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0 100 1000 10000 100000 0 100 1000 10000 100000 Serum Insulin (pmol/L) Serum Insulin (pmol/L)

FIGURE 3 Insulin effect on glucose uptake parallels that on leg blood flow.

hypertension and CVD (43-45). Furthermore, exercise has been shown to have significant therapeutic value in treating most of the components of the IRS (see below).

Cytokines and Inflammation

Several studies have suggested a role for inflammation in the etiology of the IRS and its complications. Observations suggest that cytokines arising from adipose tissue may be partly responsible for the metabolic, hemodynamic and hemostatic abnormalities associated with insulin resistance. Studies show a close relationship between obesity and circulating C-reactive protein (CRP), TNF-a and IL-6. Plasma CRP is elevated in obese subjects who have other features of the IRS (46). It has been recently recognized that some of these cytokines are predictors of CVD. Thus inflammation originating from excess adipose tissue cytokine production may contribute not only to the development of the IRS but also the associated CVD.

Increased expression of TNF-a in adipose tissue has been reported in obese subjects. TNF-a inhibits the action of lipoprotein lipase and stimulates lipolysis. It also impairs the function of the insulin-signaling pathway by effects on phosphorylation of both the insulin receptor and insulin-receptor substrate (IRS)-1 (IL-6) may also induce endothelial expression of cytokines thereby contributing to endothelial dysfunction.

Adipose tissue is a major site of energy storage and is important for energy homeostasis. During state of nutritional abundance it functions to store energy in the form of triglycerides and during nutritional deprivation, it releases the energy as FFAs (47-49).

Adipose tissue has been increasingly recognized as an important endocrine organ that secretes a number of biologically active "adipokines" (50-54). Some of these adipokines have been shown to directly or indirectly affect insulin sensitivity through modulation of insulin signaling and the molecules involved in glucose and lipid metabolism (55). Adiponectin is one of the adipokines that has attracted much attention due to its antidiabetic and antiatherogenic properties (56). The adiponectin gene encodes a secreted protein expressed exclusively in both WAT and brown adipose tissue (47). Adiponectin expression is reduced in obese, insulin-resistant rodent models (57) and in obese rhesus monkey model that frequently develop type 2 diabetes (58). In these animals, the onset of diabetes is preceeded by the decrease in plasma adiponectin levels in parallel with the observation of decreased insulin sensitivity (58). Plasma adiponectin levels have indeed been reported to be reduced in obese humans, particularly in those with visceral obesity. They correlate inversely with insulin resistance (58-62). Longitudinal and prospective studies (62-67) have shown that lower adiponectin levels are associated with a higher incidence of diabetes. Adiponectin is also significantly related to the development of type 2 diabetes in Pima Indians (65). Hypoadiponectinemia has been independently associated with the metabolic syndrome (68). Reduced plasma adiponectin levels are also commonly observed in various states associated with insulin resistance, such as CVD (69,70) and hypertension(71,72).

Dietary factors such as soy protein (73), fish oils (74), and linoleic acid (75) have been suggested to increase plasma adiponectin level, whiel a carbohydrate-rich diet appears to decrease plasma adiponectin level (76). The insulin sensitizing effect of adiponectin was first identified in 2001 (77-79). Schrere and colleagues (47) have reported that an acute increase in the level of circulating adiponectin triggers a transient decrease in basal glucose level by inhibiting both the expression of hepatic gluconeogenic enzymes and the rate of endogenous glucose production in both wild type and type 2 diabetic mice (77).

Decreased insulin-stimulated glucose transport (Glut 4) (80)activity contributes to decreased insulin-stimulated skeletal muscle glycogen synthesis in insulin resistance. This defect appears to be a result of intracellular lipid-induced inhibition of insulin-stimulated IRS-1 tyrosine phosphorylation resulting in reduced IRS-1 associated phosphatidyl inositol 3 kinase activity. Therefore, insulin resistance could be taken to be a result of accumulation of intracellular lipid metabolites (e.g., fatty acyl CoAs, diacylglycerol) in skeletal muscle and hepatocytes. Furthermore, in patients with type 2 diabetes who undergo weight loss have an increase in hepatic insulin sensitivity. This is accompanied by significant reduction in intrahepatic fat without any changes in circulating adipocytokines. Reduced mitochondrial activity may also lead to increased intramyocellular lipid content and therefore to insulin resistance in skeletal muscles. Intra-islet fat also adversely affects beta cell function and number (beta cell apoptosis) (81).

Mitochondrial Dysfunction

The common etiology of the relationship between insulin resistance and atherosclerosis may be organelle stress in response to nutrient excess occurring in mitochondria, the nucleus and the endoplasmic reticulum (82). Mitochondria are the major source of ATP production in animals. Within the inner mitochondrial membrane, occurs the process of respiration. During this reaction, reactive oxygen species are generated. These reactive oxygen species have been implicated in atherosclerosis. Additionally, the mitochondrial genome may be particularly susceptible to oxidative damage due to its lack of histones and a deficient mismatch repair system. Mitochondrial dysfunction may be involved in skeletal muscle insulin resistance. Decrease in the expression of genes essential for mitochondrial function, such as the gene encoding PGC-1a is decreased in subjects with insulin resistance (83). This is accompainied by impaired energy production in the muscles of insulin resistant subjects (84). As discussed above, insulin resistance causes an increase in circulating fatty acids. Increased fatty acid oxidation by aortic endothelial cells has recently been reported to accelerate the production of supreoxide by the mitochondrial election transport chain (85). This effect is associated with proatherogenic vascular effects thus consistent with the evidence for the role of mitochondrial metabolism in vascular disease.

