The Role of Insulin Resistance in the Pathogenesis of ACD

8/2/2019 The Role of Insulin Resistance in the Pathogenesis of ACD

1/15Copyright Italian Federation of Cardiology. Unauthorized reproduction of this article is prohibited.

The role of insulin resistance in the pathogenesis ofatherosclerotic cardiovascular disease: an updated reviewKota J. Reddya, Manmeet Singha,b, Joey R. Bangita and Richard R. Batsellc

Insulin resistance is the main pathologic mechanism that

links the constellation of clinical, metabolic and

anthropometric traits with increased risk for cardiovascular

disease and type II diabetes mellitus. These traits include

hyperinsulinemia, impaired glucose intolerance, endothelial

dysfunction, dyslipidemia, hypertension, and generalized

and upper body fat redistribution. This cluster is often

referred to as insulin resistance syndrome. The progression

of insulin resistance to diabetes mellitus parallels the

progression of endothelial dysfunction to atherosclerosis

leading to cardiovascular disease and its complications. In

fact, insulin resistance assessed by homeostasis modelassessment (HOMA) has shown to be independently

predictive of cardiovascular disease in several studies and

one unit increase in insulin resistance is associated with a

5.4% increase in cardiovascular disease risk. This review

article addresses the role of insulin resistance as a main

causal factor in the development of metabolic syndrome

and endothelial dysfunction, and its relationship with

cardiovascular disease. In addition to this, we review the

type of lifestyle modification and pharmacotherapy that

could possibly ameliorate the effect of insulin resistance

and reverse the disturbances in insulin, glucose and lipid

metabolism. J Cardiovasc Med 11:633647 Q 2010 Italian

Federation of Cardiology.

Journal of Cardiovascular Medicine 2010, 11:633647

Keywords: adipokines, cardiovascular risk, insulin resistance, metabolicsyndrome, peroxisome proliferator-activated receptors, thialidazone

aReddy Cardiac Wellness, Sugar Land, Texas, bDepartment of Internal Medicine,UCSF Fresno, 155 N. Fresno Street, Fresno, CA-93702 and cRice University,Houston, Texas, USA

Correspondence to Manmeet Singh, MD, UCSF, Fresno, Department of InternalMedicine, 155 N. Fresno Street, Fresno, CA-93702, USAE-mail: [email protected]

Received 15 May 2009 Revised 13 August 2009Accepted 22 September 2009

IntroductionInsulin resistance results in the spectrum of metabolic

disturbances that extends beyond hyperglycemia and

hyperinsulinemia and includes inflammation, endothelialdysfunction, hypertension, atherogenic dyslipidemia and

hypercoagulability. Insulin resistance is now increasingly

recognized as the cornerstone of what is termed as

metabolic syndrome or syndrome X [1]. In 1988, Reaven

[1] used the term syndrome X to describe a collection of

metabolic changes associated with cardiovascular dis-

eases (CVDs) and postulated that insulin resistance could

be seen as the center of all these changes adversely

affecting the cardiovascular system. Since then, meta-

bolic syndrome has been increasingly related to incidence

of CVD. However, metabolic syndrome may not capture

all the CVD risk associated with insulin resistance. Thisfact is supported in numerous studies in which insulin

resistance has been shown to be associated indepen-

dently with CVD, even after accounting for metabolic

syndrome in multivariate analysis [25]; thus, suggesting

that insulin resistance is the root cause for the metabolic

syndrome as well as the other risk factors such as inflam-

mation, type II diabetes mellitus and hypercoaguabilty

associated with CVD. This review article addresses the

role of insulin resistance as a main causative factor in the

development of metabolic syndrome and endothelial

dysfunction, and its relationship with CVD. In addition,

we review the type of lifestyle modification and pharma-

cotherapy that could possibly ameliorate the effect of

insulin resistance and reverse the disturbances in insulin,

glucose and lipid metabolism.

Definition of insulin resistance and itspathogenesisInsulin resistance is a condition in which the cells of body

become resistant to the effects of insulin, resulting in

development of a state of presence of an abnormally large

amount of insulin to obtain a normal biologic response.

The resistance is seen with both endogenous and exogen-

ous insulin. Resistance to endogenous insulin in the

muscle, fat and liver cells is compensated by high serum

insulin concentration in association with normal or high

glucose concentration. Insulin resistance is the pivotal

causative mechanism of type II diabetes, hypertensionand CVD. The progression of insulin resistance either to

CVD or type II diabetes can be divided into four stages

(Fig. 1) [612]. Stage 1 of insulin resistance is charac-

terized by carbohydrates craving, mild insulin resistance

and easy weight gain as increased quantity of food energy

(transformed into blood sugar) is channeled through the

liver, turned into blood fat, and then stored in fat cells. In

addition, in stage I, a carbohydrate-rich diet (within 2 h)

may result in irritability, tiredness or poor concentration.

Fasting insulin and blood glucose levels are normal.

