AIMS/HYPOTHESIS: Patients treated with human immunodeficiency virus-1 protease inhibitors often develop impaired glucose tolerance or diabetes, most likely due to an induction of insulin resistance. We therefore investigated whether the protease inhibitor indinavir alters insulin signalling. METHODS: We incubated HepG2 cells for 48 h without or with indinavir (100 micromol/l). Subsequently 125I-insulin binding to the cells and the effects of insulin stimulation on insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-Thr308-phosphorylation were measured. RESULTS: In cells not exposed to indinavir, insulin (100 nmol/l) led to rapid increases of insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-phosphorylation during the first 75 s, followed by subsequent decreases. In indinavir-treated cells, these insulin-stimulated increases during the first 75 s were reduced by 30-60% and this was not associated with alterations in cell number or viability, insulin binding to the cells or cellular insulin-receptor substrate-1-content. CONCLUSION/ INTERPRETATION: Effects of indinavir on initial insulin signalling could cause, or contribute to, the metabolic effects of human immunodeficiency virus-1 protease inhibitors.
AIMS/HYPOTHESIS: Patients treated with human immunodeficiency virus-1 protease inhibitors often develop impaired glucose tolerance or diabetes, most likely due to an induction of insulin resistance. We therefore investigated whether the protease inhibitor indinavir alters insulin signalling. METHODS: We incubated HepG2 cells for 48 h without or with indinavir (100 micromol/l). Subsequently 125I-insulin binding to the cells and the effects of insulin stimulation on insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-Thr308-phosphorylation were measured. RESULTS: In cells not exposed to indinavir, insulin (100 nmol/l) led to rapid increases of insulin-receptor substrate-1-phosphorylation, association of phosphatidylinositol 3-kinase with insulin-receptor substrate-1 and Akt-phosphorylation during the first 75 s, followed by subsequent decreases. In indinavir-treated cells, these insulin-stimulated increases during the first 75 s were reduced by 30-60% and this was not associated with alterations in cell number or viability, insulin binding to the cells or cellular insulin-receptor substrate-1-content. CONCLUSION/ INTERPRETATION: Effects of indinavir on initial insulin signalling could cause, or contribute to, the metabolic effects of human immunodeficiency virus-1 protease inhibitors.
Authors: Mustafa A Noor; Tara Seneviratne; Francesca T Aweeka; Joan C Lo; Jean-Marc Schwarz; Kathleen Mulligan; Morris Schambelan; Carl Grunfeld Journal: AIDS Date: 2002-03-29 Impact factor: 4.177
Authors: Oliver P Flint; Mustafa A Noor; Paul W Hruz; Phil B Hylemon; Kevin Yarasheski; Donald P Kotler; Rex A Parker; Aouatef Bellamine Journal: Toxicol Pathol Date: 2009-01-26 Impact factor: 1.902