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Diabetes 50:1397-1401, 2001
© 2001 by the American Diabetes Association, Inc.

The HIV Protease Inhibitor Indinavir Decreases Insulin- and Contraction-Stimulated Glucose Transport in Skeletal Muscle

Lorraine A. Nolte, Kevin E. Yarasheski, Kentaro Kawanaka, Jonathan Fisher, Ngan Le, and John O. Holloszy

Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri

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 µmol/l indinavir for 4 h. In control muscles, insulin increased 3-O-[3H]methyl-D-glucose (3MG) transport from 0.15 ± 0.03 to 1.10 ± 0.05 µmol · ml-1 · 10 min-1. Incubation of muscles with 5 µmol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 40%, whereas 20 µmol/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-[2-3H] (D-mannose-4-yloxy)-2-propylamine exofacial photolabeling technique, was reduced by ~70% in the presence of 20 µmol/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.


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