However, these signs and symptoms may vary between

individuals. Stage II of insulin resistance is set apart by

Review article

1558-2027 2010 Italian Federation of Cardiology DOI:10.2459/JCM.0b013e328333645a
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normal or elevated fasting insulin levels, normal blood

glucose, mild-to-moderate central obesity, elevated

blood pressure, early atherogenic dyslipidemia, vascular

inflammation with high circulating levels of inflammatory

markers, and endothelial dysfunction. This is followed

by stage III of insulin resistance, which is distinguished

by elevated fasting insulin levels, low blood sugar

swings with impaired glucose intolerance (prediabetes),

advanced atherogenic dyslipidemia comprising elevated

lipoproteins containing apolipoprotein B, triglycerides,

increased small dense low-density lipoprotein (LDL)

particles and low levels of high-density lipoproteins

(HDLs), and prothrombotic stage signifying anomalies

in procoagulant factors, antifibrinolytic factors and plate-

let aberrations. The stage III of insulin resistance is

collectively termed metabolic syndrome. In the fourth

stage of insulin resistance, the bodys cells are totally

resistant to insulin and the stage is marked by elevated

levels of fasting insulin and blood glucose levels. Stage IV

is the start of onset of frank type II diabetes mellitus andadvanced atherosclerotic changes with strong potential

for CVD and its complications.

Adverse lifestyle, genetic aberrations affecting individual

risk factors, and environmental factors are associated with

the development of abdominal obesity and insulin resist-

ance syndrome in adult life. Obesity is the major under-

lying risk factor for insulin resistance and results in

production of sick dysfunctional adipose tissues [13].

In addition, insulin resistance can have a genetic com-

ponent as well, which can be explained best by the fact

that insulin resistance is also seen in the condition of

lipodystrophy (deficiency of adipose tissues) [14]. Never-theless, adipose tissue dysfunction plays a crucial role in

the pathogenesis of insulin resistance and can lead to

widespread changes in glucose and lipid metabolism

(Fig. 2). Adipose tissue is an active endocrineparacrine

organ that produces complement factor B, adipsin, acyla-

tion-stimulating protein and a paracrine signal increasing

triglyceride synthesis [15]. In obese patients with insulin

resistance, adipose cells oversecrete a number of adipo-

cytokines such as tumor necrosis factor a (TNF-a),

resistin, plasminogen activator inhibitor-1 (PAI-1), inter-

leukin-6 (IL-6) and angiotensin, which promote athero-

sclerosis, vascular inflammation, endothelial dysfunctionand impair action of insulin and secretion [16]. As a result,

an increase in activation of insulin receptor in arteries

leads to the recruitment of vascular smooth muscle cells,

inflammatory cells and the innate immune system,

further potentiating atherosclerosis [17]; thus, suggesting

that insulin resistance creates a state of low-grade,

chronic, systemic inflammation, which, in turn, links

the metabolic and the vascular pathologies.

Insulin resistance may be due to defects either before

insulin binds to its receptor, or at the level of the insulin

receptor, or at a level beyond the downstream signaling.

Preinsulin receptor defect is generally caused by genetic

mutations in the insulin receptor gene or alteration in the

delivery of insulin to its receptors, whereas defects in

the insulin receptor that may contribute to insulin resist-

ance include defects in receptor number, structure, bind-

ing, affinity or signaling capacity. The insulin receptor

plays a crucial role in mediating the effects of insulin,

including the rapid stimulation of glucose uptake (via the

glucose transporter protein GLUT4) into its target meta-

bolic tissues, muscles and fat. Insulin receptor is a trans-

membrane receptor tyrosine kinase that is able to form

homodimers or heterodimers with insulin-like growth

factor receptor (IGFR) as disulfide-linked a2b2 tetramer

proteins [18]. Insulin binds with high affinity to the

a-subunit of the insulin receptor, leading to the sub-

sequent phosphorylation of the b-subunit on three intra-

cellular tyrosine residues [19]. Under physiological

circumstances, each receptor responds only to its own

ligand [20]. The insulin receptor b-subunits are also

subjected to intracellular Ser/Thr phosphorylation byprotein tyrosine phosphatases. The insulin receptor phos-

phorylates at least nine intracellular signaling molecules

including four intracellular insulin receptor substrates

[21]. The majority of receptors in cardiac and skeletal

muscle have a significant fraction of both insulin receptor

and IGFR, which occur as hybrids [22]. In human endo-

thelium, IGFR expression exceeds insulin receptor

expression and activation is mainly focused down the

antiatherogenic phosphatidylinositol-3-kinase (PI-3-K)

pathway. Any defect in receptor number, structure, bind-

ing, affinity or signaling capacity results in activation

down a pro-atherogenic mitogen-activated protein kinase

(MAPK) pathway.

Insulin resistance can also be caused by high circulating

levels of free fatty acids that increase hepatic glucose

output and reduce glucose disposal in skeletal muscle.

Free fatty acid released from adipose tissues in over-

weight and obese individuals also results in an increase in

production of triglycerides and very low-density lipopro-

tein (VLDL) secretion (Table 1). Other lipid abnormal-

ities that occur are low HDL cholesterol (HDL-C) level

and an increase in LDL cholesterol (LDL-C) level [23].

Free fatty acid induces insulin resistance in different

body tissue at the level of insulin-mediated glucose

transport by impairing the insulin-signaling pathway[24]. In a study done by Homko et al. [25], insulin

resistance appeared to increase two to four times after

an acute increase in plasma free fatty acid level and took a

similar amount of time to disappear after plasma free fatty

acid levels returned to normal.

