ACCELERATED PUBLICATION
The Mechanism of Insulin Resistance Caused by HIV Protease Inhibitor Therapy^*

Haruhiko Murata^§, Paul W. Hruz^§¶, and Mike Mueckler

From the  Department of Cell Biology and Physiology, ^¶ Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110

Retroviral protease inhibitors used as therapy for HIV-1 infection have been causally associated with serious metabolic side effects, including peripheral lipodystrophy, hyperlipidemia, insulin resistance, and in some cases, overt type 2 diabetes. The etiology of this characteristic clinical syndrome remains unknown. We demonstrate that the HIV protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner (63% inhibition observed with 100 µM indinavir). Indinavir treatment did not affect early insulin signaling events or the translocation of intracellular Glut1 or Glut4 glucose transporters to the cell surface. To determine whether indinavir may be directly affecting the intrinsic transport activity of glucose transporters, the Glut1 and Glut4 isoforms were heterologously expressed and analyzed in Xenopus laevis oocytes. Indinavir at 100 µM had no effect on Glut1 transport activity in Xenopus oocytes, whereas Glut4 activity was significantly inhibited (45% inhibition). Similar effects on glucose transport were observed for other HIV protease inhibitors. We conclude that HIV protease inhibitors as a class are capable of selectively inhibiting the transport function of Glut4 and that this effect may be responsible for a major iatrogenic complication frequently observed in HIV patients.

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^* This work was supported in part by National Institutes of Health Grant DK38495 and by the Diabetes Training and Research Center at Washington University School of Medicine.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ These authors contributed equally to this work.

To whom all correspondence should be addressed: Dept. of Cell Biology and Physiology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-4160; Fax: 314-362-7463; E-mail: mike@cellbio.wustl.edu.

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Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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