The Role of Insulin Resistance in The Pathogenesis of ACD

Review article
The role of insulin resistance in the pathogenesis of atherosclerotic cardiovascular disease: an updated review
Kota 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 model assessment (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 modication 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, metabolic syndrome, peroxisome proliferator-activated receptors, thialidazone
a Reddy 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 Internal Medicine, 155 N. Fresno Street, Fresno, CA-93702, USA E-mail: manmeetsingh79@yahoo.com Received 15 May 2009 Revised 13 August 2009 Accepted 22 September 2009
Introduction
Insulin resistance results in the spectrum of metabolic disturbances that extends beyond hyperglycemia and hyperinsulinemia and includes inammation, endothelial dysfunction, 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 diseases (CVDs) and postulated that insulin resistance could be seen as the center of all these changes adversely affecting the cardiovascular system. Since then, metabolic syndrome has been increasingly related to incidence of CVD. However, metabolic syndrome may not capture all the CVD risk associated with insulin resistance. This fact is supported in numerous studies in which insulin resistance has been shown to be associated independently 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 inammation, 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 modication and pharma1558-2027 2010 Italian Federation of Cardiology
cotherapy that could possibly ameliorate the effect of insulin resistance and reverse the disturbances in insulin, glucose and lipid metabolism.
Denition of insulin resistance and its pathogenesis

Insulin 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 exogenous 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, hypertension and 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 characterized 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
DOI:10.2459/JCM.0b013e328333645a
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634 Journal of Cardiovascular Medicine 2010, Vol 11 No 9
normal or elevated fasting insulin levels, normal blood glucose, mild-to-moderate central obesity, elevated blood pressure, early atherogenic dyslipidemia, vascular inammation with high circulating levels of inammatory 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, antibrinolytic factors and platelet 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 and advanced 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 resistance syndrome in adult life. Obesity is the major underlying risk factor for insulin resistance and results in production of sick dysfunctional adipose tissues [13]. In addition, insulin resistance can have a genetic component as well, which can be explained best by the fact that insulin resistance is also seen in the condition of lipodystrophy (deciency of adipose tissues) [14]. Nevertheless, 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, acylation-stimulating protein and a paracrine signal increasing triglyceride synthesis [15]. In obese patients with insulin resistance, adipose cells oversecrete a number of adipocytokines such as tumor necrosis factor a (TNF-a), resistin, plasminogen activator inhibitor-1 (PAI-1), interleukin-6 (IL-6) and angiotensin, which promote atherosclerosis, vascular inammation, endothelial dysfunction and 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, inammatory cells and the innate immune system, further potentiating atherosclerosis [17]; thus, suggesting that insulin resistance creates a state of low-grade, chronic, systemic inammation, 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 resistance include defects in receptor number, structure, binding, afnity 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 metabolic tissues, muscles and fat. Insulin receptor is a transmembrane receptor tyrosine kinase that is able to form homodimers or heterodimers with insulin-like growth factor receptor (IGFR) as disulde-linked a2b2 tetramer proteins [18]. Insulin binds with high afnity to the a-subunit of the insulin receptor, leading to the subsequent phosphorylation of the b-subunit on three intracellular 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 by protein tyrosine phosphatases. The insulin receptor phosphorylates at least nine intracellular signaling molecules including four intracellular insulin receptor substrates [21]. The majority of receptors in cardiac and skeletal muscle have a signicant fraction of both insulin receptor and IGFR, which occur as hybrids [22]. In human endothelium, 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, binding, afnity 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 overweight and obese individuals also results in an increase in production of triglycerides and very low-density lipoprotein (VLDL) secretion (Table 1). Other lipid abnormalities 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, inammation and endothelium