Insulin resistance, inflammation andendotheliumAs discussed earlier, insulin resistance results in dysfunc-

tional adipose fat cells that produce adipocytokines,

which play a crucial role in systemic as well as vascular

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inflammation. Insulin resistance operates through a num-

ber of adipocytokines and by direct effects of elevated

insulin to initiate endothelial dysfunction. There are two

potential mechanisms for this change: one is that the

increasing obesity (the main underlying factor of insulin

resistance) is associated with an increase in oxidative

stress, resulting in reactive oxygen species; and second

is the deregulated production of pro-inflammatory cyto-

kines. Thus, insulin resistance derived cytokines gener-ate an overall pro-inflammatory environment in the body

as well as directly impacting the endothelium to cause

endothelial dysfunction initiating the atherosclerotic

cascade. Pro-inflammatory cytokines, such as tumor

necrosis factor, angiotensin and PAI-1, activate trans-

cription factors that initiate a series of inflammatory

changes, such as increased expression of adhesion mole-

cules, inhibition of fibrin clots, thrombus formation and

decreased production of nitric oxide, which eventually

lead to endothelial dysfunction. In addition, insulin

resistance itself appears to be associated with endothelial

dysfunction risk equivalent [26].

In healthy endothelium, the activation of insulin receptors

activates insulin signaling through the PI-3-K pathway,

leading to glucose uptake. The production of nitric oxide

by endothelial cells stimulated by insulin or insulin-like

growth factor leads to anti-inflammatory and antithrombo-

tic effects, which are anti-atherogenic [27,28]. The anti-

inflammatory effects of nitric oxide include decreases in

the expression of vascular cell adhesion molecules and

decreases in the secretion of pro-inflammatory cytokines.Conversely, in the state of high insulin resistance, stimu-

lation of insulin receptors activates insulin signaling

through another pathway, the MAPK pathway, leading

to the induction of genes involved in cell proliferation and

differentiation [29]. Activation down the MAPK pathway

induces endothelin-1 (ET-1) mediated pro-atherogenic

effects such as vasoconstriction, vascular smooth cell pro-

liferation, increased vascular permeability and increased

production of interleukin-6 and monocytes, resulting in

endothelial dysfunction (Fig. 3). Moreover, endothelial

dysfunction of insulin resistance can also be a result of

decreased levels of nitric oxide and impaired blood flow

Role of insulin resistance in cardiovascular disease Reddy et al. 635

Fig. 1

Carbohydrate craving Insulin resistance

Endothelial

dysfunction

Increasinginsuli

nresistance

Increasingcardio

vascularrisk

Metabolic syndrome

and pre-diabetes

Easy weight gain

Mild insulin resistance

Normal fasting insulin and glucose

Stage II

Stage l

Environmental factorsDiet, physical activity,

smoking, obesity (aquired),

lipodystrophy (acquired)

Genetic factorsLipodystrophy (hereditary)

Autoantibodies to insulin

receptors

Obesity (hereditary)

Stage III

Stage IV

Elevated or normal insulin, normal glucose

Impaired glucose tolerance

Advance atherogenic dyslipidemia

Prothrombotic and hypercoagulable state

Elevated insulin

Abnormal insulin

Abnormal fasting glucose

Atheromatous plaque

Frank diabetes and CVD

Atherosclerotic

cardiovascular

disease and its

complications

Type II

diabetes

High blood pressure

Vascular inflammation

Early a therogenic dyslipidemia

Metabolic and vascular inflammation

(increase in CRP, IL9, TNF, adipocytokines)

Stepwise progression of insulin resistance to cardiovascular disease and type II diabetes mellitus. CVD, cardiovascular disease; CRP, C-reactive

protein; IL9, interleukin-9; THFa, tumor necrosis factor-a.



due to the downregulation of the anti-atherogenic PI-3-K

pathway [30].

Insulin resistance and metabolic syndromeThe importance of metabolic syndrome as a risk factor of

CVD is increasingly appreciated and so is the role of

obesity-induced insulin resistance as a main cause of

metabolic syndrome (MetS). Several other factors, such

as physical inactivity, environmental factors and seden-

tary lifestyle, have been implicated as well in the etiology

of MetS. In 2001, the National Cholesterol Education

Program Adult Treatment Panel III recognized MetS as a

risk partner to elevated LDL-C in cholesterol guidelines

[31,32]. MetS represents the constellation of risk factors

that are of metabolic origin and consist of atherogenic

dyslipidemia, elevated blood pressure, elevated plasma

glucose, and a pro-thrombotic and a pro-inflammatory

state. The National Cholesterol Education Program

Adult Treatment Panel III defined MetS as the presenceof three or more of the five factors listed below.

(1) central obesity (waist circumference >102 cm for

men and >88 cm for women),(2) elevated serum triglycerides (!150 mg/dl),


Fig. 3

Insulin receptor signaling in vascular endothelium. eNOS, endothelialnitric oxide synthase; ET-1, endothelin-1; MAPK, mitogen-activatedprotein kinase; PI-3-K, phosphatidylinositol 3-kinase.

Fig. 2

Consequences of dysfunctional adipocyte. FFA, free fatty acid; IL-6, interleukin-6; PAI-1, plasminogen activator inhibitor-1; TG, triglyceride; TNF-a,tumor necrosis factor-a.

Table 1 Consequences of elevated free fatty acid level

""Hepatic production of glucose##Uptake of glucose by skeletal muscles""TG and VLDL secretion""Small dense LDL

LDL, low-density lipoprotein; TG, triglycerides; VLDL, very low-density lipoprotein.



(3) low HDL cholesterol (



and hyperinsulinemic clamps to compare insulin sensitive,

insulin-resistant individuals and untreated patients with

type II diabetes, has shown that insulin resistance was

associated with an increase in VLDL size and a decrease in

LDL particle size [49]. Conversely, a study done by

Lahdenpera et al. [50] found no significant difference in

lipoprotein concentrations and LDL particle size distri-

bution among the more insulin-resistant individuals and

less insulin-resistant individuals. Nevertheless, these

results from several studies indicate that expression of

atherogenic dyslipidemia of MetS, along with LDLparticle size, is modulated by insulin resistance.

