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

Nicola Morrice; Susanne Vainio; Kirsi Mikkola; Lidy van Aalten; Jennifer R Gallagher; Michael L J Ashford; Alison D McNeilly; Rory J McCrimmon; Alexandra Grosfeld; Patricia Serradas; Jukka Koffert; Ewan R Pearson; Pirjo Nuutila; Calum Sutherland

doi:10.1016/j.molmet.2023.101807

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

Mol Metab. 2023 Nov:77:101807. doi: 10.1016/j.molmet.2023.101807. Epub 2023 Sep 16.

Affiliations

¹ Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK.
² Turku PET Centre, University of Turku, Turku, Finland; MediCity Research Laboratory, University of Turku, Turku, Finland.
³ Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, CRSA, F-75012, Paris, France.
⁴ Sorbonne Université, INSERM, Nutrition and Obesities: Systemic approaches, NutriOmics, Research group, F-75013, Paris, France.
⁵ Turku PET Centre, University of Turku, Turku, Finland; Department of Gastroenterology, Turku University Hospital, Turku, Finland.
⁶ Division of Population Health and Genomics, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK.
⁷ Turku PET Centre, University of Turku, Turku, Finland; Department of Endocrinology, Turku University Hospital, Turku, Finland.
⁸ Division of Cellular and Systems Medicine, School of Medicine, University of Dundee, Ninewells Hospital and Medical School, Dundee, Scotland, DD1 9SY, UK. Electronic address: c.d.sutherland@dundee.ac.uk.

Abstract

Objectives: 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 SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice.

Methods: 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 Slc2a2 (Slc2a2^+/-) and intestinal Slc2a2 KO, to assess the impact of metformin treatment.

Results: Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2^+/-) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2^+/+) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2^+/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2^+/- animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells.

Conclusions: 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.

Keywords: Diabetes; Glucose-uptake; Metformin; Slc2a2; [(18)F]FDG-PET.