title: Low concentrations of metformin suppress glucose production in hepatocytes through AMP-activated protein kinase (AMPK).
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 regulates AMPK activity 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.
authors.forename: Jia
authors.initials: J
authors.lastname: Cao
authors.forename: Shumei
authors.initials: S
authors.lastname: Meng
authors.forename: Evan
authors.initials: E
authors.lastname: Chang
authors.forename: Katherine
authors.initials: K
authors.lastname: Beckwith-Fickas
authors.forename: Lishou
authors.initials: L
authors.lastname: Xiong
authors.forename: Robert N
authors.initials: RN
authors.lastname: Cole
authors.forename: Sally
authors.initials: S
authors.lastname: Radovick
authors.forename: Fredric E
authors.initials: FE
authors.lastname: Wondisford
authors.forename: Ling
authors.initials: L
authors.lastname: He
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D005943:Gluconeogenesis / Q000187:drug effects*; D005947:Glucose / Q000096:biosynthesis*; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice
chemical_list: D007004:Hypoglycemic Agents; D008687:Metformin; D017868:Cyclic AMP-Dependent Protein Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose