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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 HbA(1c) 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.
