Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic β-cells

Abstract

Objectives: Lipodystrophy and insulin resistance are prevalent among human immunodeficiency virus (HIV)-infected patients on combined antiretroviral therapy (HAART). Aiming to provide a detailed description of the metabolic adverse effects of HIV-lipodystrophy, we investigated several aspects of glucose metabolism, lipid metabolism and b-cell function in lipodystrophic HIV-infected patients. Methods: [3-3 H]glucose was applied during euglycaemic hyperinsulinaemic clamps in association with indirect calorimetry in 43 normoglycaemic HIV-infected patients (18 lipodystrophic patients on HAART (LIPO), 18 patients without lipodystrophy on HAART (NONLIPO) and seven patients who were naïve to antiretroviral therapy (NAÏVE) respectively). b-cell function was evaluated by an intravenous glucose tolerance test. Results: Compared with NONLIPO and NAÏVE separately, LIPO displayed markedly reduced ratio of limb to trunk fat (RLF; . 34%, P , 0.001), hepatic insulin sensitivity (. 40%, P , 0.03), incremental glucose disposal (. 50%, P , 0.001) and incremental exogenous glucose storage (. 50%, P , 0.05). Furthermore, LIPO displayed reduced incremental glucose oxidation (P , 0.01), increased clamp free fatty acids (P , 0.05) and attenuated insulin-mediated suppression of lipid oxidation (P , 0.05) compared with NONLIPO. In combined study groups, RLF correlated with hepatic insulin sensitivity (r ¼ 0.69), incremental glucose disposal (r ¼ 0.71) and incremental exogenous glucose storage (r ¼ 0.40), all P , 0.01. Disposition index (i.e. first-phase insulin response to intravenous glucose multiplied by incremental glucose disposal) was reduced by 46% (P ¼ 0.05) in LIPO compared with the combined groups of NONLIPO and NAÏVE, indicating an impaired adaptation of b-cell function to insulin resistance in LIPO. Conclusion: Our data suggest that normoglycaemic lipodystrophic HIV-infected patients display impaired glucose and lipid metabolism in multiple pathways involving liver, muscle tissue and b-cell function.

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

“…Correlations between fat distribution versus glycogen synthase activity and effectors of insulin signaling. Fat redistribution as depicted by the ratio of limb fat to trunk fat may be more related to insulin resistance than trunk fat and limb fat masses, themselves (11,35). This relationship may also be reflected in insulin signaling.…”

“…The aim of the present study was therefore to elucidate possible aberration in insulin signaling during insulin stimulation in skeletal muscle biopsies obtained from a group of normoglycemic lipodystrophic HIV-infected patients, who displayed impaired insulin-stimulated nonoxidative glucose disposal (NOGM ins ) compared with that of their nonlipodystrophic counterparts (11). We hypothesize that the lipodystrophic patients would show defects in insulin activation of glycogen synthase, which is a key enzyme in the regulation of glycogen synthesis (18) and which has been found to be reduced in subjects with impaired nonoxidative glucose metabolism (NOGM) (19,20).…”

“…All patients were on HAART and of male sex. A description of selection, anthropometry, immunology, components of HAART, and glucose metabolism of all subjects has been presented (11,21). In brief, for case subjects, a questionnaire and a physical examination had to be positive for signs of lipodystrophy, whereas for control subjects, both the questionnaire and physical examination had to be negative.…”

“…The HIV-infected patients reported to our laboratory at 0800 after a 12-h overnight fast, including a 16-h withdrawal of HAART. A euglycemic-hyperinsulinemic clamp preceded by an intravenous glucose tolerance test was undertaken as described previously (11). In brief, a primed continuous infusion of [3-3 H]tritiated glucose (bolus, 2.05 Ci ⅐ mmol Ϫ1 ⅐ l Ϫ1 fasting plasma glucose; continuous, 0.11 Ci/min; New England Nuclear, Boston, MA) was initiated at 0900, at the start of a 150-min basal period (Ϫ150 to 0 min) and continued throughout the study, which included an intravenous glucose tolerance test (0 -30 min, 300 mg glucose/kg body wt, performed to characterize the first-phase insulin response [22]; data from the intravenous glucose tolerance test and a 120-min euglucemichyperinsulinemic clamp (30 -150 min) have been presented previously [11,21]).…”

“…NOGM was calculated as the difference between GDR and GOX. Plasma glucose, insulin, free fatty acids (FFAs), glycerol, triglyceride, total cholesterol, and HDL cholesterol were measured as described previously (11). Muscle biopsies were obtained from the vastus lateralis muscle immediately after both steady-state periods using a modified Bergströ m needle with suction under local anesthesia (glucose clamp was continued during sampling of the insulin-stimulated muscle biopsy).…”