Regulation of glucose-6-phosphatase gene expression by insulin and metformin

Research output: Contribution to journalArticlepeer-review

Authors

  • C Mues
  • P Korsten
  • D Schmoll
  • L-O Klotz
  • S R Bornstein
  • H H Klein
  • A Barthel

Colleges, School and Institutes

External organisations

  • Medizinische Klinik I, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Ruhr-Universität, Bochum, Germany.

Abstract

The biguanide derivative metformin is a potent anti-diabetic drug widely used in the treatment of type 2 diabetes mellitus. Its major effect on glucose metabolism consists in the inhibition of hepatic glucose production. Since the mechanisms of metformin action are only partially understood at the molecular level, we studied the regulation of the gene promoter activity of glucose-6-phosphatase (G6Pase), the central hepatic gluconeogenic enzyme, by this drug. We have found that both metformin and insulin inhibit the basal and dexamethasone/cAMP-stimulated G6Pase promoter activity in hepatoma cells. Since one of the pharmacological targets of metformin is AMP-activated protein kinase (AMPK) and activation of AMPK is known to inhibit hepatic glucose production by the suppression of G6Pase gene transcription, we studied the effect of AMPK in this context. Under nonstimulated conditions, the inhibitory effect of both insulin and metformin was partially counteracted to a similar extent by treatment with compound C, a specific inhibitor of AMPK. In contrast, under conditions of stimulation with dexamethasone and cAMP, treatment with compound C reversed the inhibitory effect of metformin on G6Pase promoter activity to a similar extent as compared to nonstimulated conditions, whereas the effect of insulin was almost resistant to treatment with the AMPK-antagonist. These data indicate a differential AMPK-dependent regulation of G6Pase gene expression by insulin and metformin under basal and dexamethasone/cAMP-stimulated conditions.

Bibliographic note

Georg Thieme Verlag KG Stuttgart.New York.

Details

Original languageEnglish
Pages (from-to)730-5
Number of pages6
JournalHormone and Metabolic Research
Volume41
Issue number10
Publication statusPublished - Oct 2009

Keywords

  • Animals, Cell Line, Tumor, Diabetes Mellitus, Type 2, Dose-Response Relationship, Drug, Gene Expression Regulation, Enzymologic, Glucose-6-Phosphatase, Hypoglycemic Agents, Insulin, Metformin, Phosphorylation, Promoter Regions, Genetic, Protein Kinase Inhibitors, Protein Kinases, RNA, Rats, Reverse Transcriptase Polymerase Chain Reaction