The Mechanism of Insulin Resistance Caused by HIV Protease Inhibitor Therapy*
By H. Murata, P. Hruz, M. Mueckler. Journal of Biological Chemistry, 2000
595 citations recorded by the source corpus.
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 inXenopus laevis oocytes. Indinavir at 100 μmhad no effect on Glut1 transport activity in Xenopusoocytes, 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.
Subfields: Emergency Medicine, Infectious Diseases, Virology
View Paper: https://www.semanticscholar.org/paper/b054e0c824d0877225cdabcf8576b424289ee62f
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Citations in the corpus
- Antiretroviral therapy and the prevalence and incidence of diabetes mellitus in the multicenter AIDS cohort study. (2005, background): “In vitro evidence suggests that ritonavir is associated with both the development of insulin resistance(19) and impaired -cell function.(20) In clinical studies and in healthy volunteers, administration of ritonavir-containing regimens has been linked to worse glucose homeostasis.”
- Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. (2001, background): “Possible mechanisms include the following: direct metabolic effects of antiretroviral therapies [34, 35]; metabolic dysfunction secondary to HIV disease itself, related cytokine and hormonal abnormalities, or both; an interaction between effects of antiviral therapy; and HIV disease.”
- The SLC2 (GLUT) Family of Membrane Transporters (2013, unknown): “GLUT4 is a specific target of HIV protease inhibitors that are essential components of combination drug therapy used to treat HIV infection (Murata et al., 2000).”