Details

Autor(en) / Beteiligte

• RUDICH, Assaf
• VANOUNOU, Sharon
• RIESENBERG, Klaris
• PORAT, Michal
• TIROSH, Amir
• HARMAN-BOEHM, Ilana
• GREENBERG, Andrew S
• SCHLAEFFER, Francise
• BASHAN, Nava

Titel

The HIV Protease Inhibitor Nelfinavir Induces Insulin Resistance and Increases Basal Lipolysis in 3T3-L1 Adipocytes

Ist Teil von

• Diabetes (New York, N.Y.), 2001-06, Vol.50 (6), p.1425-1431

Ort / Verlag

Alexandria, VA: American Diabetes Association

Erscheinungsjahr

2001

Quelle

MEDLINE

Beschreibungen/Notizen

• The HIV Protease Inhibitor Nelfinavir Induces Insulin Resistance and Increases Basal Lipolysis in 3T3-L1 Adipocytes Assaf Rudich 1 , Sharon Vanounou 2 , Klaris Riesenberg 5 , Michal Porat 2 , Amir Tirosh 2 , Ilana Harman-Boehm 3 6 , Andrew S. Greenberg 4 , Francisc Schlaeffer 5 and Nava Bashan 2 3 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 Abstract 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 (EC 50 = 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. Footnotes Address correspondence and reprint requests to Nava Bashan, PhD, Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, IL-84105, Israel. E-mail: nava{at}bgumail.bgu.ac.il . Received for publication 16 February 2001 and accepted 15 March 2001. A.R. and S.V. contributed equally to this work 2DG, 2-deoxyglucose; BSA, bovine serum albumin; DMEM, Dulbecco’s modified Eagle’s medium; FFA, free fatty acid; HAART, highly active anti-retroviral therapy; HPI, HIV protease inhibitor; HSL, hormone-sensitive lipase; IRS, insulin receptor substrate; KRPB, Krebs-Ringer phosphate buffer; PBS, phosphate-buffered saline; PKB, protein kinase B; RIA, radioimmunoassay; TNF, tumor necrosis factor; TZD, thiazolidinedione.