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Horm Metab Res 2009; 41(10): 730-735
DOI: 10.1055/s-0029-1225360
Original Basic

© Georg Thieme Verlag KG Stuttgart · New York

Regulation of Glucose-6-Phosphatase Gene Expression by Insulin and Metformin

C. Mues1 [*] , J. Zhou2 [*] , K. N. Manolopoulos3 , P. Korsten4 , D. Schmoll5 , L.-O. Klotz6 , S. R. Bornstein7 , H. H. Klein1 , A. Barthel7 , 8
  • 1Medizinische Klinik I, Berufsgenossenschaftliches Universitätsklinikum Bergmannsheil, Ruhr-Universität, Bochum, Germany
  • 2Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, China
  • 3Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital Oxfort, Oxford, UK
  • 4Zentrum Innere Medizin, Abteilung Nephrologie und Rheumatologie, Universität Göttingen, Göttingen, Germany
  • 5Sanofi-Aventis Pharma Deutschland GmbH, TD Metabolism, Frankfurt, Germany
  • 6Institut für Umweltmedizinische Forschung (IUF) at Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
  • 7Medizinische Klinik und Poliklinik III, Technische Universität Dresden, Germany Universitätsklinikum Carl Gustav Carus, Dresden, Germany
  • 8Endokrinologikum Ruhr, Bochum, Germany
Further Information

Publication History

received 13.03.2009

accepted 27.05.2009

Publication Date:
03 July 2009 (online)

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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.

Key words

hepatic glucose production - gluconeogenesis - diabetes mellitus type 2

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1 Equal contribution of both authors.

Correspondence

Dr. A. Barthel

Endokrinologikum Ruhr

Alter Markt 4

44866 Bochum

Germany

Phone: +49/2327/964 20

Fax: +49/2327/96 42 99

Email: Andreas.Barthel@endokrinologikum.com

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