Role of AMP-activated protein kinase in mechanism of metformin action

Metformin is a widely used drug for treatment of type 2 diabetes with no de fined cellular mechanism of action. Its glucose-lowering effect results fro m decreased hepatic glucose production and increased glucose utilization. M etformin's beneficial effects on circulating lipids have been linked to red uced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular r egulator of lipid and glucose metabolism. Here we report that metformin act ivates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activ ity, is reduced, fatty acid oxidation is induced, and expression of lipogen ic enzymes is suppressed. Activation of AMPK by metformin or an adenosine a nalogue suppresses expression of SREBP-1, a key lipogenic transcription fac tor. In metformin-treated rats, hepatic expression of SREBP-1 (and other li pogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using, a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepa tocytes. In isolated rat skeletal muscles, metformin stimulates glucose upt ake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these resu lts also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.