (vitamin A) in the circulation. Increased RBP4 has been
noted in obese insulin resistant states reducing the tissue availability of retinol. Indeed, overexpression of RBP4 in mice causes
insulin resistance whereas RBP4 knockout improves insulin sensitivity. Increased amounts of RBP4 in obese insulin resistant states
decrease glucose uptake in skeletal muscle and increase glucose
output by liver, thereby contributing to hyperglycaemia.26

Among other known adipokines, adipsin (complement for factor D) has some unconfirmed preliminary evidence suggesting
a possible association with insulin resistance; conversely, several
other adipokines have been claimed to improve insulin action.25
For example visfatin, apelin, omentin and chemerin have
received several such reports but these have not been consistently confirmed. The protease vaspin has also been considered
in this context but preliminary information awaits confirmation.

Cortisol
Resistin
Resistin, also known as Fizz3 and ADSF, is a pro-inflammatory
cytokine produced by adipocytes and macrophages. Resistin
can increase the production of TNFa and IL6, and concentrations of resistin are raised in some genetic and diet-induced
animal models of obesity and diabetes. Also, administration of
antibodies to resistin, or resistin gene knockout, has been
shown to improve insulin sensitivity and reduce hepatic glucose
production. However, the expression levels of resistin in human
adipocytes are very low and there is no apparent increase in
expression of resistin in human obese insulin resistant states
leaving the role of resistin uncertain.27

Adiponectin
Adiponectin (Arcp30 or AdipoQ) is produced only by adipocytes. The receptors for this adipokine are expressed in muscle,
liver and other tissues, including islet beta cells and endothelium where they bring about tyrosine phosphorylation and
signalling of the insulin receptor resulting in improved insulin
sensitivity. Activation of adiponectin receptors stimulates
AMPK, which increases fatty acid oxidation and glucose uptake
in muscle. Adiponectin also increases PPARa activity and
reduces inflammation. Additionally, adiponectin exerts antiatherogenic actions including a reduction in the expression of
several adhesion molecules, increased endothelial nitric oxide
production, which improves vasodilation, and reduced vascular
smooth muscle proliferation.28
An unusual feature of adiponectin is its reduced production and secretion as the adipose mass expands such that

Adipose tissue is an important site for the interconversion of

glucocorticoids. Cortisone is converted to cortisol by the
enzyme 11bHSD1; the increased capacity for the conversion
is increased as the adipose mass expands in obesity.29
Glucocorticoids antagonise the actions of insulin in various
ways: they raise plasma lipids, increase hepatic gluconeogensis, impair glucose tolerance and stimulate food intake. They
also promote differentiation of pre-adipocytes into adipocytes
and increase adipocyte hypertrophy especially increasing central adiposity. Initially glucocorticoids can expand the beta cell
mass and contribute to hyperinsulinaemia, but in the longterm they are associated with the development of glucose
intolerance and type 2 diabetes and loss of beta cell function.
Glucocorticoid levels are usually near normal in obesity as the
increased formation of active glucocorticoids is largely offset
by increased inactivation (figure 4), but the potential to exacerbate insulin resistance is appreciated.

Mitochondrial defects
There is some evidence that decreased oxidation of fatty acids
in obesity is associated with a reduction in the number, size and
activity of mitochondria.11 There is also a decrease in the proportion of mitochondrial rich type 1 muscle fibres in type 2
diabetes. The reduced capacity for glucose oxidation appears
to contribute to increased generation of ROS, which activate
serine kinases such as JNK and IKK which in turn inhibit insulin
signalling at the level of IRS1/2 and via NF-kB. JNK may also
increase cytokine production and mediate ER stress in obesity,
coinciding with insulin resistance.

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Figure 4. Activation of glucocorticoids from cortisone to cortisol occurs

mainly in liver and adipose tissue

CH2OH

C=O
OH

CH2OH

11-HSD1

HO

C=O
OH

11-HSD2
O

Cortisone

Cortisol

inactive
active
11-HSD1,11b-hydoxysteroid
11-hydoxysteroid dehydrogenase-1
dehydrogenase-1 is
is a
enzyme
11b-HSD1,
a reductase
reductase enzyme
expressed mainly in liver and adipose tissue.

expressed mainly in liver and adipose tissue.

Autonomic adjustments
Reduced activity of the sympathetic nervous system has been
noted in several genetically obese insulin resistant animal models and this appears to contribute to reduced thermogenesis in
brown fat and weight gain. Although diet-induced obesity is
also often associated with increased sympathetic activity, this
is not a consistent nervous effect and clinical evidence is
equivocal.

The islet beta cell

The foregoing sections have illustrated the multiplicity of
mechanisms through which increased adiposity hastens the
onset and increases the severity of insulin resistance. While the
initial process appears to be strongly related to a positive
energy balance it is evident that a vicious spiral is set in motion
in which the excess adipose tissue and the associated metabolic

disturbances further exacerbate the impairment of insulin

action (figure 5). To prevent glucose homeostasis becoming
impaired it is incumbent upon the pancreatic beta cells to
respond to the demand for more insulin to overcome insulin
resistance. Indeed, in IGT there is typically an increase in circulating insulin levels, although these are not sufficient to overcome the effects of the insulin resistance. Indeed, the gradual
deterioration of insulin sensitivity is accompanied by subtle
alterations in beta cell function such that it is difficult to demonstrate the exact manner in which the two processes are interrelated.21,30 Although it is tempting to speculate that marginal
repeated increments in glucose concentrations stimulate extra
insulin production and secretion it could be that small repeated
increments in circulating lipids play an important role. Shortterm elevations in each of these nutrients increase insulin secretion, but chronic exposure is known to impair insulin secretion,
and insulin resistance of the beta cell itself further complicates
the situation.