Elevated blood pressure as a component of metabolic

syndrome could also be a result of high insulin resistance

(Fig. 4). There is clinical evidence of a link between

insulin resistance and hypertension, as many patients

with essential hypertension show insulin resistance

[51]. Obese patients who have marked insulin resistance

and hyperinsulinemia are at an increased risk of acquiring

hypertension. In fact, obese hypertensive patients are

more insulin resistant than normotensive obese patients

[51]. In the offspring of essential hypertension patients,insulin resistance and hyperinsulinemia, as well as related

increases in serum LDLs and triglycerides, often occur

prior to the development of essential hypertension, over-

weight or central redistribution of body fat [51]. This

cycle explains the potential causative role of insulin

resistance and hyperinsulinemia in the development of

hypertension. Furthermore, hyperinsulinemia (a marker

of insulin resistance) has shown to predict the develop-

ment of hypertension in normotensive individuals. On

the contrary, half of the essential hypertension patients

do not show evidence of insulin resistance, suggesting

that the association between insulin resistance and elev-

ated blood pressure is not absolute [51]. The possible

explanation of why insulin resistance might influence

blood pressure could be secondary to the production of

adipocytokines such as leptin and angiotensinogen, as

well as a high level of insulin itself, which can influence

sympthatic activation to the kidney, which may lead to

blood pressure elevation [52]. Similarly, high insulin

levels and anigiotensinogen associated with insulin resist-

ance can also enhance the sympathetic activity leading to

blood pressure elevation [53]. At the same time, in the

state of high insulin resistance, there is excessive insulin-stimulated reabsorption of sodium in the kidneys [23].

Furthermore, endothelial dysfunction can further result

in the development of elevated blood pressure secondary

to the decreased release of nitric oxide and increased

expression of adhesion molecules, platelets and mono-

cytes [54]. However, there is a lack of firm evidence that

insulin resistance per se results in hypertension.

Leptin, elevated blood pressure and insulinresistanceLeptin is a 167 amino acid hormone discovered in 1994

and is almost exclusively produced by adipose tissue andpossibly secreted by a constitutive mechanism. Leptin is

considered a homeostatic hormone regulating food intake

and body weight. Acting on the hypothalamic nuclei,

leptin decreases appetite and increases energy expendi-

ture through sympathetic activation, which consequently

decreases adipose tissue mass and body weight [55,56]. In

addition, leptin has been found to be involved in cardio-

vascular physiological processes such as sympathetic

nerve system activation, renal hemodynamics, blood

vessel tone and blood pressure. In the kidney, leptin

may affect blood pressure mainly by two opposing pro-

cesses: the first is through renal sympathetic activation


Fig. 4

Flow diagram of the role of insulin resistance in increasing blood pressure. NO, nitric oxide; RAAS, renninangiotensinaldosterone system; SNS,sympathetic nervous system.


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nondiabetic American Indians. The study exhibited an

increase in the risk of diabetes as a function of baseline

HOMA-insulin resistance and MetS, whereas CVD risk

did not increase either as a function of HOMA-insulin

resistance or MetS. The results in these studies are

mixed, showing significant independent relationships

between HOMA-insulin resistance and incident CVD

in some but not all of the studies. The most likely

explanation could be the lack of a gold standard tech-

nique to quantify insulin resistance as in a small study of

33 healthy volunteers it was found that the correlation of

insulin resistance assessed with clamp-derived and CVD

was greater than any surrogates used to measure insulin

resistance, thus indicating that additional prospective

studies using standard clamp-derived methods to assess

insulin resistance are required to establish the more

robust independent association between insulin resist-

ance and CVD.

In addition to this, insulin resistance causes pathophy-

siological abnormalities that adversely affect heart struc-

ture and function. Insulin resistance induced reactive

oxygen species play a causal role in left ventricular

remodeling and myocardial dysfunction. Moreover,

50% of asymptomatic normotensive insulin resistance

patients have diastolic dysfunction, which may contribute

to a four- to eight-fold increase in the risk of heart failure

and other myocardial dysfunctions that often progress to

sudden death [69]. Along the same line of thinking,

AlZadjali et al. [70] showed that insulin resistance is

highly prevalent among nondiabetic coronary heart fail-

ure (CHF) patients as compared with healthy patients

and is associated with decreased exercise capacity inpatients with CHF. Also, insulin resistance in the same

study was associated with increased cardiovascular risk

factors such as waist circumference, increased leptin

levels and endothelial dysfunction, and significantly wor-

sens the New York Heart Association (NYHA) functional

class of CHF. Importantly, these associations were inde-

pendent of factors associated with increased insulin

resistance such as BMI and serum triglycerides.

The role of insulin resistance in CVD pathogenesis

becomes more affirmative from the results of a study

that examined the association between adipokines, insu-

lin resistance and coronary artery calcification CAC, (ameasure of subclinical atherosclerosis) in 860 asympto-

matic, nondiabetic participants in the Study of Inherited

Risk of Coronary Atherosclerosis (SIRCA) [71]. The

study reported that of several metabolic and inflamma-

tory biomarkers, leptin and the HOMA-insulin resistance

index had the most robust independent association

with CAC. Leptin is produced in increased amounts

by insulin resistance induced dysfunctional adipocytes

and increased levels of plasma leptin levels in recent

studies are associated with atherosclerotic CVD, includ-

ing angiographic coronary artery disease (CAD) and CVD

events [72,73]. In a case-control nested within WOS-

COPS (West of Scotland Coronary Prevention Study),

plasma leptin levels predicted CVD events even after

adjustment for traditional risk factors, BMI and plasma

CRP levels [74]. Similarly, using radiotracer-based tech-

niques to make noninvasive assessments of coronary

artery reactivity in response to various stressors, Schelbert

demonstrated that insulin resistance is associated with

important functional disturbances of the coronary circu-

lation [75]. The magnitude of these disturbances is

proportional to the severity of the insulin resistance.

