Inhibition of Lipolysis Stimulates Peripheral Glucose Uptake but Has No Effect on Endogenous Glucose Production in HIV Lipodystrophy

Abstract

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. Using a randomized, placebo-controlled, cross-over design, we studied the effects of an overnight acipimox-induced suppression of FFAs on glucose and FFA metabolism by using stable isotopelabeled tracer techniques during basal conditions and a two-stage euglycemic-hyperinsulinemic clamp (20 and 50 mU insulin/m 2 per min, respectively) 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. Acipimox treatment reduced basal FFA rate of appearance by 68.9% (95% CI 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 with placebo (acipimox: 26. 85 , decreased phosphorylation of glycogen synthase (GS) site 3a ؉ b, and increased GS activity (percent 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. 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.

Metabolic complications and selected cytokines in HIV‑infected individuals

“…24 An increased serum FFA concentration is related to the degree of insulin resistance, as FFAs have been proposed to induce skeletal muscle insulin resistance. 17,25 Our results confirm the observation that HIV itself induces lipid metabolic changes, which makes patients more vulnerable to the side effects of ARV.…”

Acipimox reduces circulating levels of insulin and associated neutrophilic inflammation in metabolic syndrome

“…On the other hand, neutrophil infiltration within atherosclerotic plaques has also been shown to be strongly associated with plaque vulnerability in humans (8,16). Our research approach was further supported by the recent discovery of the potential "pleiotropic" activities of acipimox through the binding with its receptor GPR109 (12,30,34). High levels of recombinant insulin have previously been shown to induce neutrophil recruitment toward the proinflammatory CC chemokine CCL3 that is expressed in atherosclerotic plaques (14,16).…”

The second-meal phenomenon is associated with enhanced muscle glycogen storage in humans

“…Conversely, prolonged pharmacological suppression of plasma NEFAs with the nicotinic acid analogue acipimox improves insulin action in patients with Type 2 diabetes mellitus by increasing non-oxidative glucose disposal, with skeletal muscle biopsies showing an increase in glycogen concentration [26][27][28]. In patients with HIV lipodystrophy, overnight suppression of NEFAs increased glucose uptake and muscle glycogen synthase activity during euglycaemichyperinsulinaemic clamp [29]. One study of oral glucose administration has examined the effect of NEFA suppression and this was observed to improve glucose tolerance and muscle glucose uptake [30].…”