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Skeletal Muscle Insulin Signaling Defects Downstream of Phosphatidylinositol 3-Kinase at the Level of Akt Are Associated With Impaired Nonoxidative Glucose Disposal in HIV Lipodystrophy

¹ Department of Infectious Diseases, Hvidovre University Hospital, Hvidovre, Copenhagen
² Department of Endocrinology and Internal Medicine, Hvidovre University Hospital, Hvidovre, Copenhagen
³ Clinical Research Unit, Hvidovre University Hospital, Hvidovre, Copenhagen
⁴ Copenhagen Muscle Research Centre, Institute of Exercise and Sport Sciences, Department of Human Physiology, University of Copenhagen, Copenhagen, Denmark

More than 40% of HIV-infected patients on highly active antiretroviral therapy (HAART) experience fat redistribution (lipodystrophy), a syndrome associated with insulin resistance primarily affecting insulin-stimulated nonoxidative glucose metabolism (NOGM_ins). Skeletal muscle biopsies, obtained from 18 lipodystrophic nondiabetic patients (LIPO) and 18 nondiabetic patients without lipodystrophy (NONLIPO) before and during hyperinsulinemic (40 mU · m^–2 · min^–1)-euglycemic clamps, were analyzed for insulin signaling effectors. All patients were on HAART. Both LIPO and NONLIPO patients were normoglycemic (4.9 ± 0.1 and 4.8 ± 0.1 mmol/l, respectively); however, NOGM_ins was reduced by 49% in LIPO patients (P < 0.001). NOGM_ins correlated positively with insulin-stimulated glycogen synthase activity (I-form, P < 0.001, n = 36). Glycogen synthase activity (I-form) correlated inversely with phosphorylation of glycogen synthase sites 2+2a (P < 0.001, n = 36) and sites 3a+b (P < 0.001, n = 36) during clamp. Incremental glycogen synthase-kinase–3 and –3ß phosphorylation was attenuated in LIPO patients (Ps < 0.05). Insulin-stimulated Akt Ser473 and Akt Thr308 phosphorylation was decreased in LIPO patients (P < 0.05), whereas insulin receptor substrate-1–associated phosphatidylinositol (PI) 3-kinase activity increased significantly (P < 0.001) and similarly (NS) in both groups during clamp. Thus, low glycogen synthase activity explained impaired NOGM_ins in HIV lipodystrophy, and insulin signaling defects were downstream of PI 3-kinase at the level of Akt. These results suggest mechanisms for the insulin resistance greatly enhancing the risk of type 2 diabetes in HIV lipodystrophy.

Abbreviations: FFA, free fatty acid; FV, fractional velocity; G6P, glucose-6-phosphate; GDR, glucose disposal rate; GOX, glucose oxidation; HAART, highly active antiretroviral therapy; IRS-1, insulin receptor substrate-1; NOGM, nonoxidative glucose metabolism; NOGM_ins, insulin-stimulated nonoxidative glucose metabolism; PI, phosphatidylinositol; TBST, Tris-buffered saline with 1% Tween

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