Metformin acutely lowers blood glucose levels by inhibition of intestinal glucose transport

Olga Horakova,Jana Buresova,Martin Rossmeisl,Jan Kopecky,Petra Kroupova,Petra Janovska,Kristina Bardova

doi:10.1038/s41598-019-42531-0

Abstract

Metformin is currently the most prescribed drug for treatment of type 2 diabetes mellitus in humans. It has been well established that long-term treatment with metformin improves glucose tolerance in mice by inhibiting hepatic gluconeogenesis. Interestingly, a single dose of orally administered metformin acutely lowers blood glucose levels, however, little is known about the mechanism involved in this effect. Glucose tolerance, as assessed by the glucose tolerance test, was improved in response to prior oral metformin administration when compared to vehicle-treated mice, irrespective of whether the animals were fed either the standard or high-fat diet. Blood glucose-lowering effects of acutely administered metformin were also observed in mice lacking functional AMP-activated protein kinase, and were independent of glucagon-like-peptide-1 or N-methyl-D-aspartate receptors signaling. [18F]-FDG/PET revealed a slower intestinal transit of labeled glucose after metformin as compared to vehicle administration. Finally, metformin in a dose-dependent but indirect manner decreased glucose transport from the intestinal lumen into the blood, which was observed ex vivo as well as in vivo. Our results support the view that the inhibition of transepithelial glucose transport in the intestine is responsible for lowering blood glucose levels during an early response to oral administration of metformin.

Highlights

Metformin, the most potent of the biguanide analogs, was synthetized at the beginning of 20th century and introduced to human medicine in 19581
To assess the impact of the route of glucose administration regarding the effect of metformin on blood glucose levels, overnight fasted mice were gavaged with M400 or vehicle and 30 min later they received glucose via i.p. injections in the frame of a standard intraperitoneal glucose tolerance test (IPGTT)
The change in plasma insulin levels that were determined at the baseline and 30 min after oral glucose administration was similar in all metformin-treated groups, suggesting that metformin-induced lowering of glycaemia during the oral glucose tolerance test (OGTT) cannot be explained by changes in plasma insulin levels (Figs 1d and S1)

Summary

Introduction

The most potent of the biguanide analogs, was synthetized at the beginning of 20th century and introduced to human medicine in 19581. The expression of GLP-1 receptor (GLP1R) is widely distributed throughout the brain including neurons producing N-methyl-D-aspartate[19], and vagal afferent activation enhances N-methyl-D-aspartate receptor (NMDAR)-mediated neuronal transmission in the nucleus of the solitary tract to lower glucose production via the hepatic vagal branch[20]. Further in this context, a rapid blood glucose-lowering effect during an oral glucose tolerance test (OGTT) has been demonstrated in mice and rats after oral administration of metformin[16,21], no clear explanation for this effect was provided. Our results strongly implicate changes in glucose uptake and transport in the small intestine in the blood glucose-lowering effect of orally administered metformin and suggest that these effects are independent of functional AMPK, as well as of GLP1R and NMDAR signaling

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