Schelbert stated that functional disturbance is initially

confined to endothelium-related vasomotion, which

increases in severity with more severe states of insulin

resistance and eventually compromises the total vasodi-

lator capacity. This attenuation of blood flow responses to

sympathetic stimulation could be secondary to dimin-

ished nitric oxide bioavailabilty. Consequently, in

the high insulin resistance state, there is a defect in

the insulin receptor signaling pathway downstream to

the insulin receptor and phosphorylation of insulin recep-tor protein and activation down the PI-3-K pathway.

Other mechanisms that could also result in coronary

circulatory functional abnormalities in the insulin resist-

ance state are increased free fatty acids, triglycerides,

oxidized LDL particles, adipokines, reactive oxygen

species and hyperglycemia. Irrespective of the mechan-

ism involved, endothelial dysfunction in the insulin

resistance state, even in the absence of macrovascular

coronary artery lesions, may result in failure to appro-

priately augument coronary flow and promotion of the

development of atherosclerosis, leading to myocardial

ischemia [76].

In another study, insulin resistance was able to predict a

variety of age-related diseases. Baseline measurements

of insulin resistance and other related variables were

made in 208 apparently healthy, nonobese individuals

from1988 to 1995 and then were re-evaluated 411 years

later for the appearance of age-related diseases such as

hypertension, coronary artery disease, stroke, cancer and

type II diabetes [4]. The study demonstrated that most

clinical events were seen in the most insulin-resistant

tertile group. Moreover, in the same study, insulin resist-

ance was an independent predictor of all clinical events,

using both multiple logistic regressions and Coxs pro-portional hazard analysis. Interestingly, results from the

same study showed that over an average follow-up of 6.3

years, no clinical events took place in the insulin-sensi-

tive tertile cohort. This indicates that if the association

found between insulin sensitivity and age-related disease

hold true in subsequent studies, the public health

implications are enormous, and reducing insulin resist-

ance could possibly alter the course of many age-related

diseases. Thus, considering that low insulin resistance

state has the potential to reduce cardiovascular morbidity

and mortality by modulating risk factors known to

increase CVD risk as well as the functionality of the




heart, targeting insulin resistance with lifestyle modifi-

cation and pharmacotherapies makes sense. Further-

more, the available data on insulin resistance and CVD

make at least one thing clear, if not the cause and effect,

that insulin resistance plays a crucial role in the patho-

physiology of CVD.

Lifestyle modification, biguanides,peroxisome proliferator-activated receptors,and insulin resistanceLifestyle modification in terms of weight reduction,

increased physical activity, anti-atherogenic diet and

smoking cessation has potential to reduce and reverse

the insulin resistance induced risk factors associated with

the development of CVD. However, lifestyle modifi-

cation is often neglected over drug therapy in routine

practice. As obesity and overweight are the main causa-

tive factors for the development of insulin resistance,

weight reduction along with increased physical activity

should be the primary intervention to ameliorate theadverse effects of insulin resistance. Moreover, it is not

required to achieve ideal body weight to reverse insulin

resistance; a weight reduction of 510% or more may be

valuable to achieve clinical benefits [77]. At the same

time, one should also remember that obesity is not the

only reason for having insulin resistance, as regional fat

distribution, central adiposity, lean body mass, genetic

diseases, and autoantibodies against insulin receptors are

other related important factors that mediate insulin resist-

ance [78]. Consequently, a complete approach compris-

ing of lifestyle modification along with pharmacothera-

pies targeting related risk factors resulting in insulin

resistance should be adopted.

Dietary intervention is the cornerstone for halting the

progression and reversal of insulin resistance. The impact

of diet on insulin resistance is most likely mediated by

dietary composition [79,80]. Available evidence suggests

that different dietary macronutrients affect insulin sen-

sitivity differently. For instance, different types of fatty

acids modulate insulin sensitivity differently and are

independent of the total amount of fat consumption

per se. The impact of fatty acid consumption on insulin

may be mediated through modifications in fatty acid

composition of cell membranes [81,82]. A specific typeof fatty acid profile in the cell membrane might affect the

action of insulin through several potential mechanisms,

including changing ion permeability, cell signaling and

altering insulin receptor affinity. Higher saturated fatty

acid content in the cell membrane increases insulin

resistance, thus, suggesting that diets rich in saturated

fats may impair insulin action on the cell membrane and

render them insulin resistant. The other mechanism by

which saturated fatty acids could alter insulin sensitivity

partly depends on the activities of enzymes responsible

for synthesizing, desaturating and elongating fatty acids

in the body, as well as partly on the dietary fatty acid

composition of the diet [83]. Indeed, results from a

couple of reports suggest that insulin resistance is related

to the fatty acid pattern characterized by high proportions

of palmitic acid (16 : 0) and palmitoleic acid and a low

proportion of linoleic acid. Similar fatty acid patterns of

high palmitic acid (saturated fatty acid) and low linoleic

acid (unsaturated fatty acids) have been linked to insulin

resistance in both prospective and cross-sectional studies

[84]. Furthermore, various saturated fatty acids have

different effects on insulin secretion in experiments

and clinical studies. Long-chain saturated fatty acids,

in particular, have a significant adverse effect on insulin

sensitivity, resulting in insulin resistance. In contrast,

omega-3 fatty acids may improve insulin resistance and

help in reversing the negative effects of saturated fatty

acids on insulin action [85,86].

