The HIV protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle

In many patients with human immunodeficiency virus (HIV) treated with HIV p rotease inhibitors, a complication develops that resembles abdominal obesit y syndrome, with insulin resistance and glucose intolerance that, in some c ases, progresses to diabetes. In this study, we tested the hypothesis that indinavir, an HIV-protease inhibitor, directly induces insulin resistance o f glucose transport in skeletal muscle. Rat epitrochlearis muscles were inc ubated with a maximally effective insulin concentration (12 nmol/l) and 0, 1, 5, 20, or 40 mu mol/l indinavir for 4 h. In control muscles, insulin inc reased 3-O-[H-3]methyl-D-glucose (3MG) transport from 0.15 +/- 0.03 to 1.10 +/- 0.05 mu mol.ml(-1).10 min(-1). Incubation of muscles with 5 mu mol/l i ndinavir reduced the insulin-stimulated increase in 3MG transport by 40%, w hereas 20 mu mol/l indinavir reduced the insulin-stimulated increase in 3MG transport by 58%. Indinavir induced a similar reduction in maximally insul in-stimulated 3MG transport in the soleus muscle. The increase in glucose t ransport 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)b enzoyl-1,3-bis-[2-H-3] (D-mannose-4-yloxy)-2-propylamine exofacial photolab eling technique, was reduced by similar to 70% in the presence of 20 mu mol /l indinavir. Insulin stimulation of phosphatidylinositol 3-kinase activity and phosphorylation of protein kinase B were not decreased by indinavir. T hese results provide evidence that indinavir inhibits the translocation or intrinsic activity of GLUT4 rather than insulin signaling.