As discussed earlier, insulin resistance results in dysfunctional adipose fat cells that produce adipocytokines, which play a crucial role in systemic as well as vascular
Role of insulin resistance in cardiovascular disease Reddy et al. 635
Fig. 1
Environmental factors
Diet, physical activity, smoking, obesity (aquired), lipodystrophy (acquired)
Genetic factors
Lipodystrophy (hereditary) Autoantibodies to insulin receptors Obesity (hereditary)
Stage l
Carbohydrate craving Easy weight gain Mild insulin resistance Normal fasting insulin and glucose
Insulin resistance
Metabolic and vascular inflammation (increase in CRP, IL9, TNF, adipocytokines)
Stage II
Elevated or normal insulin, normal glucose High blood pressure Vascular inflammation Early atherogenic dyslipidemia
Increasing cardiovascular risk
Increasing insulin resistance
Endothelial dysfunction
Stage III
Elevated insulin Impaired glucose tolerance Advance atherogenic dyslipidemia Prothrombotic and hypercoagulable state
Metabolic syndrome and pre-diabetes
Stage IV
Abnormal insulin Abnormal fasting glucose Atheromatous plaque Frank diabetes and CVD
Atherosclerotic cardiovascular disease and its complications
Type II diabetes
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.
inammation. Insulin resistance operates through a number 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-inammatory cytokines. Thus, insulin resistance derived cytokines generate an overall pro-inammatory environment in the body as well as directly impacting the endothelium to cause endothelial dysfunction initiating the atherosclerotic cascade. Pro-inammatory cytokines, such as tumor necrosis factor, angiotensin and PAI-1, activate transcription factors that initiate a series of inammatory changes, such as increased expression of adhesion molecules, inhibition of brin 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-inammatory and antithrombotic effects, which are anti-atherogenic [27,28]. The antiinammatory effects of nitric oxide include decreases in the expression of vascular cell adhesion molecules and decreases in the secretion of pro-inammatory cytokines. Conversely, in the state of high insulin resistance, stimulation 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 proliferation, 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 ow
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.
due to the downregulation of the anti-atherogenic PI-3-K pathway [30].
Fig. 3
Insulin resistance and metabolic syndrome