Alteration of the DNA structure or function is termed genomic stress. Oxidative modifications are frequently responsible for the genomic stress which is another likely contributor to both insulin resistance and atherosclerosis (82). Saturated fatty acids may also induce endoplasmic reticulum stress (86). Both dietary and genetic models of obesity disrupt normal protein folding in the endoplasmic reticulum, leading to stress signals mediated in part by JNK (87). Deficiency of the insulin receptor in macrophages has been shown to increase the endoplasmic reticulum stress response and apoptosis in a mouse model of atherosclerosis (88). Thus, mitochondrial dysfunction plays a key molecular role in insulin resistance.

Abnormal Insulin Signaling, Hyperinsulinemia, and the Vasculature

As outlined above, IR with resultant hyperinsulinemia is an independent risk factor for CVD. However, the specific role of insulin in the pathogenesis of atherosclerosis remains unclear. Several mechanistic hypotheses have been proposed to explain this association (2,89). Firstly, insulin is a growth factor that stimulates vascular cell growth and synthesis of matrix proteins. Secondly, the insulin signaling pathway thought to be responsible for abnormalities in glucose metabolism is also involved in NO production. Thus, the abnormal intracellular signaling that causes hyperglycemia may also be responsible for vascular disease due to loss of insulin's antiatherogenic properties, while hyperinsulinemia continues to stimulate growth promoting enzymes such as MAP kinase (89) Although some controversy remains, this hypothesis (Fig. 4) has been supported by many studies. In addition, imbalances in insulin homeostasis are associated with abnormalities in expression and action of various peptides, growth factors and cytokines. These include angiotensin II, endothelin -land insulin -like growth factor -1 (89).

While the exact role of peroxisome proliferator-activated receptors in the pathogenesis of this syndrome is unclear, several studies support the concept that they may have a role in the development of not only insulin resistance but also atherosclerosis (90). For example, these receptors are present in vascular tissue, heterozygous mutations in the ligand-binding domain of PPAR gamma are occasionally associated with insulin resistance, and agonists of these receptors have a significant impact on the syndrome. Thus it is possible that PPARs play a role in the pathogenesis of the complete syndrome that is the subject of much current research.

Drug Induced

Several classes of drugs have been associated with insulin resistance. These include corticosteroids, which frequently cause insulin resistance and type 2 diabetes. Recent data with protease inhibitors, used for the treatment of human immunodeficiency virus infection, frequently cause several manifestations of the IRS (91). Hypertriglyceridemia appears to be an early manifestation of protease inhibitor induced lipodystrophy and is associated with changes in body fat distribution and marked insulin resistance. The long-term effects of these drugs on CVD are unknown.

Intrauterine/Postpartum Growth and Development

Some data have suggested that a low birth weight and/or rapid gain of weight in the early life are associated with the later development of multiple features of the IRS including, type 2 diabetes and other risk factors for CVD (92-94). The mechanisms by which fetal under nutrition and hence, low birth weight increase the risk of developing these diseases are unclear. Animal experiments (94) have been done with a rat model of under nutrition, involving an overall reduction in maternal food intake. In this study, intrauterine growth retardation (IUGR) have a decreased beta cell mass, which persists into adulthood. Maternal under nutrition also causes elevations in glucocorticoid concentrations, which in turn have been implicated in causing reduction of the beta cell mass. A prospective study done in

FIGURE 4 Insulin: potential atherogenic and antiatherogenic actions in vascular cells. Abbreviations: IRS, insulin receptor substrate; JRS-1,2, insulin receptor substrate; MAPK, mitogen activated protein kinase; MEK, MAP kinase-kinase; PI-3-Kinase, phosphatidylinositol-3-kinase; PKC, protein kinase C. Source: From Ref. 89.

Atherogenic Antiatherogenic

Vascular CeN Growth NO-Mediated Vasodilation

Synthesis of Extracellular Matrix Proteins

FIGURE 4 Insulin: potential atherogenic and antiatherogenic actions in vascular cells. Abbreviations: IRS, insulin receptor substrate; JRS-1,2, insulin receptor substrate; MAPK, mitogen activated protein kinase; MEK, MAP kinase-kinase; PI-3-Kinase, phosphatidylinositol-3-kinase; PKC, protein kinase C. Source: From Ref. 89.

630 children (95) has shown that maternal gestational diabetes mellitus results in adiposity and higher glucose and insulin concentrations in female offsprings at 5 years. Metabolic abnormalities persist in adulthood as well as demonstrated by a study done in adults who were born with IUGR (96). Using peripheral glucose uptake and monitoring FFA concentrations under euglycemic hyperinsulinemic clamp, subjects who were born with IUGR, were shown to have decreased insulin-stimulated glucose uptake as early as 25 years of age without major impairment of insulin secretion. Low glucose uptake is associated with a lesser degree of FFA suppression in adipose tissue, which suggests a role of adipose tissue at an early stage of insulin resistance in these subjects. It has also been shown that Large for Gestational Age (LGA) offsprings of mothers with diabetes were at significant risk of developing the metabolic syndrome in childhood when compared to appropriate-for-age (AGA) children (97). Low birth weight is also important. The Bogalusa heart study supports the relationship between low birth weight and the later development of important CV risk factors in African Americans and white individuals. This relationship tends to be stronger in African Americans than in whites, except for systolic blood pressure (98). A study done among children with low birth weight in India supports this relationship between low birth weight and subsequent development of insulin resistance (99). Thus, it has become increasingly evident that impaired intrauterine growth plays a decisive role in the future physiology and function of many organs and body systems.

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