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.