Shankar Sudha S, Considine Robert V, Gorski J Christopher, Steinberg Helmut O
Division of Endocrinology, Department of Medicine, Indiana University School of Medicine, 975 W. Walnut, IB 424 D, Indianapolis, IN 46202, USA.
Am J Physiol Endocrinol Metab. 2006 Oct;291(4):E691-6. doi: 10.1152/ajpendo.00006.2006. Epub 2006 May 16.
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.
内皮功能障碍与胰岛素抵抗密切相关，这一点已得到充分证实。然而，尚不清楚内皮功能障碍本身是否足以损害胰岛素介导的葡萄糖摄取。我们之前报道过，向HIV阴性受试者施用4周的人类免疫缺陷病毒（HIV）-1蛋白酶抑制剂茚地那韦会导致内皮功能障碍。因此，我们推测茚地那韦诱导的内皮功能障碍与胰岛素介导的葡萄糖处理受损有关。我们通过对另一组HIV阴性健康非肥胖受试者（n = 13）在每日口服茚地那韦4周前后进行高胰岛素正常血糖钳夹和血管功能研究，来测量全身、骨骼肌和脉管系统水平上胰岛素介导的葡萄糖处理情况。茚地那韦治疗4周导致内皮依赖性血管舒张降低了113 +/- 29%（P < 0.01），这与我们之前的研究结果一致。此外，胰岛素介导的血管舒张也有显著受损（茚地那韦治疗前为101 +/- 14%，治疗后为35 +/- 15%；P < 0.05）。然而，全身水平（茚地那韦治疗前为8.9 +/- 0.5，治疗后为8.5 +/- 0.6 mg·kg(-1)·min(-1)；P = 0.4）或骨骼肌中胰岛素介导的葡萄糖处理没有显著变化。此外，在另一组4名HIV阴性健康非肥胖受试者中，我们发现茚地那韦治疗4周对脂肪组织中胰岛素刺激的葡萄糖摄取没有持续影响。因此，我们的研究结果表明：1）单独的内皮功能障碍不足以损害胰岛素介导的葡萄糖处理；2）茚地那韦诱导的内皮功能障碍可能是由于该药物对内皮的直接作用，而不是与胰岛素抵抗的诱导相关。
