The mechanism of insulin resistance caused by HIV protease inhibitor therapy.
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.
Murata
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Department of Cell Biology and Physiology, Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Hruz
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PW
Mueckler
M
M
D016475:3T3 Cells; D017667:Adipocytes; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003847:Deoxyglucose / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000201:enzymology*; D006801:Humans; D019469:Indinavir / Q000494:pharmacology; D007333:Insulin Resistance; D051379:Mice; D008856:Microscopy, Fluorescence; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D009865:Oocytes / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014982:Xenopus laevis
D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D017320:HIV Protease Inhibitors; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; C495677:SLC2A1 protein, human; C495692:SLC2A4 protein, human; C495678:Slc2a1 protein, mouse; C495693:Slc2a4 protein, mouse; D019469:Indinavir; D003847:Deoxyglucose