Lipid and lipoprotein dysregulation in insulin resistant states.

Insulin resistant states are commonly associated with an atherogenic dyslipidemia that contributes to significantly higher risk of atherosclerosis and cardiovascular disease. Indeed, disorders of carbohydrate and lipid metabolism co-exist in the majority of subjects with the "metabolic syndrome" and form the basis for the definition and diagnosis of this complex syndrome. The most fundamental defect in these patients is resistance to cellular actions of insulin, particularly resistance to insulin-stimulated glucose uptake. Insulin insensitivity appears to cause hyperinsulinemia, enhanced hepatic gluconeogenesis and glucose output, reduced suppression of lipolysis in adipose tissue leading to a high free fatty acid flux, and increased hepatic very low density lipoprotein (VLDL) secretion causing hypertriglyceridemia and reduced plasma levels of high density lipoprotein (HDL) cholesterol. Although the link between insulin resistance and dysregulation of lipoprotein metabolism is well established, a significant gap of knowledge exists regarding the underlying cellular and molecular mechanisms. Emerging evidence suggests that insulin resistance and its associated metabolic dyslipidemia result from perturbations in key molecules of the insulin signaling pathway, including overexpression of key phosphatases, downregulation and/or activation of key protein kinase cascades, leading to a state of mixed hepatic insulin resistance and sensitivity. These signaling changes in turn cause an increased expression of sterol regulatory element binding protein (SREBP) 1c, induction of de novo lipogensis and higher activity of microsomal triglyceride transfer protein (MTP), which together with high exogenous free fatty acid (FFA) flux collectively stimulate the hepatic production of apolipoprotein B (apoB)-containing VLDL particles. VLDL overproduction underlies the high triglyceride/low HDL-cholesterol lipid profile commonly observed in insulin resistant subjects.