Nolte L A, Yarasheski K E, Kawanaka K, Fisher J, Le N, Holloszy J O
Department of Internal Medicine, Washington University School of Medicine, 4566 Scott Ave., St. Louis, MO 63110, USA.
Diabetes. 2001 Jun;50(6):1397-401. doi: 10.2337/diabetes.50.6.1397.
In many patients with human immunodeficiency virus (HIV) treated with HIV protease inhibitors, a complication develops that resembles abdominal obesity syndrome, with insulin resistance and glucose intolerance that, in some cases, progresses to diabetes. In this study, we tested the hypothesis that indinavir, an HIV-protease inhibitor, directly induces insulin resistance of glucose transport in skeletal muscle. Rat epitrochlearis muscles were incubated with a maximally effective insulin concentration (12 nmol/l) and 0, 1, 5, 20, or 40 micromol/l indinavir for 4 h. In control muscles, insulin increased 3-O-[(3)H]methyl-D-glucose (3MG) transport from 0.15 +/- 0.03 to 1.10 +/- 0.05 micromol. ml(-)(1). 10 min(-)(1). Incubation of muscles with 5 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 40%, whereas 20 micromol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 58%. Indinavir induced a similar reduction in maximally insulin-stimulated 3MG transport in the soleus muscle. The increase in glucose transport activity induced by stimulating epitrochlearis muscles to contract was also markedly reduced by indinavir. The insulin-stimulated increase in cell-surface GLUT4, assessed using the 2-N-4-(1-azi-2,2,2-trifluoroethyl)benzoyl-1,3-bis-[2-(3)H] (D-mannose-4-yloxy)-2-propylamine exofacial photolabeling technique, was reduced by approximately 70% in the presence of 20 micromol/l indinavir. Insulin stimulation of phosphatidylinositol 3-kinase activity and phosphorylation of protein kinase B were not decreased by indinavir. These results provide evidence that indinavir inhibits the translocation or intrinsic activity of GLUT4 rather than insulin signaling.
在许多接受HIV蛋白酶抑制剂治疗的人类免疫缺陷病毒（HIV）患者中，会出现一种类似于腹部肥胖综合征的并发症，伴有胰岛素抵抗和葡萄糖不耐受，在某些情况下会发展为糖尿病。在本研究中，我们检验了以下假设：HIV蛋白酶抑制剂茚地那韦直接诱导骨骼肌中葡萄糖转运的胰岛素抵抗。将大鼠肱三头肌与最大有效胰岛素浓度（12 nmol/l）以及0、1、5、20或40 μmol/l茚地那韦一起孵育4小时。在对照肌肉中，胰岛素使3-O-[(3)H]甲基-D-葡萄糖（3MG）转运从0.15±0.03增加到1.10±0.05 μmol·ml⁻¹·10 min⁻¹。肌肉与5 μmol/l茚地那韦孵育使胰岛素刺激的3MG转运增加减少了40%，而20 μmol/l茚地那韦使胰岛素刺激的3MG转运增加减少了58%。茚地那韦在比目鱼肌中对最大胰岛素刺激的3MG转运也产生了类似的降低作用。刺激肱三头肌收缩所诱导的葡萄糖转运活性增加也被茚地那韦显著降低。使用2-N-4-(1-叠氮-2,2,2-三氟乙基)苯甲酰基-1,3-双-[2-(3)H]（D-甘露糖-4-氧基）-2-丙胺外表面光标记技术评估，在存在20 μmol/l茚地那韦的情况下，胰岛素刺激的细胞表面葡萄糖转运蛋白4（GLUT4）增加减少了约70%。茚地那韦并未降低胰岛素对磷脂酰肌醇3激酶活性的刺激以及蛋白激酶B的磷酸化。这些结果提供了证据表明茚地那韦抑制GLUT4的转位或内在活性而非胰岛素信号传导。
