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J. Biol. Chem., Vol. 275, Issue 27, 20251-20254, July 7, 2000
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From the 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.
ACCELERATED PUBLICATION
The Mechanism of Insulin Resistance Caused by HIV Protease
Inhibitor Therapy*
§,§¶, and
Department of Cell Biology and Physiology,
¶ Department of Pediatrics, Washington University School of
Medicine, St. Louis, Missouri 63110
*
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.
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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 Insulin Resistance in HIV Lipodystro |