Beta cell dysfunction

The earliest alterations of beta cell function are a small delay
and reduction in the acute first phase of glucose-induced
insulin secretion, and an increased and protracted chronic second phase response. The normal pulsatile rhythm of basal
insulin secretion is also disturbed and the proportion of prandially secreted proinsulin is increased. These observations suggest
that the initial sensing of an increased glucose stimulus and the
intracellular processing of proinsulin to insulin by the beta cells
are early functions to become defective.20,30
By the time insulin resistance is established and glucose tolerance is becoming impaired the first phase of glucose-induced

Figure 5. Pathogenesis of type 2 diabetes, insulin resistance and beta cell dysfunction

-CELL
DYSFUNCTION

Diabesity genes
Lifestyle
Adipokines
Inflammation

OBESITY

Surplus
energy

 Insulin

INSULIN
RESISTANCE

Glucotoxicity
Lipotoxicity
 Lipolysis

 Free fatty acids

 Glucose
production

 Glucose
uptake

 Blood glucose

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insulin secretion is substantially reduced, while the second phase

is markedly enhanced and extended. This is customarily interpreted as a compensatory adaptation of the beta cells to address
the modest emergent hyperglycaemia in the face of insulin
resistance.
Obesity is typically associated with an increase in beta cell
mass involving hypertrophy and hyperplasia,31 supporting the
concept of an adaptation to meet an increased demand for
insulin. At this stage the beta cells remain rich in insulin granules, suggesting that it is the acute component of the stimulussecretion process that is inadequate.

Key messages
Obesity is a major driver of type 2 diabetes
Excess fatty acids from an expanded adipose mass

cause and exaggerate insulin resistance

Various adipokines (e.g. TNFa and IL6) aggravate

insulin resistance
Chronic lipotoxicity worsens the prognosis for obese

type 2 diabetes patients

Genetic influences
Many individuals are able to sustain an increased, but delayed
insulin secretory response to meals which is sufficient to prevent glucose intolerance progressing to type 2 diabetes.
However, individuals in whom the beta cells are unable to sustain increased insulin secretion experience rising hyperglycaemia into a state of type 2 diabetes.
Polymorphisms and alterations in expression levels of several genes have been identified that appear to increase the
susceptibility of beta cells to a functional deterioration when
placed under increasing metabolic demand. These include several promoters and transcription factors associated with beta
cell division and differentiation such as TCF7L2. Also implicated
are the KCNJ11 gene for the Kir6.2 potassium channel and the
zinc transporter gene SLC30A8.32 The expression of some
genes by the beta cell may also be affected by the metabolic
environment in utero and early postnatal life such that poor
nutrition at these times may programme a smaller and less
adaptive beta cell mass.

Beta cell insulin resistance

While loss of normal insulin sensitivity is well recognised to
adversely affect nutrient metabolism in adipose tissue, muscle
and liver of obese individuals, it is also apparent that the pancreatic beta cells themselves are susceptible to insulin resistance. Gene knockout studies have shown that insulin signalling
via IRS proteins is important for beta cell viability and replication. Loss of insulin sensitivity of the beta cell appears to restrict
the adaptive changes in beta cell mass and could hasten progression from IGT to type 2 diabetes.

Glucotoxicity and lipotoxicity

Beta cells are particularly vulnerable to elevated circulating
concentrations of glucose and fatty acids.14,33 The uptake of
glucose into the beta cell is directly proportional to the circulating glucose concentration, and small defects of glucose
metabolism probably arise due to alterations of mitochondrial function in the beta cells. These disturbances increase
ROS formation, which damages DNA and increases susceptibility to apoptosis. Chronic exposure to fatty acids accentuates triglyceride accumulation within beta cells, generates
further ROS and peroxidation of lipids leading to membrane
dysfunction.33

Adipokines, hormones and other factors

In addition to the production of insulin, the beta cell is a source
of several other hormones. The main product is amylin (islet
amyloid polypeptide), which is co-secreted with insulin. Thus
increased production of insulin in obesity and insulin resistance
may lead to accumulation of amylin within and surrounding
the beta cells. Amylin precipitation may contribute to the
premature demise of beta cells. Leptin and possibly other
adipokines, including TNFa, might reduce insulin secretion and
increase beta cell death.34,35

Co-morbidities
Accumulation of excess lipid in cardiomyocytes further impairs
cardiac function. Excess adiposity, insulin resistance, beta-cell
dysfunction, lipotoxicity and glucotoxicity typically conspire to
cause the clinical sequelae associated with type 2 diabetes,
most notably the development of microvascular and macrovascular diseases. Microvascular disease (retinopathy, nephropathy
and neuropathy) is more strongly associated with hyperglycaemia. High circulating glucose concentrations generate AGEs,
which contribute to thickened but leaky capillary basement
membranes. Macrovascular disease (cerebrovascular, cardiovascular and peripheral vascular disease) develops in part as a
consequence of poor glycaemic control, but is also strongly
determined by dyslipidaemia, hypertension and a pro-coagulant
state, all of which are associated with insulin resistance and
commonplace in obesity. The main result is formation of
atheromatous plaque, and when this becomes unstable, the
rheological changes and opportunity for thrombus formation
bring about the typical diabetic macrovascular scenario. Also,
microvascular disease impinges on macrovascular disease and
vice versa in diabetes, e.g. the diabetic foot and increased
fatality rates for myocardial infarction reflect combined failure
of large and small vessel function.

Conclusion
An overpositive energy balance leading to obesity, especially
excess visceral adiposity, provides an adverse metabolic environment that fosters the development of insulin resistance and
beta cell dysfunction. In susceptible individuals who are unable

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to sustain increased insulin secretion this results in the emergence of glucose intolerance and type 2 diabetes.

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