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Impaired Insulin Activation and Dephosphorylation of Glycogen Synthase in Skeletal Muscle of Women with Polycystic Ovary Syndrome Is Reversed by Pioglitazone Treatment

Department of Endocrinology (D.G., K.H., H.B.-N.), Diabetes Research Centre, Odense University Hospital, DK-5230 Odense, Denmark; Copenhagen Muscle Research Centre (N.R.A., J.F.P.W.), Institute of Exercise and Sport Sciences, Department of Human Physiology, University of Copenhagen, DK-2100 Copenhagen, Denmark; and Department of Diabetes Biology (B.F.H.), Novo Nordisk A/S, DK-2760 Måløv, Denmark

Address all correspondence and requests for reprints to: Kurt Højlund, M.D., Ph.D., Department of Endocrinology, Odense University Hospital, Kloevervaenget 6, DK-5000 Odense C, Denmark. E-mail: k.hojlund{at}dadlnet.dk.

Context: Insulin resistance is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). The molecular mechanisms underlying reduced insulin-mediated glycogen synthesis in skeletal muscle of patients with PCOS have not been established.

Subjects and Methods: We investigated protein content, activity, and phosphorylation of glycogen synthase (GS) and its major upstream inhibitor, GS kinase (GSK)-3 in skeletal muscle biopsies from 24 PCOS patients (before treatment) and 14 matched control subjects and 10 PCOS patients after 16 wk treatment with pioglitazone. All were metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry.

Results: Reduced insulin-mediated glucose disposal (P < 0.05) was associated with a lower insulin-stimulated GS activity in PCOS patients (P < 0.05), compared with controls. This was, in part, explained by absent insulin-mediated dephosphorylation of GS at the NH₂-terminal sites 2+2a, whereas dephosphorylation at the COOH-terminal sites 3a+3b was intact in PCOS subjects (P < 0.05). Consistently, multiple linear regression analysis showed that insulin activation of GS was dependent on dephosphorylation of sites 3a+3b in women with PCOS. No significant abnormalities in GSK-3 or -3β were found in PCOS subjects. Pioglitazone treatment improved insulin-stimulated glucose metabolism and GS activity in PCOS (all P < 0.05) and restored the ability of insulin to dephosphorylate GS at sites 2 and 2a.

Conclusions: Impaired insulin activation of GS including absent dephosphorylation at sites 2+2a contributes to insulin resistance in skeletal muscle in PCOS. The ability of pioglitazone to enhance insulin sensitivity, in part, involves improved insulin action on GS activity and dephosphorylation at NH₂-terminal sites.