A high concentration of trans fatty acids can cause harm-

ful metabolic effects similar to consumption of saturated

fatty acids. In a recent animal experiment under con-

trolled feeding conditions, long-term consumption of

trans fatty acids was shown to be an independent factor

in weight gain. Trans fatty acids enhanced intra-abdomi-

nal deposition of fat, even in the absence of caloric excess,

and were associated with insulin resistance, with evi-

dence of impaired signal transduction after insulin recep-

tor binding. The adverse effects of trans fatty acids on

insulin resistance in humans are somewhat controversial

and have not been consistently demonstrated in different

studies. Randomized-controlled cross-over studies com-

paring trans fatty acid with monounsaturated fatty acids

in healthy individuals showed no difference in terms of

insulin sensitivity and insulin resistance [87]. Conversely,an intervention study done among diabetic patients

showed that trans fatty acid could impair insulin sensi-

tivity [88,89]. The inconsistency shown in the effects of

trans fatty acids on insulin resistance in these studies

could be partly secondary to the presence of confounding

factors (hyperglycemia), small sample size, differences in

study designs and amount of trans fatty acids. There are

more questions than answers regarding the effects oftrans

fatty acid on insulin sensitivity. Similarly, evidence relat-

ing the effects of a high-protein diet on insulin sensitivity

is limited. However, there are some available data that

suggest high protein consumption and a high salt intake

cause insulin resistance [90].

Like saturated fatty acids, dietary carbohydrates can also

modulate insulin sensitivity. The available literature

suggests that different carbohydrates may affect insulin

sensitivity more than the amount in the terms of energy

intake and body weight maintenance [91]. Insulin resist-

ance is more marked in high-carbohydrate diets than in

monounsaturated fat diets [92,93]. Importantly, studies

demonstrated that the adverse effects of carbohydrates

were not dependent on whether that carbohydrate was

rich in dietary fiber or low in glycemic index [9497].

Moreover, despite the fact that low glycemic index or




high fiber carbohydrate diets exert beneficial effects on

blood glucose, data from their long-term effects on insu-

lin sensitivity are unconvincing [96100]. Consequently,

the inconclusive role of low glycemic index carbohydrate

foods in ameliorating insulin resistance indicates that

segregating carbohydrates on the basis of glycemic index

needs more evidence.

Nutritional supplements like chromium can alter insulin,

glucose and lipid metabolism. Chromium is an essential

mineral that appears to have a beneficial role in the

regulation of insulin action, metabolic syndrome and

CVD [101,102]. There is growing evidence that

chromium may facilitate insulin signaling and, therefore,

chromium supplementation may improve systemic insu-

lin sensitivity. Tissue chromium levels of patients with

diabetes are lower than those of normal controls, and a

correlation exists between low circulating levels of

chromium and the incidence of type II diabetes [103].

Recently, a study evaluated the impact of three different

chromium forms chromic chloride (CrCl), chromium

picolinate (CrPic), and a newly synthesized complex of

chromium chelated with small peptides (CrSP) on

glucose uptake and metabolism in vitro. In cultured

skeletal muscle cells, chromium augmented insulin-

stimulated glucose uptake and metabolism, as assessed

by a reduced glucose concentration of culture medium

[104]. Similarly, another randomized double-blinded

clinical placebo control trial [105] determined the effects

of combined supplementation with chromium and vita-

mins C and E on oxidative stress in type II diabetes in 30

adults with HbA1c more than 8.5%. The participants in

this trial were divided into three groups: placebo, Cr, andCrCE. The Cr group received 1000 mg of Cr (as Cr

yeast); the CrCE group received Cr (1000mg as Cr

yeast) together with vitamins C (1000mg) and E (800 IU);

and control group received placebo. Following the

6-month study period, oxidative stress, fasting glucose,

HbA1c, and insulin resistance were significantly decreased

in the Cr and CrCE groups but not in the placebo

group [105]. However, the need for chromium supple-

mentation on a regular basis is stillcontroversial. The side-

effects of chromium are seldom seen, but long-term safety

concerns and other potential side-effects associated

with regular chromium supplementation still need to

be determined.

At present, the pharmacotherapies that have direct action

on ameliorating the adverse effects of insulin resistance

are biguanides (e.g. metformins) and thialidazones, (e.g.

rosiglitazones or pioglitazones). The biguanide metfor-

min is considered an insulin-sensitizing agent. Metformin

improves insulin resistance most likely secondary to a

reduction in plasma free fatty acid concentration as well

as by improving endothelial dysfunction [106]. In

addition to this, metformin also improves insulin resist-

ance by decreasing hepatic glucose production, improv-

ing glucose uptake by skeletal muscles and adipose

tissues and decreasing calorie intake and appetite. Met-

formin also favorably alters lipid parameters by decreas-

ing LDL-C levels [107,108] and increasing HDL-C

concentrations [109111]. Most common side-effects

associated with metformin are abdominal discomfort,

diarrhea and anorexia [112], whereas lactic acidosis is

the most revealed possible adverse effect. The common

effects are

(1) decreased lipolysis and circulating free fatty acids,

(2) decreased hepatic glucose production,

(3) increased insulin action on peripheral tissue,(4) increased insulin secretion from b-pancreatic cells,

(5) increased HDL-C and increased or no effect on

LDL-C,

(6) decreased glucose level and(7) decreased circulating plasma levels of IL-6, hs-CRP,

TNF-a, and PAI-1.

