Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism

Biochem Biophys Res Commun. 2009 Oct 16;388(2):311-6. doi: 10.1016/j.bbrc.2009.07.164. Epub 2009 Aug 5.


Metformin is widely used as a hypoglycemic agent for the treatment of type 2 diabetes. Both metformin and rotenone, an inhibitor of respiratory chain complex I, suppressed glucose-6-phosphatase (G6pc), a rate limiting enzyme of liver glucose production, mRNA expression in a rat hepatoma cell line accompanied by a reduction of intracellular ATP concentration and an activation of AMP-activated protein kinase (AMPK). When yeast NADH-quinone oxidoreductase 1 (NDI1) gene was introduced into the cells, neither inhibition of ATP synthesis nor activation of AMPK was induced by these agents. Interestingly, in contrast to rotenone treatment, G6pc mRNA down-regulation was observed in the NDI1 expressing cells after metformin treatment. Since NDI1 can functionally complement the complex I under the presence of metformin or rotenone, our results indicate that metformin induces down-regulation of G6pc expression through an inhibition of complex I and an activation of AMPK-independent mechanism.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Line, Tumor
  • Down-Regulation
  • Electron Transport Complex I / antagonists & inhibitors*
  • Glucose-6-Phosphatase / antagonists & inhibitors*
  • Glucose-6-Phosphatase / biosynthesis
  • Hypoglycemic Agents / pharmacology*
  • Metformin / pharmacology*
  • Mice
  • Rats
  • Saccharomyces cerevisiae Proteins / antagonists & inhibitors*


  • Hypoglycemic Agents
  • Ndi1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Metformin
  • AMP-Activated Protein Kinases
  • Glucose-6-Phosphatase
  • Electron Transport Complex I