title: Insulin sensitivity is preserved despite disrupted endothelial function.
abstract: It is well established that endothelial dysfunction and insulin resistance go hand in hand. However, it is unclear whether endothelial dysfunction per se is sufficient to impair insulin-mediated glucose uptake. We have previously reported that 4 wk of administration of the human immunodeficiency virus (HIV)-1 protease inhibitor indinavir to HIV-negative subjects induces endothelial dysfunction. Hence, we hypothesized that indinavir-induced endothelial dysfunction was associated with impaired insulin-mediated glucose disposal. We measured insulin-mediated glucose disposal at the level of the whole body, skeletal muscle, and vasculature by performing hyperinsulinemic euglycemic clamp, and vascular function studies, in a separate group of HIV-negative healthy nonobese subjects (n = 13) before and after 4 wk of daily oral indinavir. Four weeks of indinavir resulted in a 113 +/- 29% (P < 0.01) reduction of endothelium-dependent vasodilation, consistent with our earlier findings. In addition, there was a significant impairment of insulin-mediated vasodilation (101 +/- 14% before indinavir vs. 35 +/- 15% after indinavir; P < 0.05). However, there was no significant change in insulin-mediated glucose disposal at the level of the whole body (8.9 +/- 0.5 before indinavir vs. 8.5 +/- 0.6 mgxkg(-1)xmin(-1) after indinavir; P = 0.4), or skeletal muscle. Furthermore, in a separate group of four HIV-negative healthy nonobese subjects, we found that 4 wk of indinavir has no sustained effect on insulin-stimulated glucose uptake in adipose tissue. Thus our findings indicate that 1) endothelial dysfunction alone is insufficient to impair insulin-mediated glucose disposal, and 2) indinavir-induced endothelial dysfunction is likely due to a direct effect of the drug on the endothelium and is not coupled to the induction of insulin resistance.
authors.affiliation: Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 975 W. Walnut, IB 424 D, Indianapolis, IN 46202, USA.
authors.forename: Sudha S
authors.initials: SS
authors.lastname: Shankar
authors.forename: Robert V
authors.initials: RV
authors.lastname: Considine
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Gorski
authors.forename: Helmut O
authors.initials: HO
authors.lastname: Steinberg
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000378:metabolism; D000328:Adult; D001783:Blood Flow Velocity / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D005260:Female; D005263:Femoral Artery / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D017320:HIV Protease Inhibitors / Q000097:blood / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D019469:Indinavir / Q000097:blood / Q000494:pharmacology*; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D017320:HIV Protease Inhibitors; D008055:Lipids; D014665:Vasodilator Agents; D019469:Indinavir; D005947:Glucose