Abstract
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 micrometer 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 microm 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.
Highlights
From the ‡Department of Cell Biology and Physiology, ¶Department of Pediatrics, Washington University School of Medicine, St
We demonstrate that the human immunodeficiency virus (HIV) protease inhibitor, indinavir, dramatically inhibits insulin-stimulated glucose uptake in 3T3-L1 adipocytes in a dose-dependent manner (63% inhibition observed with 100 M indinavir)
We initially examined the effect of the HIV-1 protease inhibitor indinavir on glucose uptake in 3T3-L1 adipocytes, a system that responds robustly to insulin
Summary
From the ‡Department of Cell Biology and Physiology, ¶Department of Pediatrics, Washington University School of Medicine, St. 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. Insulin signaling impinges on intracellular Glut vesicles, causing their rapid exocytosis and fusion with the plasma membrane [9, 13, 14] This phenomenon, known as Glut translocation, can account for most of the increase in cellular glucose uptake capacity stimulated by insulin in fat [24, 25] and muscle [26]. We demonstrate here that HIV protease inhibitors selectively and potently decrease the intrinsic transport activity of the insulin-regulated glucose transporter isoform Glut without substantially affecting early insulin signaling events or Glut translocation.
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