5-Aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase

Insulin regulates the rate of expression of many hepatic genes, including P EPCK, glucose-6-phosphatase (G6Pase), and glucose-6-phosphate dehydrogenase (G6PDHase). The expression of these genes is also abnormally regulated in type 2 diabetes. We demonstrate here that treatment of hepatoma cells with 5-aminoimidazole-4-carboxamide riboside (AICAR), an agent that activates AM P-activated protein kinase (AMPK), mimics the ability of insulin to repress PEPCK gene transcription. It also partially represses G6Pase gene transcri ption and yet has no effect on the expression of G6PDHase or the constituti vely expressed genes cyclophilin or beta-actin. Several lines of evidence s uggest that the insulin-mimetic effects of AICAR are mediated by activation of AMPK. Also, insulin does not activate AMPK in H4IIE cells, suggesting t hat: this protein kinase does not link the insulin receptor to the PEPCK an d G6Pase gene promoters. Instead, AMPK and insulin may lie on distinct path ways that converge at a point upstream of these 2 gene promoters. Investiga tion of the pathway by which AMPK acts may therefore give insight into the mechanism of action of insulin. Our results also suggest that activation of AMPK would inhibit hepatic gluconeogenesis in an insulin-independent manne r and thus help to reverse the hyperglycemia associated with type 2 diabete s.