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Impaired Insulin-Stimulated Phosphorylation of Akt and AS160 in Skeletal Muscle of Women With Polycystic Ovary Syndrome Is Reversed by Pioglitazone Treatment

¹ Department of Endocrinology, Diabetes Research Centre, Odense University Hospital, Odense, Denmark
² Department of Exercise and Sport Sciences, Section of Human Physiology Copenhagen Muscle Research Centre, University of Copenhagen, Copenhagen, Denmark

Address correspondence and reprint requests to Kurt Højlund, MD, PhD, Department of Endocrinology, Odense University Hospital, Kloevervaenget 6, DK-5000 Odense C, Denmark. E-mail: k.hojlund{at}dadlnet.dk

Abbreviations: AMPK, AMP-activated protein kinase; AS160, Akt substrate of 160 kDa; FDR, first-degree relative; GAP, GTPase-activating protein; IR, insulin receptor; IRS-1, insulin receptor substrate-1; NOGD, nonoxidative glucose disposal; PCOS, polycystic ovary syndrome; PI3K, phosphatidylinositol-3 kinase; PPAR, peroxisome proliferator–activated receptor; TZD, thiazolidinedione

OBJECTIVE— Insulin resistance in skeletal muscle is a major risk factor for type 2 diabetes in women with polycystic ovary syndrome (PCOS). However, the molecular mechanisms underlying skeletal muscle insulin resistance and the insulin-sensitizing effect of thiazolidinediones in PCOS in vivo are less well characterized.

RESEARCH DESIGN AND METHODS— We determined molecular mediators of insulin signaling to glucose transport in skeletal muscle biopsies of 24 PCOS patients and 14 matched control subjects metabolically characterized by euglycemic-hyperinsulinemic clamps and indirect calorimetry, and we examined the effect of 16 weeks of treatment with pioglitazone in PCOS patients.

RESULTS— Impaired insulin-mediated total (R_d) oxidative and nonoxidative glucose disposal (NOGD) was paralleled by reduced insulin-stimulated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation in muscle of PCOS patients. Akt phosphorylation at Ser473 and Thr308 correlated positively with R_d and NOGD in the insulin-stimulated state. Serum free testosterone was inversely related to insulin-stimulated R_d and NOGD in PCOS. Importantly, the pioglitazone-mediated improvement in insulin-stimulated glucose metabolism, which did not fully reach normal levels, was accompanied by normalization of insulin-mediated Akt phosphorylation at Ser473 and Thr308 and AS160 phosphorylation. AMPK activity and phosphorylation were similar in the two groups and did not respond to pioglitazone in PCOS patients.

CONCLUSIONS— Impaired insulin signaling through Akt and AS160 in part explains insulin resistance at the molecular level in skeletal muscle in PCOS, and the ability of pioglitazone to enhance insulin sensitivity involves improved signaling through Akt and AS160. Moreover, our data provide correlative evidence that hyperandrogenism in PCOS may contribute to insulin resistance.

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