Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression

Abstract

<p>Objectives</p><p>Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human <em>SLC2A2</em> gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model <em>Slc2a2</em> deficiency and measure the impact on glucose homoeostasis and metformin response in mice.<br></p><p>Methods</p><p>We performed extensive metabolic phenotyping and 2-deoxy-2-[¹⁸F]fluoro-d-glucose ([¹⁸F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced <em>Slc2a2</em> (<em>Slc2a2^+/−</em>) and intestinal <em>Slc2a2</em> KO, to assess the impact of metformin treatment.<br></p><p>Results</p><p><em>Slc2a2</em> partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced <em>Slc2a2</em> expression (<em>Slc2a2^+/−</em>) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (<em>Slc2a2^+/+</em>) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in <em>Slc2a2^+/+</em> animals fed HFD and this action of the drug was significantly higher in <em>Slc2a2^+/−</em> animals. However, there was no effect of specifically knocking-out <em>Slc2a2</em> in the mouse intestinal epithelial cells.<br></p><p>Conclusions</p><p>Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing.</p>