Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2

• DOI: 10.1210/jc.2002-021394
• Publication Date: 2003-03-11T02:02:44Z
• Authors: Jenny E. Gunton; Patric J. D. Delh...; Shin-Ichiro Takah...; Robert C. Baxter
• Keywords: Insulin receptor substrate

Metformin decreases endogenous glucose production by the liver. Few studies have examined effect of metformin on insulin-signaling pathway in liver models, and none presented data normal human Huh7 hepatoma cells primary hepatocytes were used. Insulin receptor (IR) IR substrates (IRS)-1 -2 assessed immunoprecipitation immunoblot. Normal was used to assay kinase activity (IR-KA). Tyrphostin AG1024 inhibit IR-KA examine effects deoxyglucose uptake. (1 micro g/ml) increased tyrosine phosphorylation 78% (P = 0.0007) 30 min IRS-2 but not IRS-1 activation, downstream increase uptake mediated via translocation GLUT-1 plasma membrane. did augment maximal or submaximal insulin-stimulated activation. basal 150% 0.0001). inhibited metformin-induced IR-beta a concentration-dependent manner abolished 2-deoxyglucose This study demonstrates that mechanism action involves followed selective translocation. The completely blocked an inhibitor.