The 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 sedentary 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-inammatory state. The National Cholesterol Education Program Adult Treatment Panel III dened MetS as the presence of three or more of the ve factors listed below. (1) central obesity (waist circumference >102 cm for men and >88 cm for women), (2) elevated serum triglycerides (!150 mg/dl),
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.
Insulin receptor signaling in vascular endothelium. eNOS, endothelial nitric oxide synthase; ET-1, endothelin-1; MAPK, mitogen-activated protein kinase; PI-3-K, phosphatidylinositol 3-kinase.
(3) low HDL cholesterol (<40 mg/dl in men and <50 mg/dl in women), (4) hypertension (!130/85 mmHg) and (5) elevated fasting blood glucose (>110 mg/dl). In addition to these lipid abnormalities, small dense LDL particles are also present in the metabolic syndrome. The WHO criteria of MetS require the presence of insulin resistance, impaired glucose tolerance, impaired fasting glucose, or diabetes mellitus along with two of the following risk factors: (1) blood pressure higher than 140/90 mmHg; (2) dyslipidemia: triglycerides, 1.695 mmol/l or more, and high-density lipoprotein cholesterol (HDL-C) 0.9 mmol/l or less (male) and 1.0 mmol/l or less (female); (3) central obesity: waist : hip ratio higher than 0.90 (male), higher than 0.85 (female), and/or body mass index (BMI) higher than 30 kg/m2; and (4) microalbuminuria: urinary albumin excretion ratio 20 mg/min odds ratio (OR) or more, or albumin : creatinine ratio 30 mg/g or more. Similarly, the European Group for the Study of Insulin Resistance (1999) denes insulin resistance as the top 25% of the fasting insulin values among nondiabetic individuals and two or more of the following: (1) central obesity: waist circumference 94 cm or more (male) and 80 cm or more (female), (2) dyslipidaemia: triglycerides (TG) 2.0 mmol/l or more and/or HDL-C less than 1.0 mmol/l or treated for dyslipidaemia, (3) hypertension: blood pressure 140/90 mmHg or more or antihypertensive medication, and (4) fasting plasma glucose at least 6.1 mmol/l. Insulin resistance is the pathogenic link underlying different metabolic abnormalities clustering in metabolic syndrome. Atherogenic dyslipidemia of metabolic syndrome can be attributed to the insulin resistance induced endothelial dysfunction and defective insulin signaling of circulating monocytes and macrophages. Insulin and insulin-like growth factor-1 are present on circulating monocytes and macrophages. Normally, insulin-treated monocytes and macrophages in vascular tissues show typical activation down the PI-3-K system, which is anti-atherogenic [33]. Conversely, in insulin-resistant humans, the downregulation of insulin receptor number on macrophages and monocytes eventually slows down the activation and signaling. This defective signaling is implicated in the formation of macrophage foam cells [34]. Moreover, in the high insulin resistance state, the protective effect of insulin in reducing macrophage apoptosis is blunted and may contribute to further monocyte recruitment by release of cytokines that can aggravate
atherosclerotic lesions and play a part in plaque rupture [35]. In this context, a study evaluated the relationship between lipoprotein phenotype associated with familial hyperlipidemia (high triglycerides and apolipoprotein B) and presence of insulin resistance in 132 familial hyperlipidemic individuals [36]. The results reported that insulin resistance assessed by the homeostatic model assessment (HOMA) was associated with atherogenic lipid phenotype expression, and a change in insulinresistant state was associated with a change in lipid phenotype expression over 5 years. HOMA is a simple, indirect method of quantifying insulin resistance, and insulin resistance values assessed by HOMA correlate reasonably well with directly measured clamp-derived gold standard values. HOMA has been widely employed in clinical research to assess insulin resistance. The product of the fasting insulin values of glucose (expressed as mg/dl) and insulin (expressed in mU/ml) is divided by 405. The constant 405 should be replaced by 22.5 if the glucose is expressed in SI units (mmole/l). Similarly, a study done in Japan [37] investigated the relationship between insulin resistance (assessed by HOMA) and various factors for atherosclerosis in 378 men (average age 63.8 15.2 years) and 509 women (averaged age 67.1 13.5 years). BMI, triglycerides, remnant-like cholesterol particle, high-sensitivity-C-reactive protein (hs-CRP), small dense LDL particle and LDL-C showed a statistically signicant correlation with insulin resistance. However, in the same study, oxidized LDL-C and systolic blood pressure did not show any correlation with insulin resistance. The results from this study suggest that insulin resistance is closely related to various lipid parameters clustered in metabolic syndrome. Similarly, another study [38] looked at the correlation of LDL particle size, HDL-C, triglycerides and LDL-C with indices of insulin sensitivity among 46 patients with type II diabetes mellitus. Of the four lipid parameters, LDL particle size showed the strongest correlation with log ISI (comp) (R 0.61, P < 0.001) and log HOMA-insulin resistance (R 0.53, P 0.001), whereas correlation with HDL-C and triglycerides was weaker but still signicant. Along the same line of thinking, Reaven et al. [39] have demonstrated that among a group of 100 normal, apparently healthy adults, individuals with small dense LDL particles were more insulin resistant than those with large LDL particles (evaluated by an oral glucose challenge). Importantly, this relationship persisted even when differences in sex, age and the degree of obesity were taken into account. In addition, several studies conducted among normal, nondiabetic inviduals (to avoid confounding by hyperglycemia) have established that hypertriglyceridemia, low HDL-C, and decreased LDL particle size are frequent abnormalities in insulin resistance [4043] and are associated with an increased risk of CVD [4448]. Another study, which used nuclear magnetic resonance
Fig. 4
Flow diagram of the role of insulin resistance in increasing blood pressure. NO, nitric oxide; RAAS, renninangiotensinaldosterone system; SNS, sympathetic nervous system.
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 signicant difference in lipoprotein concentrations and LDL particle size distribution 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 LDL particle 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, overweight 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 development 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 inuence 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 inuence sympthatic activation to the kidney, which may lead to blood pressure elevation [52]. Similarly, high insulin levels and anigiotensinogen associated with insulin resistance 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 insulinstimulated 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 monocytes [54]. However, there is a lack of rm evidence that insulin resistance per se results in hypertension.
Leptin, elevated blood pressure and insulin resistance

