title: Metformin supports the antidiabetic effect of a sodium glucose cotransporter 2 inhibitor by suppressing endogenous glucose production in diabetic mice.
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.
authors: Institute 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.
authors: Susanne
authors: S
authors: Neschen
authors: Institute 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.
authors: Markus
authors: M
authors: Scheerer
authors: Institute 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.
authors: Anett
authors: A
authors: Seelig
authors: Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Center for Diabetes Research, Neuherberg/Munich, Germany.
authors: Peter
authors: P
authors: Huypens
authors: Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany.
authors: Jürgen
authors: J
authors: Schultheiss
authors: Institute 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.
authors: Moya
authors: M
authors: Wu
authors: Institute 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.
authors: Wolfgang
authors: W
authors: Wurst
authors: Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, Neuherberg/Munich, Germany.
authors: Birgit
authors: B
authors: Rathkolb
authors: Institute 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.
authors: Karsten
authors: K
authors: Suhre
authors: Molecular Animal Breeding and Biotechnology, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany.
authors: Eckhard
authors: E
authors: Wolf
authors: 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.
authors: Johannes
authors: J
authors: Beckers
authors: Institute 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.
authors: Martin
authors: M
authors: Hrabé de Angelis
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D005947:Glucose / Q000096:biosynthesis*; D015309:Glucose Clamp Technique; D005960:Glucosides / Q000494:pharmacology*; D006442:Glycated Hemoglobin / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008687:Metformin / Q000494:pharmacology*; D018345:Mice, Knockout; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors
chemical_list: D005947:Glucose; D005960:Glucosides; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D008687:Metformin; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; C535206:AVE2268; C558406:HbA(1c) protein, mouse; C490299:Slc5a2 protein, mouse