Dissecting the role of insulin resistance in the metabolic syndrome

Purpose of Review—Over twenty years ago, insulin resistance was postulated to play a central role in the pathogenesis of the metabolic syndrome. However, this has been difficult to prove, leading to a great deal of controversy within the field. Recent studies in mice and humans with genetic defects in insulin signaling have allowed us, for the first time, to dissect which features of the metabolic syndrome can be caused by insulin resistance. Recent Findings—Mice with liver specific knockout of the insulin receptor (LIRKO) show that hepatic insulin resistance can produce (1) hyperglycemia; (2) increased Apob secretion and atherosclerosis; and (3) increased biliary cholesterol secretion and cholesterol gallstones. Many of these changes may be due to dis-inhibition of the transcription factor, FoxO1. Yet, neither LIRKO mice nor humans with insulin receptor mutations develop the hypertriglyceridemia or hepatic steatosis associated with the metabolic syndrome. Conclusion—These data point to a central role for insulin resistance in the pathogenesis of the metabolic syndrome, as hyperglycemia, atherosclerosis, and cholesterol gallstones can all be caused by insulin resistance. However, hypertriglyceridemia and hepatic steatosis are not due directly to insulin resistance, and should be considered pathogenically distinct features of the metabolic syndrome.