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.
Lorea Zubiaga  1 ,  Olivier Briand  2 ,  Florent Auger  3 ,  Veronique Touche  2 ,  Thomas Hubert  1 ,  Julien Thevenet  1 ,  Camille Marciniak  1 ,  Audrey Quenon  1 ,  Caroline Bonner  1  4 ,  Simon Peschard  2 ,  Violeta Raverdy  1 ,  Mehdi Daoudi  1 ,  Julie Kerr-Conte  1 ,  Gianni Pasquetti  1 ,  Hermann Koepsell  5 ,  Daniela Zdzieblo  5 ,  Markus Mühlemann  5 ,  Bernard Thorens  6 ,  Nathalie D Delzenne  7 ,  Laure B Bindels  7 ,  Benoit Deprez  8 ,  Marie C Vantyghem  1 ,  Blandine Laferrère  9 ,  Bart Staels  2 ,  Damien Huglo  3 ,  Sophie Lestavel  2 ,  François Pattou  1
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.
PMID: 36942050 DOI: 10.1016/j.isci.2023.106057
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.
Products