title: Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism.
abstract: 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.
authors: Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana, Osaka 554-0022, Japan.
authors: Shinichi
authors: S
authors: Ota
authors: Kazuhiko
authors: K
authors: Horigome
authors: Takayuki
authors: T
authors: Ishii
authors: Michio
authors: M
authors: Nakai
authors: Koji
authors: K
authors: Hayashi
authors: Takao
authors: T
authors: Kawamura
authors: Akiyoshi
authors: A
authors: Kishino
authors: Mutsuo
authors: M
authors: Taiji
authors: Toru
authors: T
authors: Kimura
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation; D042967:Electron Transport Complex I / Q000037:antagonists & inhibitors*; D005952:Glucose-6-Phosphatase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D051381:Rats; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors*
chemical_list: D007004:Hypoglycemic Agents; C493237:Ndi1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D005952:Glucose-6-Phosphatase; D042967:Electron Transport Complex I