Leptin is a 167 amino acid hormone discovered in 1994 and is almost exclusively produced by adipose tissue and possibly 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 expenditure through sympathetic activation, which consequently decreases adipose tissue mass and body weight [55,56]. In addition, leptin has been found to be involved in cardiovascular 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 processes: the rst is through renal sympathetic activation
and the second is related to nitric oxide synthesis [55,56]. The effects of leptins seem divergent: in some contexts, leptin seems to promote atherogenesis and insulin resistance. By contrast, in other contexts, leptin may have antiatherogenic and insulin-sensitizing effects. These opposing actions of leptin are maintained in balance under healthy conditions. In pathological conditions such as obesity, the balance of leptin actions may shift to stimulate vascular inammation, oxidative stress and vascular smooth muscle hypertrophy. Thus, these actions may contribute to the pathogenesis of hypertension, atherosclerosis, left ventricular hypertrophy and type II diabetes mellitus.
HDL-C and physical activity levels, but strongly inversely associated with non-HDL lipids, triglycerides and apolipoprotein B 100 levels. Adiponectin was also inversely associated with brinogen, intracellular adhesion molecule 1, E-selectins and CRP, thus suggesting that adiponectin may have direct effects on cardiovascular risk factors. However, the direct causal relationship of adiponectin with CVD is complex, controversial and far from fully revealed. A health professional follow-up study observed a 20% reduction in myocardial infarction with a two-fold increase in adiponectin levels even after adjusting for classical risk factors [65]. Conversely, a meta-analysis of more than 1300 cases of heart disease showed no association with adiponectin levels [66].
Insulin resistance and adiponectin

Adiponectin is a collagen-like circulating protein secreted by adipocytes, which plays a unique role in regulating insulin sensitivity [57]. Atheroprotective effects of adiponectin may be directed through inhibition of the nuclear factor-kB inammatory pathway in vascular cells and attenuation of foam cell formation [58,59]. Adiponectin increases insulin sensitivity by decreasing the proliferation and migration of vascular smooth muscle, increasing the smooth muscle glucose intake, increasing free fatty acid oxidation, and decreasing hepatic glucose production. However, in an obesity-induced insulin resistance state, the secretion of adiponectin is reduced. Plasma adiponectin levels are negatively correlated with insulin resistance and have a stronger link to insulin resistance than that to body fat levels. Circulating levels of adiponectin, particularly the higher glycosylated forms, may be a useful marker of insulin resistance [60,61]. In order to further elucidate the relationship between insulin resistance and adiponectin, Weyer et al. [62] measured plasma adiponectin concentrations, body composition, insulin sensitivity and glucose tolerance in 23 white persons and 121 Pima Indians. The results demonstrated that plasma adiponectin concentration is more closely related to insulin sensitivity and fasting insulinemia than to adiposity and glycemia. The low levels of adiponectin in obese and type II diabetic patients were mainly attributed to insulin resistance or hyperinsulinemia. Further evidence of the role of adiponectin in insulin resistance was demonstrated by Maeda et al. [63], who examined in vivo the mechanism of action of adiponectin in mice. Removal of adiponectin delayed the clearance of free fatty acid in plasma-induced and severe diet-induced insulin resistance with reduced insulin receptor activity in muscle. The association of low adiponectin levels with obesity, insulin resistance and development of type II diabetes mellitus may contribute to the development of atherosclerotic CVD. Mantzoros et al. [64] studied the relationship between the adiponectin and atherosclerosis in 925 diabetic women from the Nurses Health Study. Adiponectin levels were found to be strongly associated with
Insulin resistance and cardiovascular disease

