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Selective Insulin Resistance in the Polycystic Ovary Syndrome¹

Division of Women’s Health (A.D.), Departments of Medicine and Obstetrics and Gynecology, Brigham and Women’s Hospital, Boston, Massachusetts 02115; and the Department of Medicine, Pennsylvania State University College of Medicine (C.-B.B., A.D.), Hershey, Pennsylvania 17033

Address all correspondence and requests for reprints to: Andrea Dunaif, M.D., Division of Women’s Health, PBB 5, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02155. E-mail: adunaif{at}bics.bwh.harvard.edu

Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia that is amplified by insulin in the presence of resistance to insulin’s action to stimulate glucose uptake in muscle and fat. To explore the mechanisms for this paradox, we examined the metabolic and mitogenic actions of insulin and insulin-like growth factor I (IGF-I) in cultured skin fibroblasts from PCOS (n = 16) and control (n = 11) women. There were no significant decreases in the number or affinity of insulin- or IGF-I-binding sites in PCOS compared to control fibroblasts. Basal rates were similar, but there were significant decreases in insulin-stimulated (control, 51.8 ± 7.0; PCOS, 29.5 ± 2.9 nmol/10⁶ cells·2 h at 1,000,000 pmol/L; P < 0.005) and IGF-I-stimulated (control, 48.9 ± 6.7; PCOS, 33.0 ± 3.2 PCOS nmol/10⁶ cells·2 h at 100,000 pmol/L IGF-I; P < 0.05) glucose incorporation into glycogen in PCOS fibroblasts, a metabolic action of insulin. Stimulation of thymidine incorporation, a mitogenic action of insulin, was similar in PCOS and control fibroblasts in response to both insulin and IGF-I. There were also no significant differences in insulin- or IGF-I-stimulated insulin receptor substrate-1-associated phosphatidylinositol-3-kinase activity in PCOS compared to control fibroblast cells. We conclude that 1) there is a selective defect in insulin action in PCOS fibroblasts that affects metabolic, but not mitogenic, signaling pathways; 2) there is a similar defect in IGF-I action, suggesting that insulin and IGF-I stimulate glycogen synthesis by the same postreceptor pathways; and 3) insulin receptor substrate-1-associated phosphatidylinositol 3-kinase activation by insulin and IGF-I is similar to the control value, suggesting that the metabolic signaling defect is in another pathway or downstream of this signaling step in PCOS fibroblasts.

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