Cellular mechanisms of insulin resistance in polycystic ovarian syndrome.
Insulin resistance is a predominant feature in women with polycystic ovarian syndrome (PCO). The cellular mechanisms for this insulin resistance have not been defined. In this study, major steps in the insulin action cascade, receptor binding, kinase activity, and glucose transport activity were evaluated in isolated adipocytes prepared from PCO subjects (n = 8) without acanthosis nigricans and in a group of age and weight-matched controls [normal cycling (NC) n = 8]. The PCO group was hyperinsulinemic and displayed elevated insulin responses to an iv glucose load. The binding of 125I-insulin to adipocytes was similar in cells from PCO and NC subjects. In PCO, autophosphorylation of the insulin receptor-subunit in the absence of insulin was normal but a significant decrease (30% below control) in maximal insulin stimulated autophosphorylation was observed. However, receptor kinase activity measured against the exogenous substrate poly glu:tyr (4:1) was normal. Cells from PCO subjects transported glucose at the same rate, in both the absence and presence of a maximal insulin concentration, as those from NC subjects. Strikingly, there was a large rightward shift in the insulin dose-response curve for transport stimulation in PCO cells (EC50 = 87 +/- 14 pmol in NC vs. 757 +/- 138 in PCO, P less than 0.0005); 8-fold greater insulin concentrations were required to attain comparable glucose transport rates in cells from PCO against NC. In conclusion, our results suggest that insulin resistance in PCO, as assessed in the adipocyte, is accompanied by normal function of insulin receptors, but involves a novel postreceptor defect in the insulin signal transduction chain between the receptor kinase and glucose transport.
Ciaraldi
T P
TP
Department of Medicine, University of California, La Jolla 92093.
el-Roeiy
A
A
Madar
Z
Z
Reichart
D
D
Olefsky
J M
JM
Yen
S S
SS
D000273:Adipose Tissue / Q000378:metabolism / Q000473:pathology; D000293:Adolescent; D000328:Adult; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D011085:Polycystic Ovary Syndrome / Q000473:pathology / Q000503:physiopathology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin; D012016:Reference Values
D007328:Insulin; D009004:Monosaccharide Transport Proteins; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin