Cadiovascular Risk Factors in Metabolic Syndrome - Impact of Insulin Resistance on Lipids, Hypertension, and the Development of Diabetes and Cardiac Events

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The central components of CV risk in MS are visceral (central) obesity and resultant insulin resistance. Although obesity is a powerful risk factor for DM and CVD, substantial heterogeneity exists in the distribution of fat and the relationship between metabolic disturbances and obesity. A significant minority of obese subjects are not insulin-resistant and, conversely, lean subjects may be insulin-resistant. Adipocytes secrete multiple pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-╬▒), and it is now well appreciated that MS is a proinflammatory condition, leading to increased vascular oxidative stress and the early development of endothelial dysfunction. Adipocytes also secrete and influence the actions of multiple signaling molecules ('adipokinesÔÇÖ), such as leptin, resistin, and adiponectin that contribute to insulin resistance and CV risk. For example, adiponectin levels are inversely correlated with insulin resistance and coronary artery disease (CAD).

It has been estimated that 30% of IL-6 production comes from adipocytes and directly influences the hepatic production of C-reactive protein (CRP). CRP levels vary in direct proportion to the number of metabolic abnormalities. Chronic subclinical inflammation is an important part of MS, as CRP is independently related to obesity, insulin sensitivity, and MS itself. CRP remains a highly significant predictor of both DM and CV events when adjusted for other CV risk factors. In addition to correlating well with all five of the easily measured components of MS, CRP also correlates with insulin resistance, endothelial dysfunction, and impaired fibrinolysis. Environmental factors (high caloric density diet and sedentary lifestyle) are also dominant factors in the epidemic of obesity and MS and the search continues to define specific genetic abnormalities associated with MS.

The lipoprotein abnormalities of MS (increased levels of triglycerides and triglyceride rich particles, small dense low-density lipoprotein (LDL) particles, with marked reductions in HDL (including HDL-2 particles)) are extremely atherogenic and play an enormous role in the development of CV events. Hypertriglyceridemia leads to low HDL levels and increased sd-LDL particles, primarily due to the activity of cholesterol ester transfer protein (CETP).Triglyceride-rich HDL is hydrolyzed by hepatic lipase, and, to a lesser extent, lipoprotein lipase, which generates smaller HDL particles. Small dense HDL particles shed apolipoprotein-A1, which is then catabolized in the kidney. Similarly, VLDL triglyceride is exchanged for LDL cholesterol in the presence of CETP. The hydrolysis of LDL triglyceride generates sd-LDL particles.

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