Background We have shown that the HIV-1 protease inhibitor indinavir (IDV) impairs endothelial function. Insulin resistance has been known to be associated with endothelial dysfunction.
Hypothesis We 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.
Methods Towards 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.
Results Our 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).
Summary Thus, 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.
Conclusions Thus, 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.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.