Low concentrations of metformin suppress glucose production in hepatocytes through AMPK [Metabolism]

June 13th, 2014 by Cao, J., Meng, S., Chang, E., Beckwith-Fickas, K., Xiong, L., Cole, R. N., Radovick, S., Wondisford, F. E., He, L.

Metformin is a first-line anti-diabetic agent taken by 150 million people across the world every year, yet its mechanism remains only partially understood and controversial. It was proposed that suppression of glucose production in hepatocytes by metformin is AMPK independent; however, unachievablely high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMPK [adenosine monophosphate (AMP) activated protein kinase]-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60-80 uM). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA (3'-5'-cyclic adenosine monophosphate-protein kinase A) pathway negatively regulates AMPK activity through phosphorylation at S485/497 on the α subunit, which in turn reduces net phosphorylation at T172. Since diabetic patients often have hyperglucagonemia, AMPKα phosphorylation at S485/497 is a therapeutic target to improve metformin efficacy.