Insulin sensitivity is preserved despite disrupted endothelial function

• Published in: American journal of physiology: endocrinology and metabolism 2006-10, Vol.291 (4), p.E691-E696
• Main Authors: Shankar, Sudha S, Considine, Robert V, Gorski, J. Christopher, Steinberg, Helmut O
• Format: Article
• Language: English
• Subjects: Adipose Tissue - drug effects; Adipose Tissue - metabolism; Adult; Blood Flow Velocity - physiology; Blood Pressure - drug effects; Endothelium, Vascular - drug effects; Endothelium, Vascular - physiology; Female; Femoral Artery - physiology; Glucose - metabolism; Glucose Clamp Technique; Heart Rate - drug effects; HIV Protease Inhibitors - blood; HIV Protease Inhibitors - pharmacology; Human immunodeficiency virus; Humans; Indinavir - blood; Indinavir - pharmacology; Insulin Resistance - physiology; Lipids - blood; Male; Middle Aged; Muscle, Skeletal - drug effects; Muscle, Skeletal - metabolism; Vasodilation - drug effects; Vasodilation - physiology; Vasodilator Agents - pharmacology
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00006.2006

Divisions of 1 Endocrinology and 2 Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana Submitted 5 January 2006 ; accepted in final form 8 May 2006 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 mg·kg –1 ·min –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. endothelium; protease inhibitor; vascular function; glucose disposal Address for reprint requests and other correspondence: H. O. Steinberg, Indiana Univ. School of Medicine, 975 W. Walnut, IB 424 D, Indianapolis, IN 46202 (e-mail: hsteinbe{at}iupui.edu )