Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD.

The metabolic syndrome represents a summation of obesity-driven risk factors for atherosclerotic CVD and type 2 diabetes. Definitions of the syndrome vary but in general agree closely in identifying subjects. The relationships between the metabolic syndrome and atherosclerotic CVD and diabetes also vary, with relative risks of approximately 1.5-3.0 and approximately 3.0-5.0 respectively. Insulin resistance appears to explain much of the pathophysiology of the syndrome. Both increased fatty acid flux and an excess of circulating pro-inflammatory cytokines are likely mediators. With increased waist circumference, increases in fatty acid delivery to the liver result in higher rates of hepatic glucose production and increases in the secretion of apoB-containing lipoproteins. Concomitant changes in HDL ensue, including a replacement of the cholesterol content with TAG, an accelerated clearance from the plasma and thus a reduced number of HDL particles. Typically also present are increases in small dense LDL. Hypertension in part relates to the insulin resistance, but may involve other mechanisms. Impaired fasting glucose often relates to defects in insulin secretion in addition to insulin resistance, and probably more than any other component of the syndrome predicts the increased incidence of type 2 diabetes. Although not included in the diagnostic criteria, increases in pro-inflammatory cytokines and pro-thrombotic factors, in addition to decreases in plasma adiponectin, may also contribute to the increased incidence of atherosclerotic CVD and diabetes. In general, the greater the number of metabolic syndrome components, the greater the risk for these outcomes. The cytokines and pro-thrombotic factors also appear to contribute.