Inhibition of phosphoenolpyruvate carboxykinase gene expression by metformin in cultured hepatocytes.
OBJECTIVE
To investigate the effect and mechanism of the antihyperglycemic agent metformin on the expression of phosphoenolpyruvate carboxykinase (PEPCK) gene in hepatocytes and to determine whether the effects of metformin in hepatocytes are transmitted throughout the known insulin signaling pathways.


METHODS
Confluent H4IIE rat heptoma cells were cultured for 16 h with 0.1 mmol/L metformin either in absence or presence of 0.1 nmol/L insulin, and then stimulated with various agents. The expression of PEPCK gene was examined by Northern blot analysis.


RESULTS
Therapeutic concentrations of metformin significantly inhibited basal PEPCK mRNA expression and also decreased cAMP and dexamethasone induced PEPCK gene expression through interaction with insulin. In the presence of insulin signaling pathway inhibitors wortmannin and UO126, metformin reduced PEPCK mRNA levels, but wortmannin blocked inhibitory regulation of insulin on PEPCK gene expression.


CONCLUSIONS
Metformin inhibits PEPCK gene expression via either an insulin-independent or an interacting-with-insulin manner. The results suggest that a possible mechanism by which metformin reduces gluconeogenesis could be associated with the inhibition of PEPCK gene expression.
Yuan
Li
L
Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. yuanli18cn@yahoo.com.cn
Ziegler
Reinhard
R
Hamann
Andreas
A
D000730:Androstadienes / Q000494:pharmacology; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D000077191:Wortmannin
D000730:Androstadienes; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D008687:Metformin; D019869:Phosphatidylinositol 3-Kinases; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D000077191:Wortmannin