Thialidazone or TZD activates the peroxisome prolif-

erator-activated receptor (PPAR) agonist family of

nuclear receptors that are closely related to thyroid hor-

mone and retinoid receptor [113]. Three PPARs have

been identified, PPAR-a, PPAR-b, and PPAR-g. PPAR-

g is found most abundantly in adipose tissue but also in

pancreatic-b cells, vascular endothelium, macrophages

and skeletal muscles [114]. PPAR-g activation plays an

important role in the modulation of glucose metabolism

and insulin resistance. TZDs have a high affinity for the

PPAR-g subtype of receptor and activation of PPAR-g by

TZDs has beneficial effects on various factors associated

with insulin resistance. PPAR-g activation results in

decreased amount of circulating free fatty acid in thebody via adipocyte differentiation and apoptosis. As a

result of decreased level of circulating free fatty acid and

reduced lipolysis, hepatic production of glucose and

metabolism are improved [115]. TZDs also influence

the signaling pathways that promote atherosclerosis

and cardiovascular events. PPAR-g agonists (TZDs) inhi-

bit the activation of nuclear factor-kB that controls the

expression of many genes involved in immune and

inflammatory responses [116]. This has the effect of

downregulating pro-inflammatory genes involved in the

formation of the atheromatous plaque. PPAR-g activation

results in improved endothelial-dependent vasodilatation

via increased nitric oxide production from endothelialcells, which has antithrombotic and anti-atherogenic

effects [117].

Undoubtedly, PPAR-g has numerous beneficial effects in

terms of reducing insulin resistance and improving glu-

cose metabolism. However, numerous side-effects are

well recognized with the use of TZDs. First, TZDs have

been shown to increase total cholesterol and LDL-C

levels as well as body weight [118]. On average, there

is a 3 6 kg weight gain over the first year of treatment

[119]. Second, treatment with TZDs, especially troglita-

zone, results in hepatoxicity, a feature that does not




appear to be a class effect, with two TZDs currently

available [120]. Finally, in a recent meta-analysis, rosigli-

tazone was associated with a statistically significant

increase in myocardial infarction and an increased risk

of death from cardiovascular causes [121], thus indicating

that these risks should weigh out against potential

benefits when considering treatment with TZDs. In

addition to PPAR-g, another subclass of PPARs, selective

PPAR-a agonist, also has been shown to improve insulin

resistance [122]. Fibrates is a selective PPAR-a agonist

that also helps to decrease plasma free fatty acid and

triglycerides and overall improve insulin resistance. Con-

sidering the beneficial effects of both PPAR-g and PPAR-

a agonists, Willson et al. [123] and Chinetti et al. [124]

recommended that a combination of PPAR-a and PPAR-

g could offer superior treatment for insulin resistance and

cardioprotection compared with an individual agonist

[123,124]. However, at present dual PPAR-g and PPAR-

a agonists are being developed. In summation, all these

drugs show a promising domino effect on reversing thecascade of risk factors related to insulin resistance; how-

ever, stronger evidence regarding their safety and efficacy

is needed before they can be approved for routine use in

patients with insulin resistance.

Beyond the scope of selective and dualperoxisome proliferator-activated receptors:new pharmaceuticals and insulin resistanceTwo weight-reducing drugs, sibutramine and orlisat, are

already approved by the Food and Drug Administration

[125,126]. Apart from achieving moderate weight loss,

these drugs have been shown to improve insulin resist-

ance and reduce cardiovascular risk factors such as trigly-cerides and hyperglycemia and improve HDL-C levels

[127,128]. A study conducted with orlisat in combination

with a hypocaloric diet in obese adults and adolescents

with or without co-morbidities showed improved meta-

bolic risk factors and reduced risk for the development of

type II diabetes [129]. Rimonabant is a new and prom-

ising weight-loss drug that is associated with favorable

changes in serum lipid levels, metabolic risk factors and

glucose levels [130]. Rimonabant is a selective blocker of

the cannabinoid receptor type I (CB-1). Rimonabant is a

part of the endocannabinoid system (ECS) that produces

cannabinoids that play an important role in activating thedrive for food ingestion, energy storage and hepatic

lipogenesis [131]. An overactivated ECS system is impli-

cated in obesity, leading to insulin resistance, dyslipid-

emia and other metabolic cardiovascular risk factors.

Therefore, rimonabant represents a new therapeutic

approach for the treatment of obesity and associated

cardiovascular and metabolic risk factors [132]. The

CB-1 receptor is found in the brain and appears to

regulate the activity of mesolimbic dopamine neurons,

thus influencing reward behaviors mediated by dopa-

mine. Presently, four randomized double-blind placebo-

controlled trials in humans have studied the effects of

rimonabant in obesity (RIO) [133137] RIO-LIPID

Trial, RIO-EUROPE Trial, RIO-NA Trial and RIO-

DIABETES Trial. All these RIO trials were associated

with significant reduction in weight, waist circumference,

triglycerides, improvement in HDL levels and were able

to lower the proportion of individuals satisfying the

criteria for metabolic syndrome. However, the weight

reduction achieved was not sustained after withdrawal of

drug and individuals regained their weight by the end of

1 year. The most common adverse side-effects related to

rimonabant that led to its discontinuation were depressed

mood disorders, nausea and dizziness. Nevertheless, the

data from the RIO trials administering rimonabant

showed promising results in obese patients, including

those with cardiovascular co-morbidities, in reducing

weight and waist circumference as compared with

placebo. Such a therapy also favorably modulated other

insulin resistance induced cardiometabolic risk factors

(metabolic syndrome, CRP, and low HDL levels) and

improved glycemic control in type II diabetes.

