EXCESSIVE INSULIN-RECEPTOR SERINE PHOSPHORYLATION IN CULTURED FIBROBLASTS AND IN SKELETAL-MUSCLE - A POTENTIAL MECHANISM FOR INSULIN-RESISTANCE IN THE POLYCYSTIC-OVARY-SYNDROME

We investigated the cellular mechanisms of the unique disorder of insu lin action found in the polycystic ovary syndrome (PCOS). Approximatel y 50% of PCOS women (PCOS-Ser) had a significant increase in insulin-i ndependent beta-subunit [P-32]phosphate incorporation (3.7-fold, P < 0 .05 vs other groups) in skin fibroblast insulin receptors that was pre sent in serine residues while insulin-induced tyrosine phosphorylation was decreased (both P < 0.05 vs other groups). PCOS skeletal muscle i nsulin receptors had the same abnormal phosphorylation pattern. The re maining PCOS women (PCOS-n1) had basal and insulin-stimulated receptor autophosphorylation similar to control. Phosphorylation of the artifi cial substrate poly GLU4:TYR1 by the PCOS-Ser insulin receptors was si gnificantly decreased (P < 0.05) compared to control and PCOS-n1 recep tors. The factor responsible for excessive serine phosphorylation appe ared to be extrinsic to the receptor since no insulin receptor gene mu tations were identified, immunoprecipitation before autophosphorylatio n corrected the phosphorylation defect and control insulin receptors m ixed with lectin eluates from affected PCOS fibroblasts displayed incr eased serine phosphorylation. Our findings suggest that increased insu lin receptor serine phosphorylation decreases its protein tyrosine kin ase activity and is one mechanism for the post-binding defect in insul in action characteristic of PCOS.