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© 2001 by the American Diabetes Association, Inc.
The HIV Protease Inhibitor Nelfinavir Induces Insulin Resistance and Increases Basal Lipolysis in 3T3-L1 Adipocytes
1 S. Daniel Abraham Center for Health and Nutrition, the
2 Department of Clinical Biochemistry, and the
3 Leslie and Susan Gonda (Goldschmied) Laboratory for Multi-Disciplinary Diabetes Research, Ben-Gurion University of the Negev, Beer-Sheva, Israel
4 Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
5 Infectious Disease Unit and the
6 Diabetes Unit, Soroka Medical Center, Beer-Sheva, Israel
HIV protease inhibitors (HPIs) are potent antiretroviral agents clinically used in the management of HIV infection. Recently, HPI therapy has been linked to the development of a metabolic syndrome in which adipocyte insulin resistance appears to play a major role. In this study, we assessed the effect of nelfinavir on glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. An 18-h exposure to nelfinavir resulted in an impaired insulin-stimulated glucose uptake and activation of basal lipolysis. Impaired insulin stimulation of glucose up take occurred at nelfinavir concentrations >10 µmol/l (EC50 = 20 µmol/l) and could be attributed to impaired GLUT4 translocation. Basal glycerol and free fatty acid (FFA) release were significantly enhanced with as low as 5 µmol/l nelfinavir, displaying fivefold stimulation of FFA release at 10 µmol/l. Yet, the antilipolytic action of insulin was preserved at this concentration. Potential underlying mechanisms for these metabolic effects included both impaired insulin stimulation of protein kinase B Ser 473 phosphorylation with preserved insulin receptor substrate tyrosine phosphorylation and decreased expression of the lipolysis regulator perilipin. Troglitazone pre- and cotreatment with nelfinavir partly protected the cells from the increase in basal lipoysis, but it had no effect on the impairment in insulin-stimulated glucose uptake induced by this HPI. This study demonstrates that nelfinavir induces insulin resistance and activates basal lipolysis in differentiated 3T3-L1 adipocytes, providing potential cellular mechanisms that may contribute to altered adipocyte metabolism in treated HIV patients.
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