In addition to being a precursor of type 2 diabetes and an independent risk factor for CVD, insulin resistance is also closely associated with several other CV risk factors. The interrelatedness of insulin resistance with the other factors is discussed below.
Obesity is frequently associated with several of the components of the IRS and may be critical for the development of the syndrome. The contemporary view is now centered on visceral adiposity Several mechanisms have been proposed for the link between obesity and the IRS (21) CV morbidity and mortality are increased in obese individuals independently of other risk factors. Insulin resistance is very common in obese individuals. However, some nonobese individuals demonstrate hyperinsulinemia and the other features of the IRS (22). Thus, obesity may not be essential for the expression of the syndrome but the presence of obesity or weight gain may accentuate the pathophysiological changes associated with the syndrome.
Body fat distribution rather than body mass may actually be a better predictor of insulin resistance and CV risk (23). Insulin resistance, type 2 diabetes and hypertension are more closely associated with a central distribution of adiposity than with general increases in fat mass. Waist circumference serves as a clinical surrogate of intra-abdominal fat.
One of the earliest relationships between insulin resistance and a CV risk factor is with "diabetic dyslipidemia". The hallmark of the syndrome is hypertriglyceridemia and low plasma HDL cholesterol concentration. Plasma LDL cholesterol concentrations in insulin resistant subjects are no different from those in insulin sensitive subjects. However, there are qualitative changes in LDL cholesterol resulting in "pattern B" distribution of LDL particles-which consists of smaller LDL particles that are more susceptible to oxidation and thus potentially more atherogenic (24).
Several hypotheses have been proposed for the mechanism of the association between insulin resistance and dyslipidemia. Insulin resistance at the level of adipose tissue may result in increased activity of hormone sensitive lipase and therefore increased breakdown of stored triglycerides. Free fatty acids (FFA) released from adipocytes, particularly intra-abdominal adipocytes, can be transported to the liver where they stimulate synthesis of triglycerides and assembly and secretion of very low density lipoprotein (VLDL). Increased plasma VLDL triglycerides exchange with cholesterol esters from HDL, resulting in a lower plasma HDL cholesterol. On the other hand, an increase in circulating FFA has been proposed as having an etiological role in the development of IR (25).
FFAs released from adipose tissue play a pivotal role in insulin resistance. In the skeletal muscle of lean, healthy subjects, a progressive increase in plasma FFA causes a dose-dependent inhibition of insulin-medicated glucose disposal and insulin signaling. The inhibitory effect of plasma FFA develops at concentrations that are well within the physiological range (i.e., at plasma FFA levels observed in obesity and type 2 diabetes).
Boden et al. (26) studied mechanisms by which FFAs cause hepatic insulin resistance by using euglycemic-hyperinsulinemic clamps with and without the infusion of lipid/heparin (to raise or lower FFAs) in alert male rats. FFA-induced hepatic insulin resistance was associated with increased hepatic diacylglycerol content (+ 210%), increased activation of the proinflammatory nuclear NF-kappa B pathway, increased activities of two serine/threonine kinases, and increased expression of inflammatory cytokines (TNF-a, Interleukin-lbeta).
In subjects with insulin resistance, elevated circulating FFA levels precede the onset of glucose metabolism abnormalities. Inappropriate insulin signaling, especially in peripheral tissues such as adipose cells, results in abnormal lipid metabolism. Impaired insulin signaling leads to loss of suppression of Lipolysis (27)and perhaps defects in storage of fatty acids in the adipocytes (28)from the review). The excess amount of lipid from various sources (circulating FFAs originating in the fat, endocytosis of triglyceride-rich lipoproteins, and de novo lipogenesis) leads to the posttranslational stabilization of aopB, the major apolipoprotein of
VLDL, which enhances the assembly and secretion of VLDL particles (29). Insulin signaling, through P13K-dependent pathways, also promotes the degradation of apoB. Thus, a combination of excess delivery of fatty acids and limited degradation of apoB explains the hypertriglyceridemia characteristic of insulin resistance. Insulin resistance also decreases the lipoprotein lipase activity, the major mediator of VLDL clearance.
Although it is well established that essential hypertension is frequently associated with insulin resistance, the impact of this abnormality on blood pressure homeostasis is still a matter of debate. Fasting plasma insulin is frequently higher in hypertensive subjects and glucose disposal during an euglycemic clamp is decreased. The association between hypertension and insulin resistance is more convincing in obese subjects. Significant decreases in blood pressure have been observed in obese subjects, who lose modest amounts of weight, correlating closely with the decline in fasting plasma insulin concentrations. Plasma insulin concentrations are higher and insulin-mediated total-body glucose disposal is reduced in young, normal weight individuals with essential hypertension (2). The impairment in insulin-mediated glucose disposal was closely related to the increase in blood pressure. Multiple potential mechanisms by which IR may cause hypertension have been proposed (30), These include resistance to insulin mediated vasodilatation, impaired endothelial function, sympathetic nervous system over-activity, sodium retention, increased vascular sensitivity to the vasoconstrictor effect of pressor amines and enhanced growth factor activity leading to proliferation of smooth muscle walls. However, some studies do not support the association of metabolic insulin resistance with essential hypertension. Clearly, hypertension is itself a complex disorder with many etiologies, and not all subjects with essential hypertension are insulin resistant.
Factors contributing to a prothrombotic state in diabetes are summarized in Table 3. The endogenous fibrinolytic system represents equilibrium between activators of plasminogen (primarily tissue type plasminogen activator-tPA) and inhibitors of these activators (such as plasminogen activator inhibitor type 1- PAI 1) (31). Coagulation is a continuous process and the fibrinolytic system maintains fluidity of blood. Excessive inhibition of fibrinolysis will lead to coagulation and thrombosis, a critical process in CV events (31). Impaired fibrinolytic function in diabetes correlates with severity of vascular disease in diabetes and is a risk factor for myocardial infarction in both diabetic and nondiabetic subjects.
Impaired fibrinolysis is now recognized as being an important component of the IRS and probably contributes considerably to the increased risk of CV events (17). Plasma PAI 1 antigen and activity are elevated in a wide variety of insulin resistant subjects including obese subjects with and without diabetes and women with the polycystic ovarian syndrome. Immuno-histochemical analysis of coronary lesions from patients with coronary
TABLE 3 Potential Impact of Insulin Resistance and Diabetes on Thrombosis and Fibrinolysis
Factors predisposing to thrombosis "Platelet hyperaggregability "Platelet cAMP and cGMP "Thromboxane synthesis Elevated concentrations of procoagulants "Fibrinogen
"Von Willebrand factor and procoagulant activity "Thrombin activity Decreased concentration and activity of antithrombotic factors
"Antithrombin III activity Factors attenuating fibrinolysis Decreased t-PA activity Increased PAI-1 synthesis and activity Increased blood viscosity artery disease has demonstrated an imbalance of the local fibrinolytic system with increased coronary artery tissue PAI-1 in patients with type 2 diabetes. Many studies have attempted to elucidate the mechanistic link between insulin resistance and abnormal fibrinolysis. Insulin, proinsulin, abnormal cholesterol and various cytokines regulate PAI-1 synthesis and release. The greatest elevations in PAI-1 occur when there is a combination of hyperinsulinemia, hyperglycemia and increased FFAs, in obese insulin resistant subjects (32).
Other factors predisposing to thrombosis associated with insulin resistance, include increased platelet hyper-aggregation, elevated concentrations of pro-coagulants particularly fibrinogen and Von Willebrand factor and a decrease in anti-thrombotic factors such as anti thrombin III (31). Many of these abnormalities are nonspecific and the association of insulin resistance with coagulation abnormalities with is less robust than that with abnormal fibrinolysis.
The importance of the endothelium in maintaining vascular health has been widely recognized. The endothelium is a critical determinant of vascular tone, reactivity, inflammation, vascular remodeling, maintenance of vascular patency and blood fluidity (33). Many of these functions of the endothelium are maintained through regulatory substances secreted from endothelial cells, which may often have opposing actions. For example, nitric oxide (NO) is the most potent known vasodilator, is secreted by endothelial cells, having being synthesized from arginine by nitric oxide synthase (NOS). Endothelial cells also secrete other important vasodilators such as prostacyclin. The vasodilatory actions are opposed by secretion of potent vasoconstrictors such as Endothelin 1. Similarly these and others endothelial products are involved in maintaining the balance between smooth muscle cell growth, promotion and inhibition, thrombosis and fibrinolysis, inflammation and cell adhesion.
