Epidermal growth factor counteracts insulin-induced expression of glucokinase in hepatocytes

Hepatic glucokinase is induced by insulin and repressed by glucagon. The effects of epidermal growth factor (EGF) on glucokinase expression were investigated in rat hepatocytes. EGF does not affect the decline in glucokinase activity in hepatocytes cultured for 48h in the absence of insulin, but it counteracts the increase in activity induced by insulin. This effect of EGF is greater in cells cultured at low cell density than in confluent cultures. EGF suppressed the insulin-induced increase in glucokinase mRNA levels by 50% indicating that its effect is at least in part at a pretranslational level. However, it potentiated the stimulatory effect of insulin on glucose-6-phosphate dehydrogenase activity and mRNA, indicating that the effect on glucokinase expression is due to a specific post-receptor mechanism. The effect of EGF on glucokinase mRNA expression is mimicked by phospholipase D but not by phosphatidylinositol-specific phospholipase C or by phorbol ester, an activator of protein kinase C, suggesting that it is unlikely to be mediated by activation of protein kinase C.