title: 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.
abstract: 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-3alpha and -3beta 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.
authors.affiliation: Department of Infectious Diseases, Clinical Research Unit 136, Hvidovre University Hospital, DK 2650 Hvidovre, Copenhagen, Denmark. sbhau@dadlnet.dk
authors.forename: Steen B
authors.initials: SB
authors.lastname: Haugaard
authors.forename: Ove
authors.initials: O
authors.lastname: Andersen
authors.forename: Sten
authors.initials: S
authors.lastname: Madsbad
authors.forename: Christian
authors.initials: C
authors.lastname: Frøsig
authors.forename: Johan
authors.initials: J
authors.lastname: Iversen
authors.forename: Jens Ole
authors.initials: JO
authors.lastname: Nielsen
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000188:drug therapy / Q000201:enzymology / Q000503:physiopathology; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D002784:Cholesterol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D006006:Glycogen Synthase / Q000378:metabolism; D039682:HIV-Associated Lipodystrophy Syndrome / Q000097:blood / Q000201:enzymology / Q000503:physiopathology*; D006801:Humans; D007328:Insulin / Q000502:physiology*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000201:enzymology / Q000503:physiopathology; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012367:RNA, Viral / Q000302:isolation & purification; D015398:Signal Transduction / Q000502:physiology; D014280:Triglycerides / Q000097:blood; D019562:Viral Load
chemical_list: D005230:Fatty Acids, Nonesterified; D007328:Insulin; D012367:RNA, Viral; D014280:Triglycerides; D002784:Cholesterol; D006006:Glycogen Synthase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose