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Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but has no effect on Endogenous Glucose Production in HIV Lipodystrophy.

¹Centre of Inflammation and Metabolism at the Department of Infectious Diseases
²The Copenhagen Muscle Research Centre, Rigshospitalet
³The Copenhagen Muscle Research Centre, Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen
⁴Department of Biostatistics, University of Copenhagen, Denmark
⁵Washington University, School of Medicine, St. Louis, Missouri, USA

Correspondence: blm{at}rh.dk

Key Words: insulin resistance • free fatty acids • lipodystrophy • HIV • glycogen synthesis

Objective:HIV-infected patients with lipodystrophy (HIV-lipodystrophy) are insulin resistant and have elevated plasma free fatty acid (FFA) concentrations. We aimed to explore the mechanisms underlying FFA-induced insulin resistance in patients with HIV-lipodystrophy.

Research Design and Methods:Using a randomized placebo-controlled cross-over design, we studied the effects of an overnight acipimox-induced suppression of FFA on glucose and FFA metabolism by using stable isotope labelled tracer techniques during basal conditions and a two-stage euglycemic, hyperinsulinemic clamp (20 mU insulin/m²/min; 50 mU insulin/m²/min) in nine patients with nondiabetic HIV-lipodystrophy. All patients received antiretroviral therapy. Biopsies from the vastus lateralis muscle were obtained during each stage of the clamp.

Results:Acipimox treatment reduced basal FFA rate of appearance by 68.9% (52.6%-79.5%) and decreased plasma FFA concentration by 51.6 % (42.0%-58.9%), (both, P < 0.0001). Endogenous glucose production was not influenced by acipimox. During the clamp the increase in glucose-uptake was significantly greater after acipimox treatment compared to placebo (acipimox: 26.85 (18.09-39.86) vs placebo: 20.30 (13.67-30.13) µmol/kg/min; P < 0.01). Insulin increased phosphorylation of Akt (Thr³⁰⁸) and GSK-3ß (Ser⁹), decreased phosphorylation of glycogen synthase (GS) site 3a+b and increased GS-activity (I-form) in skeletal muscle (P < 0.01). Acipimox decreased phosphorylation of GS (site 3a+b) (P < 0.02) and increased GS-activity (P < 0.01) in muscle.

Conclusion:The present study provides direct evidence that suppression of lipolysis in patients with HIV-lipodystrophy improves insulin-stimulated peripheral glucose-uptake. The increased glucose-uptake may in part be explained by increased dephosphorylation of GS (site 3a+b) resulting in increased GS activity.

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