Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 (SGLT2) inhibitor by suppressing endogenous glucose production in diabetic mice

  1. Martin Hrabé de Angelis1,2,3,9
  1. 1 Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg/Munich, Germany.
  2. 2 German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg/Munich, Germany
  3. 3 Member of the German Center for Diabetes Research (DZD), Ingolstädter Landstraße 1, 85764 Neuherberg/Munich, Germany
  4. 4 Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg/Munich, Germany
  5. 5 Weill Cornell Medical College Quatar, Department of Physiology and Biophysics, Education City-Qatar Foundation, Doha, Qatar
  6. 6 Chair for Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Feodor Lynen-Straße 25, 81377 Munich, Germany
  7. 7 Institute of Developmental Genetics, Helmholtz Zentrum München, German Ingolstädter Landstraße 1, 85764 Neuherberg, Germany.
  8. 8 Max Planck Institute of Psychiatry, Kraepelinstr. 2-1080804 Munich, Germany
  9. 9 Technische Universität München-Weihenstephan, c/o Helmholtz Zentrum München, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany
  10. 10 German Center for Neurodegenerative Diseases (DZNE), Site Munich, Schillerstraße 44, 80336 Munich, Germany
  1. Corresponding author: Susanne Neschen, E-mail: susanne.neschen{at}helmholtz-muenchen.de

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 diabetic db/db and 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 counter-response and, therefore, combination therapy more efficiently maintained glycemic control. Finally, combination treatment blunted postprandial glucose excursions and improved HbA1c levels within two weeks.

Taken together, we conclude that co-application of metformin enhances the glucose-lowering actions of SGLT2I by restraining endogenous glucose production what may provide long-term improvement of glycemic control in type 2 diabetic patients.

  • Received March 9, 2014.
  • Accepted July 23, 2014.

This Article

  1. Diabetes