Insulin resistance results in many metabolic, as well as vascular, abnormalities that are well-known risk factors for the development of cardiovascular events. Inammation, endothelial dysfunction, atherogenic dyslipidemia and hypercoagulability that occur as a result of insulin resistance can inuence the CVD risk. In addition, insulin resistance assessed by HOMA has been shown to be independently predictive of CVD in several studies and a 1 unit increase in insulin resistance is associated with a 5.4% increase in CVD risk [3,67]. The San Antonio Heart Study (SAHS) [3] demonstrated that insulin resistance assessed by HOMA was signicantly and independently associated with risk of CVD outcomes among MexicanAmerican and non-Hispanic white men and women. Logistic regression analysis in SAHS indicated that the risk of a cardiovascular event increased across quintiles of HOMA-assessed insulin resistance after the adjustment for age, sex and ethnicity [quintile 5 vs. quintile 1; OR 2.52, 95% condence interval (CI) 1.464.36, P < 0.0001] [3]. Similarly, in another population-based study after adjusting for age, gender, smoking and LDL-C, HOMA-insulin resistance independently predicted the incidence of CVD [68]. The study reported a relative risk for the incidence of cardiovascular end point of 1.49 (95% CI 1.072.07) [67]. Along the same line of thinking, the association between insulin resistance measured by the euglycaemic insulin clamp and coronary heart disease (CHD) was evaluated in a population-based 10-year follow-up study in 817 men aged 70 years [5]. However, no data were presented regarding the relationship of insulin resistance and CVD after adjustment for the components of MetS or MetS itself. In the same study, multivariate analysis, adjusted for serum cholesterol, blood pressure, fasting plasma glucose, BMI and smoking, insulin resistance predicted subsequent CHD events in the elderly men. Conversely, the Strong Heart Study [68] examined the association of insulin resistance assessed by HOMA (HOMA-insulin resistance) and MetS with type II diabetes and CVD risk among 2283
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 signicant 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 technique 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 resistance and CVD. In addition to this, insulin resistance causes pathophysiological abnormalities that adversely affect heart structure 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 failure (CHF) patients as compared with healthy patients and is associated with decreased exercise capacity in patients 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 signicantly worsens the New York Heart Association (NYHA) functional class of CHF. Importantly, these associations were independent of factors associated with increased insulin resistance such as BMI and serum triglycerides. The role of insulin resistance in CVD pathogenesis becomes more afrmative from the results of a study that examined the association between adipokines, insulin resistance and coronary artery calcication CAC, (a measure of subclinical atherosclerosis) in 860 asymptomatic, nondiabetic participants in the Study of Inherited Risk of Coronary Atherosclerosis (SIRCA) [71]. The study reported that of several metabolic and inammatory 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, including 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 techniques 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 circulation [75]. The magnitude of these disturbances is proportional to the severity of the insulin resistance. Schelbert stated that functional disturbance is initially conned to endothelium-related vasomotion, which increases in severity with more severe states of insulin resistance and eventually compromises the total vasodilator capacity. This attenuation of blood ow responses to sympathetic stimulation could be secondary to diminished 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 receptor protein and activation down the PI-3-K pathway. Other mechanisms that could also result in coronary circulatory functional abnormalities in the insulin resistance state are increased free fatty acids, triglycerides, oxidized LDL particles, adipokines, reactive oxygen species and hyperglycemia. Irrespective of the mechanism involved, endothelial dysfunction in the insulin resistance state, even in the absence of macrovascular coronary artery lesions, may result in failure to appropriately augument coronary ow 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 resistance was an independent predictor of all clinical events, using both multiple logistic regressions and Coxs proportional 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-sensitive 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 resistance 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 modication and pharmacotherapies makes sense. Furthermore, 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 pathophysiology of CVD.
Lifestyle modication, biguanides, peroxisome proliferator-activated receptors, and insulin resistance

