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

Shinichi Ota1, Kazuhiko Horigome, Takayuki Ishii

  • 1Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana, Osaka 554-0022, Japan.

Biochemical and Biophysical Research Communications
|August 12, 2009
PubMed

Insights

Metformin and rotenone reduce glucose-6-phosphatase (G6pc) mRNA via complex I inhibition. Metformin’s effect on G6pc is independent of AMP-activated protein kinase (AMPK) activation, unlike rotenone.

Area of Science:

  • Biochemistry
  • Cell Biology
  • Metabolic Diseases

Background:

  • Metformin is a key drug for type 2 diabetes, primarily lowering blood glucose.
  • Liver glucose production, regulated by glucose-6-phosphatase (G6pc), is a therapeutic target.
  • Complex I of the mitochondrial respiratory chain is implicated in cellular energy metabolism.

Purpose of the Study:

  • To investigate the mechanism by which metformin and rotenone affect G6pc mRNA expression.
  • To determine the role of mitochondrial respiratory chain complex I and AMP-activated protein kinase (AMPK) in metformin's action.

Main Methods:

  • Utilized a rat hepatoma cell line.
  • Expressed yeast NADH-quinone oxidoreductase 1 (NDI1) to functionally complement complex I.
  • Measured G6pc mRNA levels, intracellular ATP concentration, and AMPK activation.

Main Results:

  • Both metformin and rotenone suppressed G6pc mRNA, reduced ATP, and activated AMPK.
  • NDI1 expression prevented ATP reduction and AMPK activation by both agents.
  • Metformin, but not rotenone, still downregulated G6pc mRNA in NDI1-expressing cells.

Conclusions:

  • Metformin down-regulates G6pc expression through complex I inhibition.
  • This metformin-induced G6pc suppression is independent of AMPK activation.
  • The findings elucidate a novel AMPK-independent pathway for metformin's glucose-lowering effects.

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