This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints, Permissions and Rights Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Glintborg, D. Articles by Wojtaszewski, J. F. P. Search for Related Content PubMed PubMed Citation Articles by Glintborg, D. Articles by Wojtaszewski, J. F. P. Related Collections Diabetes and Insulin Female Endocrinology Metabolism

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.

This article has been cited by other articles:

				K. Hojlund, J. B. Birk, D. K. Klein, K. Levin, A. J. Rose, B. F. Hansen, J. N. Nielsen, H. Beck-Nielsen, and J. F. P. Wojtaszewski Dysregulation of Glycogen Synthase COOH- and NH2-Terminal Phosphorylation by Insulin in Obesity and Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., November 1, 2009; 94(11): 4547 - 4556. [Abstract] [Full Text] [PDF]

				C. Prats, J. W. Helge, P. Nordby, K. Qvortrup, T. Ploug, F. Dela, and J. F. P. Wojtaszewski Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization J. Biol. Chem., June 5, 2009; 284(23): 15692 - 15700. [Abstract] [Full Text] [PDF]