An energetic tale of AMPK-independent effects of metformin

J Clin Invest. 2010 Jul;120(7):2267-70. doi: 10.1172/JCI43661. Epub 2010 Jun 23.


Metformin has become a mainstay in the modest therapeutic armamentarium for the treatment of the insulin resistance of type 2 diabetes mellitus. Although metformin functions primarily by reducing hepatic glucose output, the molecular mechanism mediating this effect had remained elusive until recently. Metformin impairs ATP production, activating the conserved sensor of nutritional stress AMP-activated protein kinase (AMPK), thus providing a plausible and generally accepted model for suppression of gluconeogenic gene expression and glucose output. In this issue of the JCI, Foretz et al. refute this hypothesis by showing that AMPK is dispensable for the effects of metformin on hepatic glucose output in primary hepatocytes; rather, their data suggest that the antidiabetic effects of metformin in the liver are mediated directly by reducing energy charge.

Publication types

  • Research Support, N.I.H., Extramural
  • Review
  • Comment

MeSH terms

  • AMP-Activated Protein Kinases
  • Carbohydrate Metabolism
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Gene Expression / drug effects
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Humans
  • Hypoglycemic Agents* / metabolism
  • Hypoglycemic Agents* / pharmacology
  • Hypoglycemic Agents* / therapeutic use
  • Insulin Resistance
  • Liver / drug effects
  • Liver / metabolism
  • Metformin* / metabolism
  • Metformin* / pharmacology
  • Metformin* / therapeutic use
  • Protein Kinases / metabolism
  • Protein Kinases / pharmacology
  • Signal Transduction / drug effects


  • Hypoglycemic Agents
  • Metformin
  • Protein Kinases
  • AMP-Activated Protein Kinases