Insulin resistance in polycystic ovary syndrome: progress and paradoxes.
Over the past 20 years, it has been clearly documented that 1) polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and 2) insulin resistance plays an important role in the pathogenesis of the reproductive abnormalities of the disorder. Women with PCOS are at significantly increased risk of developing type 2 diabetes mellitus (DM). Studies in isolated adipocytes and in cultured skin fibroblasts from PCOS women have demonstrated intrinsic postbinding defects in insulin-mediated glucose metabolism. In fibroblasts, the mitogenic pathway of insulin action is intact, 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 factors in producing insulin resistance in this tissue. Excessive serine phosphorylation of the insulin receptor or downstream signaling proteins may be involved in the pathogenesis of insulin resistance in PCOS. The putative serine kinase is extrinsic to the insulin receptor but its identity is unknown. The explanations for tissue-specific and signaling pathway-specific differences in insulin action in PCOS are unknown but may involve differential roles of insulin receptor substrate (IRS)-1 and IRS-2 in insulin signal transduction.
The Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
A M
AM
Venkatesan
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A
Dunaif
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A
Corbould
D017667:Adipocytes / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins; D008954:Models, Biological; D018482:Muscle, Skeletal / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000150:complications*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction
C526292:IRS1 protein, human; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases