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Background:  Metabolic complications occur in as many as 40% of patients receiving highly active antiretroviral therapy (HAART) for HIV infection. The underlying metabolic alterations associated with HIV-related metabolic complications are poorly understood. We hypothesized that HIV- related metabolic complications subjects would have blunted insulin-mediated suppression of lipolysis and glucose production, and impaired insulin-stimulated glucose disposal.

Methods:  We evaluated lipid and glucose kinetics in 13 subjects with HIV-MC (body-fat redistribution assessed by DEXA, plasma triglyceride >250 mg/dL or impaired glucose tolerance) and 15 HIV-infected subjects without related metabolic complications (HIV-N), matched for body mass index (26±1 kg·m^-2 vs 26±1 kg·m^-2), during basal conditions and during a low (plasma insulin concentration ~35 µ/mL) and high dose (plasma insulin concentration ~80 µ/mL) euglycemic hyperinsulinemic clamp with infusion of stable isotope labeled tracers. One-way ANOVA was used for group comparisons.

Results:  In HIV-MC, all subjects were receiving HAART; 6 receiving protease inhibitors (PI). In HIV-N, 8 were naïve to therapy, 2 were receiving PI-based HAART, and 5 were receiving non-PI based HAART. Those with HIV-related metabolic complications had greater basal plasma triglycerides (446±45 mg/dL vs 118±16 mg/dL, p <0.01), glucose (97±1 mg/dL vs 92±1 mg/dL, p <0.01), and insulin (14±2 µ/mL vs 7±1 µ/mL, p <0.01) concentrations than HIV-N. At all insulin levels, whole-body lipolytic rates  (palmitate Ra; µmol·kgFFM^-1·min^-1) were greater in HIV-MC than HIV-N; basal (1.12±0.09  vs 0.86±0.07, p = 0.05), low (0.57±0.06  vs 0.27±0.02, p <0.01), and high insulin conditions (0.36±0.05 vs 0.20±0.01, p <0.01). Insulin-mediated suppression of lipolysis during low insulin was blunted in HIV-related metabolic complications vs HIV-N (-49±4% vs -67±3%, p <0.01). Glucose production rates (glucose Ra; µmol·kg FFM^-1·min^-1) were similar between groups (12.4±0.4 vs 12.4±0.5) during basal conditions, but during low dose insulin conditions, suppression of glucose production was blunted in HIV-related metabolic complications vs HIV-N (-62±4% vs -78±3%, p <0.01). Whole-body glucose disposal rates were markedly lower in HIV-related metabolic complications vs HIV-N (37±3 vs 60±5 µmol·kg FFM^-1·min^-1, p <0.01) during high insulin conditions.

Conclusions:  Patients with HIV-related metabolic complications have marked impairment in the ability of insulin to suppress lipolysis and glucose production, and to promote glucose disposal. Increased mobilization of lipid stores likely contributes to dyslipidemia and body fat redistribution seen in HIV infection.

Keywords: HIV-dyslipidemia; Insulin-resistance; Lipid kinetics