Along the same line of thinking, protein kinase C inhibi-

tors and tyrosine kinase enhancers are other potential

drugs under investigation and can modulate the glucose

uptake and insulin sensitivity as well as delay the onset or

stop the progression of diabetic microvascular and cardio-

vascular complications [138,139]. Increased diacylgly-

cerol (DAG) levels and protein kinase C (PKC) activity,

especially b, b1/2 and delta isoforms in retina, aorta,

heart, renal glomeruli and circulating macrophages have

been reported in diabetes [140]. Increased PKC acti-

vation has been associated with changes in blood flow,

basement membrane thickening, and extracellular matrixexpansion. Ruboxistaruin is a PKC-b isoform selective

inhibitor that has been shown to normalize the endo-

thelial dysfunction, diabetic nephropathy, and CVD risk

factors [141].

Dipeptidyl peptidase 4 (DDP-4) inhibitors also represent

another therapeutic approach for type II diabetes and

increase insulin secretion and insulin sensitivity [142].

DDP-4 inhibitors prevent the inactivation of incretin

hormone. Incretins are intestinal hormones that are

released after oral glucose and augment insulin secretion.

This increase in plasma levels of insulin by incretins

exceeds the insulin levels that are seen after intravenousglucose administration when glucose levels during the

two are matched [143,144]. The two most important

incretin-producing hormones are glucose-dependent

insulinotropic polypeptide (GIP) and glucagon-like pep-

tide (GLP-1). More than 70% of the insulin response

to an oral glucose challenge is mediated by incretin

hormones. However, the incretin effect is reduced in

type II diabetes secondary to inactivation of GLP-1 and

defective action of GIP. Sitagliptin and vildagliptin are

two DDP-4 inhibitors that are orally active compounds

with a long duration that prevent inactivation of GLP-1

and thus improve insulin sensitivity and metabolic




control in type II diabetes [145]. Sitagliptin and vilda-

gliptin can be used as monotherapy or in combination

with metformin and TZD [140145]. Initial results from

clinical studies of DDP-4 inhibitors are promising; how-

ever, the durability and long-term safety of DDP-4

inhibition remain to be established. Thus, in spite of

the positive impact of these new drugs on insulin, glucose

and lipids, they have to cross many hurdles before they

are approved for the routine use in practice to ameliorate

the obesity-induced insulin resistance vascular and meta-

bolic effects.

ConclusionInsulin resistance plays a crucial role in the pathogenesis

of various metabolic and vascular abnormalities leading to

the development of atherosclerotic CVD. Insulin resist-

ance induces hyperglycemia, systemic as well as vascular

inflammation, endothelial dysfunction atherogenic dysli-

pidemia, metabolic syndrome, a prothrombotic and a

hypercoaguable state. Available data converge to indicatethat to prevent and reverse CVD and its complications,

efforts must focus on reversing the disturbances in insu-

lin, glucose and lipid metabolism. Insulin resistance

assessed by HOMA has been shown to be independently

predictive of CVD in some but not all studies, indicating

that additional prospective studies using a gold-standard

technique to assess insulin resistance should be con-

ducted to establish the role of insulin resistance as a

causal factor for CVD. In addition, a state of high insulin

resistance has been associated with abnormalities in the

structure and function of heart. Biguanides and TZDs are

currently available pharmacotherapies that can diminish

and slow the catastrophic adverse effects of insulin resist-ance. New drugs such as dual PPAR-g and PPAR-a

agonists, which have fewer side-effects but the same

efficacy as traditional TZDs are being developed and

have better potential to treat insulin resistance as a whole.

Endocannabinoid antagonist and other weight-loss drugs

that target obesity-associated cardiovascular and meta-

bolic risk factors have been shown to have favorable

effects on glucose level, HbA1c and lipid profile. Protein

kinase C inhibitors, tyrosine kinase enhancers and DDP-

4 inhibitors are other investigational drugs that represent

a novel approach to modulate insulin resistance by affect-

ing plasma glucose and insulin levels. However, thesenew drugs also have numerous adverse side-effects,

which must be weighed out before prescribing them

routinely for insulin resistance. Furthermore, if insulin

resistance is the underlying mechanism for the develop-

ment of CVD, then lifestyle modification along with

pharmacotherapy that addresses the insulin resistance

represents the most effective therapeutic approach. Life-

style modification that has shown to be beneficial in this

respect includes weight reduction, physical activity, and

an anti-atherogenic diet. Nutritional supplements like

chromium have also been shown to alter favorably insulin

secretion and sensitivity. Among different dietary macro-

nutrients, present data suggest that consumption of less

saturated fatty acid along with a low intake of carbo-

hydrate appears to be far superior in modulating insulin

resistance. Thus, there is enough evidence that insulin

resistance can have profound pathophysiologic effects on

the cardiovascular system and ameliorating the adverse

effects of insulin resistance has the potential to prevent

and reverse CVD.

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