Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK)

Jia Cao, Shumei Meng, Evan Chang, Katherine Beckwith-Fickas, Lishou Xiong, Robert N. Cole, Sally Radovick, Fredric E. Wondisford, Ling He

Research output: Contribution to journalArticlepeer-review

Abstract

Metformin is a first-line antidiabetic 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, unachievably high concentrations of metformin were employed in these studies. In the current study, we find that metformin, via an AMP-activated protein kinase (AMPK)-dependent mechanism, suppresses glucose production and gluconeogenic gene expression in primary hepatocytes at concentrations found in the portal vein of animals (60-80 μM). Metformin also inhibits gluconeogenic gene expression in the liver of mice administered orally with metformin. Furthermore, the cAMP-PKA pathway negatively regulatesAMPKactivity through phosphorylation at Ser-485/497 on the α subunit, which in turn reduces net phosphorylation at Thr-172. Because diabetic patients often have hyperglucagonemia, AMPKα phosphorylation at Ser-485/497 is a therapeutic target to improve metformin efficacy.

Original languageEnglish (US)
Pages (from-to)20435-20446
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number30
DOIs
StatePublished - Jul 25 2014

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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