Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism.
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.
Ota
Shinichi
S
Dainippon Sumitomo Pharma Co., Ltd., 3-1-98 Kasugade-naka, Konohana, Osaka 554-0022, Japan.
Horigome
Kazuhiko
K
Ishii
Takayuki
T
Nakai
Michio
M
Hayashi
Koji
K
Kawamura
Takao
T
Kishino
Akiyoshi
A
Taiji
Mutsuo
M
Kimura
Toru
T
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*
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