Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance

Rasmus Kjøbsted*, Jonas Møller Kristensen, Jesper Bratz Birk, Nicolas Oldenburg Jørgensen, Kohei Kido, Nicoline Resen Andersen, Jeppe K Larsen, Marc Foretz, Benoit Viollet, Flemming Nielsen, Kim Brøsen, Niels Jessen, Ylva Hellsten, Kurt Højlund, Jørgen Wojtaszewski

*Corresponding author for this work

Research output: Working paperPreprintResearch

Abstract

Metformin is an inexpensive oral anti-hyperglycemic agent used worldwide as a first-choice drug for the prevention of type 2 diabetes mellitus (T2DM). Although current view suggests that metformin exerts its anti-hyperglycemic effect by lowering hepatic glucose production, it has been proposed that metformin also reduce hyperglycemia by increasing glucose uptake in skeletal muscle via activation of AMP-activated protein kinase (AMPK). Herein, we demonstrate in lean and diet-induced obese (DIO) male and female mouse models that the antihyperglycemic effect of metformin occurs independently of muscle AMPK, and instead relies on elevated intestinal glucose clearance. Furthermore, we report that the AMPK activity is elevated in skeletal muscle from patients with T2DM following chronic metformin treatment, but this is not associated with enhanced peripheral insulin sensitivity. These results argue against existing paradigms and emphasize the non-essential role of muscle AMPK but important
role of the intestine for the anti-hyperglycemic effect of metformin.
Original languageEnglish
PublisherbioRxiv
Pages1-33
Number of pages33
DOIs
Publication statusPublished - 24 May 2022

Keywords

  • Faculty of Science
  • Metformin
  • Anti-hyperglycemic effect
  • Intestinal glucose clearance

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