Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes

Lorea Zubiaga; Olivier Briand; Florent Auger; Veronique Touche; Thomas Hubert; Julien Thevenet; Camille Marciniak; Audrey Quenon; Caroline Bonner; Simon Peschard; Violeta Raverdy; Mehdi Daoudi; Julie Kerr-Conte; Gianni Pasquetti; Hermann Koepsell; Daniela Zdzieblo; Markus Mühlemann; Bernard Thorens; Nathalie D Delzenne; Laure B Bindels; Benoit Deprez; Marie C Vantyghem; Blandine Laferrère; Bart Staels; Damien Huglo; Sophie Lestavel; François Pattou

doi:10.1016/j.isci.2023.106057

Oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of sodium-glucose co-transporter 1 in enterocytes

iScience. 2023 Jan 25;26(4):106057. doi: 10.1016/j.isci.2023.106057. eCollection 2023 Apr 21.

Authors

Lorea Zubiaga¹, Olivier Briand², Florent Auger³, Veronique Touche², Thomas Hubert¹, Julien Thevenet¹, Camille Marciniak¹, Audrey Quenon¹, Caroline Bonner^{1

4}, Simon Peschard², Violeta Raverdy¹, Mehdi Daoudi¹, Julie Kerr-Conte¹, Gianni Pasquetti¹, Hermann Koepsell⁵, Daniela Zdzieblo⁵, Markus Mühlemann⁵, Bernard Thorens⁶, Nathalie D Delzenne⁷, Laure B Bindels⁷, Benoit Deprez⁸, Marie C Vantyghem¹, Blandine Laferrère⁹, Bart Staels², Damien Huglo³, Sophie Lestavel², François Pattou¹

Affiliations

¹ University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1190, 59000 Lille, France.
² University of Lille, Inserm, Centre Hospitalier Universitaire de Lille, Institut Pasteur de Lille, U1011-EGID, 59000 Lille, France.
³ University of Lille, Preclinical Imaging Core Facility, 59000 Lille, France.
⁴ Institut Pasteur de Lille, 59000 Lille, France.
⁵ Institute of Anatomy and Cell Biology, University of Würzburg, 97070 Würzburg, Germany.
⁶ University of Lausanne, Center for Integrative Genomics, Lausanne, Switzerland.
⁷ Université catholique de Louvain, Metabolism and Nutrition Research Group, Louvain Drug Research Institute, Brussels, Belgium.
⁸ University of Lille, Centre Hospitalier Universitaire de Lille, European Genomic Institute for Diabetes, Inserm UMR-1177, 59000 Lille, France.
⁹ Department of Medicine, New York Nutrition Obesity Research Center, Columbia University College of Physicians and Surgeons, New York, NY, USA.

Abstract

Metformin (MET) is the most prescribed antidiabetic drug, but its mechanisms of action remain elusive. Recent data point to the gut as MET's primary target. Here, we explored the effect of MET on the gut glucose transport machinery. Using human enterocytes (Caco-2/TC7 cells) in vitro, we showed that MET transiently reduced the apical density of sodium-glucose transporter 1 (SGLT1) and decreased the absorption of glucose, without changes in the mRNA levels of the transporter. Administered 1 h before a glucose challenge in rats (Wistar, GK), C57BL6 mice and mice pigs, oral MET reduced the post-prandial glucose response (PGR). This effect was abrogated in SGLT1-KO mice. MET also reduced the luminal clearance of 2-(¹⁸F)-fluoro-2-deoxy-D-glucose after oral administration in rats. In conclusion, oral metformin transiently lowers post-prandial glucose response by reducing the apical expression of SGLT1 in enterocytes, which may contribute to the clinical effects of the drug.

Keywords: Drugs; Endocrinology; Molecular physiology.