Lifestyle modication 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 modication is often neglected over drug therapy in routine practice. As obesity and overweight are the main causative factors for the development of insulin resistance, weight reduction along with increased physical activity should be the primary intervention to ameliorate the adverse 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 benets [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 resistance [78]. Consequently, a complete approach comprising of lifestyle modication along with pharmacotherapies 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 sensitivity 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 modications in fatty acid composition of cell membranes [81,82]. A specic type of fatty acid prole in the cell membrane might affect the action of insulin through several potential mechanisms, including changing ion permeability, cell signaling and altering insulin receptor afnity. 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 signicant 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 harmful metabolic effects similar to consumption of saturated fatty acids. In a recent animal experiment under controlled feeding conditions, long-term consumption of trans fatty acids was shown to be an independent factor in weight gain. Trans fatty acids enhanced intra-abdominal deposition of fat, even in the absence of caloric excess, and were associated with insulin resistance, with evidence of impaired signal transduction after insulin receptor 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 comparing 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 sensitivity [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 of trans fatty acid on insulin sensitivity. Similarly, evidence relating 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 resistance 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 ber or low in glycemic index [9497]. Moreover, despite the fact that low glycemic index or
high ber carbohydrate diets exert benecial effects on blood glucose, data from their long-term effects on insulin 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 benecial 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 insulin 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 insulinstimulated 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 vitamins 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, and Cr C E. The Cr group received 1000 mg of Cr (as Cr yeast); the Cr C E group received Cr (1000 mg as Cr yeast) together with vitamins C (1000 mg) and E (800 IU); and control group received placebo. Following the 6-month study period, oxidative stress, fasting glucose, HbA1c, and insulin resistance were signicantly decreased in the Cr and Cr C E groups but not in the placebo group [105]. However, the need for chromium supplementation on a regular basis is still controversial. The sideeffects 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 metformin 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 resistance by decreasing hepatic glucose production, improving glucose uptake by skeletal muscles and adipose
tissues and decreasing calorie intake and appetite. Metformin also favorably alters lipid parameters by decreasing 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) (2) (3) (4) (5) decreased lipolysis and circulating free fatty acids, decreased hepatic glucose production, increased insulin action on peripheral tissue, increased insulin secretion from b-pancreatic cells, 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 proliferator-activated receptor (PPAR) agonist family of nuclear receptors that are closely related to thyroid hormone and retinoid receptor [113]. Three PPARs have been identied, PPAR-a, PPAR-b, and PPAR-g. PPARg 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 afnity for the PPAR-g subtype of receptor and activation of PPAR-g by TZDs has benecial effects on various factors associated with insulin resistance. PPAR-g activation results in decreased amount of circulating free fatty acid in the body 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 inuence the signaling pathways that promote atherosclerosis and cardiovascular events. PPAR-g agonists (TZDs) inhibit the activation of nuclear factor-kB that controls the expression of many genes involved in immune and inammatory responses [116]. This has the effect of downregulating pro-inammatory genes involved in the formation of the atheromatous plaque. PPAR-g activation results in improved endothelial-dependent vasodilatation via increased nitric oxide production from endothelial cells, which has antithrombotic and anti-atherogenic effects [117]. Undoubtedly, PPAR-g has numerous benecial effects in terms of reducing insulin resistance and improving glucose 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 36 kg weight gain over the rst year of treatment [119]. Second, treatment with TZDs, especially troglitazone, 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, rosiglitazone was associated with a statistically signicant increase in myocardial infarction and an increased risk of death from cardiovascular causes [121], thus indicating that these risks should weigh out against potential benets 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. Considering the benecial effects of both PPAR-g and PPARa agonists, Willson et al. [123] and Chinetti et al. [124] recommended that a combination of PPAR-a and PPARg could offer superior treatment for insulin resistance and cardioprotection compared with an individual agonist [123,124]. However, at present dual PPAR-g and PPARa agonists are being developed. In summation, all these drugs show a promising domino effect on reversing the cascade of risk factors related to insulin resistance; however, stronger evidence regarding their safety and efcacy is needed before they can be approved for routine use in patients with insulin resistance.
rimonabant in obesity (RIO) [133137] RIO-LIPID Trial, RIO-EUROPE Trial, RIO-NA Trial and RIODIABETES Trial. All these RIO trials were associated with signicant 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 inhibitors 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 cardiovascular complications [138,139]. Increased diacylglycerol (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 activation has been associated with changes in blood ow, basement membrane thickening, and extracellular matrix expansion. Ruboxistaruin is a PKC-b isoform selective inhibitor that has been shown to normalize the endothelial 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 intravenous glucose 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 peptide (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
Beyond the scope of selective and dual peroxisome proliferator-activated receptors: new pharmaceuticals and insulin resistance
Two 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 resistance and reduce cardiovascular risk factors such as triglycerides 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 metabolic risk factors and reduced risk for the development of type II diabetes [129]. Rimonabant is a new and promising 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 the drive for food ingestion, energy storage and hepatic lipogenesis [131]. An overactivated ECS system is implicated in obesity, leading to insulin resistance, dyslipidemia 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 inuencing reward behaviors mediated by dopamine. Presently, four randomized double-blind placebocontrolled trials in humans have studied the effects of
control in type II diabetes [145]. Sitagliptin and vildagliptin can be used as monotherapy or in combination with metformin and TZD [140145]. Initial results from clinical studies of DDP-4 inhibitors are promising; however, 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 metabolic effects.
nutrients, present data suggest that consumption of less saturated fatty acid along with a low intake of carbohydrate 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.
References
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Conclusion
Insulin resistance plays a crucial role in the pathogenesis of various metabolic and vascular abnormalities leading to the development of atherosclerotic CVD. Insulin resistance induces hyperglycemia, systemic as well as vascular inammation, endothelial dysfunction atherogenic dyslipidemia, metabolic syndrome, a prothrombotic and a hypercoaguable state. Available data converge to indicate that to prevent and reverse CVD and its complications, efforts must focus on reversing the disturbances in insulin, 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 conducted 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 resistance. New drugs such as dual PPAR-g and PPAR-a agonists, which have fewer side-effects but the same efcacy 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 metabolic risk factors have been shown to have favorable effects on glucose level, HbA1c and lipid prole. Protein kinase C inhibitors, tyrosine kinase enhancers and DDP4 inhibitors are other investigational drugs that represent a novel approach to modulate insulin resistance by affecting plasma glucose and insulin levels. However, these new 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 development of CVD, then lifestyle modication along with pharmacotherapy that addresses the insulin resistance represents the most effective therapeutic approach. Lifestyle modication that has shown to be benecial 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-
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The Role of Insulin Resistance in The Pathogenesis of ACD

