Metformin modulates insulin receptor signaling in normal and cholesterol-treated human hepatoma cells (HepG2)

The effects of the biguanide anti-hyperglycemic agent, metfornin (N,N'-dime thyl-biguanide), on insulin signaling was studied in a human hepatoma cell. line (HepG2). Cells were cultured in the absence (control cells) or in the presence of 100 mu M of a cholesterol derivative, hemisuccinate of cholest erol. Cholesterol hemisuccinate-treatment alters cholesterol and lipid cont ent of HepG2 and modulates membrane fluidity. Cholesterol hemisuccinate-tre atment induces a decrease in insulin responsiveness and creates an "insulin -resistant' state in these cells. Exposure to 100 mu M of metformin resulte d in a significant enhancement of insulin-stimulated lipogenesis in control and cholesterol hemisuccinate-treated cells. In control cells, metformin a ltered glycogenesis in a biphasic manner. In cholesterol hemisuccinate-trea ted cells, metformin inhibited basal glycogenesis but restored insulin-stim ulated glycogenesis. Hence, to understand the mechanism of metformin action , we analyzed early steps in the insulin signaling pathway, including insul in receptor autophosphorylation, mitogen-activated-protein kinase and phosp hatidylinositol 3-kinase activities, in both control and cholesterol hemisu ccinate-treated cells. Overall, the results suggest that metformin may inte ract with the insulin receptor and/or a component involved in the early ste ps of insulin signal transduction. (C) 1999 Elsevier Science B.V. All right s reserved.