Selective insulin resistance in the polycystic ovary syndrome

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 fo r 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 decreas es in the number or affinity of insulin- or IGF-I-binding sites in PCOS com pared to control fibroblasts. Basal rates were similar, but there were sign ificant decreases in insulin-stimulated (control, 51.8 +/- 7.0; PCOS, 29.5 +/- 2.9 nmol/10(6) cells.2 h at 1,000,000 pmol/L; P < 0.005) and IGF-I-stim ulated (control, 48.9 +/- 6.7; PCOS, 33.0 +/- 3.2 PCOS nmol/10(6) 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 i ncorporation, a mitogenic action of insulin, was similar in PCOS and contro l fibroblasts in response to both insulin and IGF-I. There were also no sig nificant differences in insulin- or IGF-I-stimulated insulin receptor subst rate-1-associated phosphatidylinositol-3-kinase activity in PCOS compared t o control fibroblast cells. We conclude that 1) there is a selective defect in insulin action in PCOS fibroblasts that affects metabolic, but not mito genic, signaling pathways; 2) there is a similar defect in IGF-I action, su ggesting that insulin and IGF-I stimulate glycogen synthesis by the same po streceptor pathways; and 3) insulin receptor substrate-1-associated phospha tidylinositol 3-kinase activation by insulin and IGF-I is similar to the co ntrol value, suggesting that the metabolic signaling defect is in another p athway or downstream of this signaling step in PCOS fibroblasts.