title: Metformin-induced suppression of glucose-6-phosphatase expression is independent of insulin signaling in rat hepatoma cells.
abstract: Metformin is thought to decrease blood glucose levels by reducing hepatic glucose output. To elucidate the pharmacological action of metformin on hepatic glucose production, we examined its effect on the gene expression of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, in H4IIE rat hepatoma cell line by RT-PCR and quantitative real-time PCR. Metformin suppressed dexamethasone/cAMP-induced expression of G6Pase mRNA in a dose dependent manner, its maximum effect being observed at 2 mM (79.3% inhibition, P<0.05). Pretreatment with the PI3-kinase inhibitor wortmannin, the MEK-1 inhibitor PD98059 or the protein kinase C inhibitor GF109203X had no effect on suppressed G6Pase expression by metformin. Moreover, metformin did not stimulate Akt phosphorylation. In the present study, we demonstrate that metformin suppresses G6Pase mRNA expression by a mechanism that is independent of the activation of PI3-kinase, Akt, MAP kinase and protein kinase C pathway in hepatocytes.
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Mie University School of Medicine, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Morioka
authors.forename: Kaname
authors.initials: K
authors.lastname: Nakatani
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Hideki
authors.initials: H
authors.lastname: Urakawa
authors.forename: Nagako
authors.initials: N
authors.lastname: Kitagawa
authors.forename: Akira
authors.initials: A
authors.lastname: Katsuki
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Hori
authors.forename: Esteban C
authors.initials: EC
authors.lastname: Gabazza
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Yano
authors.forename: Junji
authors.initials: J
authors.lastname: Nishioka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nobori
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Sumida
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Adachi
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000235:genetics*; D007328:Insulin / Q000378:metabolism*; D008687:Metformin / Q000494:pharmacology*; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction
chemical_list: D007328:Insulin; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D008687:Metformin; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D005952:Glucose-6-Phosphatase