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BackgroundWe have shown that the HIV-1 protease inhibitor indinavir (IDV) impairs endothelial function. Insulin resistance has been known to be associated with endothelial dysfunction.HypothesisWe hypothesized that 1) indinavir-induced endothelial dysfunction is a result of insulin resistance, and that 2) the insulin resistance is due to impaired Glut4 activity in skeletal muscle.MethodsTowards testing our hypothesis, we assessed insulin sensitivity, as well as insulin-mediated vasodilation in a group of 14 lean healthy HIV-negative male subjects before and after four weeks of daily oral indinavir at 800 mg three times a day. We measured insulin sensitivity using the euglycemic hyperinsulinemic clamp technique. We assessed insulin-mediated vasodilation by measuring changes in leg blood flow (LBF) at steady-state of the clamp. We also measured arteriovenous glucose difference (AVGΔ in our subjects at steady-state, and calculated glucose extraction as a measure of skeletal muscle insulin sensitivity using the formula LGU = AVGΔ × LBF. Results were analyzed using a paired t-test, and are expressed as mean ± SEM, post-indinavir versus pre-indinavir.ResultsOur subjects showed no change in weight, waist-to-hip ratio, systolic and diastolic blood pressure, as well as total, LDL and HDL cholesterol and triglycerides after indinavir. Our subjects had normal, robust insulin-mediated vasodilatory responses before indinavir. The same subjects showed a significant blunting of insulin-mediated vasodilation (16 ± 6% post-indinavir vs 70 ± 10% pre-indinavir; p<0.05) after indinavir. There was no change in the steady-state whole body glucose-disposal rate after indinavir (7.5 ± 0.6 mg/kg/min vs 8.0 ± 0.6 mg/kg/min), at comparable steady-state plasma glucose levels. AVGΔ at steady-state was higher after indinavir (31 ± 5 vs 26 ± 4 mg%; p = 0.05). However rates of LGU did not differ (85 ± 2 mg/min vs 91 ± 1 mg/min; p = ns).SummaryThus, in vivo, in healthy subjects, four weeks of indinavir 1) impairs insulin-mediated vasodilation, 2) does not impair whole body glucose disposal, 3) does not impair glucose extraction (Glut 4 transport activity) at the level of the skeletal muscle.ConclusionsThus, in this model of indinavir-induced endothelial dysfunction, there is an uncoupling of endothelial function and insulin sensitivity. Further studies need to be performed to better elucidate the mechanisms underlying the uncoupling.

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