Endothelial dysfunction is now recognized as being an early abnormality in the natural history of CVD may be a good predictor of CV events. Abnormalities in production of NO, increased inactivation of NO along with increased activation of angiotensin converting enzyme and local mediators of inflammation, may be key precursors of clinical events in the IRS.
The ability of blood vessels to dilate in response to stimuli, including ischemia is called vascular reactivity, or flow mediated dilatation (FMD). Brachial artery vascular reactivity is a noninvasive method of assessing arterial endothelial function in vivo. Since endothelial injury is an early event in atherogenesis, it has been suggested that abnormal flow-mediated dilatation may precede the development of structural changes in the vessel wall. Abnormal flow-mediated dilatation has been shown in several insulin resistant states and is present in relatives of patient with type 2 diabetes who have normal glucose tolerance. In a study done in healthy subjects across a wide range of BMI (18.6 to 73.1 kg/m2), markers of total body fat/fat distribution, inflammation, metabolism, and blood pressure have been shown to coorelate with FMD (34). The markers of total body fat/fat distribution measured were waist circumference, BMI and waist hip ratio (WHR), while the markers of inflammation measured were interleukin-6 (IL-6), C-reactive protein, and tumor necrosis factor alpha (TNF-a) R2. The parameters of metabolism that were measured were fasting insulin, HDL, LDL and triglycerides. Of all the markers WHR was the only independent predictor of FMD (r2 = 0.30); p = 0.0001). It has even been proposed that endothelial dysfunction may be a precursor of the IRS (35). Figure 2 summarizes this hypothesis and illustrates the various determinants and consequences of insulin resistance. Table 4 lists various endothelial abnormalities associated with insulin resistance.
Insulin itself has vasodilatory actions via a NO dependent mechanism (21). In healthy subjects, insulin dilates arterioles supplying skeletal muscle probably through enhancement of NO production. Some in vitro studies have documented that insulin regulates NOS and that this action maybe impaired in insulin resistant subjects- an abnormality that might be attributable to either impairment in the ability of the endothelium to produce NO or enhanced inactivation of NO (36). Since NO plays a critical role in the maintenance of vascular health
(33) this abnormality may explain much of the increased CVD in the IRS. Impairment of insulin action on glucose metabolism assessed by glucose clamp parallels impairment of insulin action on the vasculature (Fig. 3). Thus obesity and type 2 diabetes are associated with resistance to insulin's vascular effects.
Finally insulin resistance is associated with increased carotid intima-media thickness (IMT) (37), This finding is compatible with the possible effect of hyperinsulinemia on growth of vascular smooth muscle cells and extracellular matrix (38). Carotid IMT is increased in newly diagnosed patients with type 2 diabetes without overt CVD (39). This finding is important since IMT represents a structural abnormality in the arterial wall and is a good predictor of subsequent CV risk (40).
Microalbuminuria is recognized as a complication of diabetes due to changes in the kidney secondary to hyperglycemia. Recent data suggests that it may occur even in nondiabetics and be a precursor of CVD and may be related to insulin resistance (41). It is possible that in individuals who are insulin resistant, microalbuminuria may be a manifestation of endothelial dysfunction, indicating endothelial permeability and is also related to increased carotid IMT (42). Microalbuminuria is included in the criteria used by the WHO to define the IRS.
Habitual physical activity is an important determinant of insulin resistance. Epidemiological studies have shown a strong correlation between a sedentary lifestyle and type 2 diabetes,
TABLE 4 Alterations in the Vascular Endothelium Associated with Diabetes Mellitus and Insulin Resistance
"Release of and responsiveness to NO
"Expression, synthesis, and plasma levels of endothelin-1
"Adhesion of platelets and monocytes
"Advanced glycosylated end products
Impaired fibrinolytic activity
Impaired endothelial function and reactivity
Vasoconstriction and hypertension
Increased monocyte adhesion to vessel wall
Foam cell formation, thrombosis and inflammation
Increased stiffness of arterial wall Decreased clot breakdown
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