Metformin Activates AMP-activated Protein Kinase by Promoting Formation of the αβγ Heterotrimeric Complex

Metformin is the most widely prescribed oral anti-diabetic agent. Recently, we have shown that low metformin concentrations found in the portal vein suppress glucose production in hepatocytes through activation of AMPK. Moreover, low concentrations of metformin were found to activate AMPK by increasing the phosphorylation of AMPKα at Thr-172. However, the mechanism underlying the increase in AMPKα phosphorylation at Thr-172 and activation by metformin remains unknown. In the current study, we find that low concentrations of metformin promote the formation of the AMPK αβγ complex, resulting in an increase in net phosphorylation of the AMPK α catalytic subunit at Thr-172 by augmenting phosphorylation by LKB1 and antagonizing dephosphorylation by PP2C. Background: The mechanism underlying the activation of AMPK by metformin remains unclear. Results: Metformin promotes the formation of AMPK αβγ heterotrimeric complex. Conclusion: The formation of the AMPK αβγ heterotrimeric complex augments AMPKα phosphorylation by LKB1 and prevents dephosphorylation by protein phosphatase. Significance: Metformin-mediated formation of the AMPK αβγ heterotrimeric complex results in AMPK activation by elevating AMPK phosphorylation at Thr-172.