A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
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
Tekijät: Morrice Nicola, Vainio Susanne, Mikkola Kirsi, van Aalten Lidy, Gallagher Jennifer R, Ashford Michael LJ, McNeilly Alison D, McCrimmon Rory J, Grosfeld Alexandra, Serradas Patricia, Koffert Jukka, Pearson Ewan R, Nuutila Pirjo, Sutherland Calum
Kustantaja: Elsevier GmbH
Julkaisuvuosi: 2023
Journal: Molecular Metabolism
Tietokannassa oleva lehden nimi: Molecular Metabolism
Artikkelin numero: 101807
Vuosikerta: 77
eISSN: 2212-8778
DOI: https://doi.org/10.1016/j.molmet.2023.101807
Verkko-osoite: https://doi.org/10.1016/j.molmet.2023.101807
Rinnakkaistallenteen osoite: https://research.utu.fi/converis/portal/detail/Publication/181479259
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.
Ladattava julkaisu This is an electronic reprint of the original article. |  |
