Insulin sensitivity is preserved despite disrupted endothelial function.
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.
Shankar
Sudha S
SS
Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 975 W. Walnut, IB 424 D, Indianapolis, IN 46202, USA.
Considine
Robert V
RV
Gorski
J Christopher
JC
Steinberg
Helmut O
HO
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
D017320:HIV Protease Inhibitors; D008055:Lipids; D014665:Vasodilator Agents; D019469:Indinavir; D005947:Glucose