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: Susanne Neschen, Markus Scheerer, Anett Seelig, Peter Huypens, Jürgen Schultheiss, Moya Wu, Wolfgang Wurst, Birgit Rathkolb, Karsten Suhre, Eckhard Wolf, Johannes Beckers, Martin Hrabé de Angelis
• Journal: Diabetes (Diabetes) Vol. 64 Issue 1 Pg. 284-90 (Jan 2015) ISSN: 1939-327X [Electronic] United States
• PMID: 25071027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Chemical References

• AVE2268
• Glucosides
• Glycated Hemoglobin A
• HbA(1c) protein, mouse
• Hypoglycemic Agents
• Slc5a2 protein, mouse
• Sodium-Glucose Transporter 2
• Sodium-Glucose Transporter 2 Inhibitors
• Metformin
• Glucose

Topics

• Animals
• Diabetes Mellitus, Experimental (drug therapy, genetics, metabolism)
• Diabetes Mellitus, Type 2 (drug therapy, genetics, metabolism)
• Disease Models, Animal
• Drug Therapy, Combination
• Glucose (biosynthesis)
• Glucose Clamp Technique
• Glucosides (pharmacology)
• Glycated Hemoglobin (metabolism)
• Hyperglycemia (drug therapy, metabolism)
• Hypoglycemic Agents (pharmacology)
• Metformin (pharmacology)
• Mice, Knockout
• Mice, Obese
• Obesity (metabolism)
• Sodium-Glucose Transporter 2 (metabolism)
• Sodium-Glucose Transporter 2 Inhibitors