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Diabetes. 2015 Jan;64(1):284-90. doi: 10.2337/db14-0393. Epub 2014 Jul 28.

Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 inhibitor by suppressing endogenous glucose production in diabetic mice.

Author information

  • 1Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Center for Diabetes Research, Neuherberg/Munich, Germany susanne.neschen@helmholtz-muenchen.de.
  • 2Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Center for Diabetes Research, Neuherberg/Munich, Germany.
  • 3Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Center for Diabetes Research, Neuherberg/Munich, Germany.
  • 4Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany.
  • 5Institute of Developmental Genetics, Helmholtz Zentrum München, Neuherberg, Germany Max Planck Institute of Psychiatry, Munich, Germany Technische Universität München-Weihenstephan, Helmholtz Zentrum München, Neuherberg, Germany German Center for Neurodegenerative Diseases, Site Munich, Munich, Germany.
  • 6Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg/Munich, Germany Department of Physiology and Biophysics, Weill Cornell Medical College in Qatar, Education City-Qatar Foundation, Doha, Qatar.
  • 7Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
  • 8Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Center for Diabetes Research, Neuherberg/Munich, Germany Technische Universität München-Weihenstephan, Helmholtz Zentrum München, Neuherberg, Germany.
  • 9Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Center for Diabetes Research, Neuherberg/Munich, Germany Technische Universität München-Weihenstephan, Helmholtz Zentrum München, Neuherberg, Germany.

Abstract

Combined use of metformin and a sodium glucose cotransporter 2 inhibitor (SGLT2I) is a promising treatment strategy for type 2 diabetes. The mechanism by which combination treatment provides better glycemic control than metformin or SGLT2I monotherapy remains elusive. Therefore, we investigated the physiological mechanism by which both compounds lower blood glucose concentrations in diabetic mice. We compared the potential of metformin and the SGLT2I AVE2268 alone or in combination to mitigate hyperglycemia and modulate glucose fluxes in db/db and diabetic Tallyho/JngJ mice. SGLT2I treatment alone elicited a rapid decline in circulating blood glucose levels, which appeared to induce endogenous glucose production. Supplementation of metformin dampened this counterresponse, and therefore, combination therapy more efficiently maintained glycemic control. Finally, combination treatment blunted postprandial glucose excursions and improved HbA1c levels within 2 weeks. We conclude that coapplication of metformin enhances the glucose-lowering actions of SGLT2I by restraining endogenous glucose production, which may provide long-term improvement of glycemic control in type 2 diabetic patients.

PMID:
25071027
DOI:
10.2337/db14-0393
[PubMed - indexed for MEDLINE]
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