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The Role of Insulin Resistance in The Pathogenesis of ACD

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Review article

Denition of insulin resistance and its pathogenesis

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634 Journal of Cardiovascular Medicine 2010, Vol 11 No 9

Insulin resistance, inammation and endothelium

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

Increasing cardiovascular risk

Increasing insulin resistance

Metabolic syndrome and pre-diabetes

Atherosclerotic cardiovascular disease and its complications

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636 Journal of Cardiovascular Medicine 2010, Vol 11 No 9

due to the downregulation of the anti-atherogenic PI-3-K pathway [30].

Insulin resistance and metabolic syndrome

Consequences of elevated free fatty acid level

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Role of insulin resistance in cardiovascular disease Reddy et al. 637

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638 Journal of Cardiovascular Medicine 2010, Vol 11 No 9

Leptin, elevated blood pressure and insulin resistance

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Role of insulin resistance in cardiovascular disease Reddy et al. 639

Insulin resistance and adiponectin

Insulin resistance and cardiovascular disease

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640 Journal of Cardiovascular Medicine 2010, Vol 11 No 9

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Role of insulin resistance in cardiovascular disease Reddy et al. 641

Lifestyle modication, biguanides, peroxisome proliferator-activated receptors, and insulin resistance

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642 Journal of Cardiovascular Medicine 2010, Vol 11 No 9

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Role of insulin resistance in cardiovascular disease Reddy et al. 643

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644 Journal of Cardiovascular Medicine 2010, Vol 11 No 9

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

Role of insulin resistance in cardiovascular disease Reddy et al. 645

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646 Journal of Cardiovascular Medicine 2010, Vol 11 No 9

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Role of insulin resistance in cardiovascular disease Reddy et al. 647

138 139 140

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