The HIV protease inhibitor indinavir impairs glycogen synthesis in HepG2 hepatoma cells.
HIV protease inhibitor treatment is associated with insulin resistance. We have recently demonstrated that the HIV protease inhibitor indinavir influences initial insulin signaling steps in HepG2 cells. Here we investigated in the same cell model whether indinavir alters insulin-stimulated glycogen synthesis. Since an altered phosphotyrosine phosphatase activity could represent a mechanism by which insulin signaling is influenced, we also assessed potential indinavir effects on protein tyrosine phosphatase activity directed against tyrosine phosphorylated insulin receptor substrate-1. HepG2 cells were incubated for 48 h without or with indinavir (100 micro mol/l). Subsequently, the insulin-stimulated incorporation of 14C-glucose into glycogen was measured. In indinavir-treated cells the insulin effect on glycogen synthesis was reduced by 30 +/- 4.5 %. Dephosphorylation of immobilized tyrosine-phosphorylated insulin-receptor substrate-1 by the cell extracts was determined using a microwell plate-based method, and indinavir treatment did not alter this dephosphorylation. In conclusion, our data suggest that indinavir affects insulin-stimulation of glycogen synthesis in liver cells, and this may be related to the previously observed alterations in insulin signaling. Direct effects of indinavir on the GLUT4 transport system, that have been suggested from data in other cell systems, are unlikely in HepG2 cells that express no or almost no GLUT4 transport system. Finally, our data do not support the hypothesis that indinavir alters insulin signaling by influencing protein tyrosine phosphatase activity directed against insulin receptor substrate-1.
Schütt
M
M
Department of Internal Medicine I, University of Lübeck, Germany. morten.schuett@web.de
Meier
M
M
Jost
M M
MM
Klein
H H
HH
D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000096:biosynthesis*; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology; D019469:Indinavir / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008113:Liver Neoplasms / Q000201:enzymology / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D013268:Stimulation, Chemical; D014407:Tumor Cells, Cultured
D017320:HIV Protease Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D019469:Indinavir; D006003:Glycogen; D017027:Protein Tyrosine Phosphatases; D005947:Glucose