Insulin resistance in polycystic ovary syndrome: Progress and paradoxes

Over the past 20 years, it has been clearly documented that 1) polycystic o vary syndrome (PCOS) has major metabolic sequelae related to insulin resist ance and 2) insulin resistance plays an important role in the pathogenesis of the reproductive abnormalities of the disorder. Women with PCOS are at s ignificantly increased risk of developing type 2 diabetes mellitus (DM). St udies in isolated adipocytes and in cultured skin fibroblasts from PCOS wom en have demonstrated intrinsic postbinding defects in insulin-mediated gluc ose metabolism In fibroblasts, the mitogenic pathway of insulin action is i ntact, consistent with a selective defect in insulin signaling. While PCOS skeletal muscle is resistant to insulin in vivo, cultured muscle cells have normal insulin sensitivity, consistent with a major role of extrinsic fact ors in producing insulin resistance in this tissue. Excessive serine phosph orylation of the insulin receptor or downstream signaling proteins may be i nvolved in the pathogenesis of insulin resistance in PCOS. The putative ser ine kinase is extrinsic to the insulin receptor but its identity is unknown . The explanations for tissue-specific and signaling pathway-specific diffe rences in insulin action in PCOS are unknown but may involve differential r oles of insulin receptor substrate (IRS)-1 and IRS-2 in insulin signal tran sduction.