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

Kjobsted, R.; Kristensen, J. M.; Birk, J. B.; Jorgensen, N. O.; Kido, K.; Andersen, N. R.; Larsen, J. K.; Foretz, M.; Benoit, V.; Nielsen, F.; Brosen, K.; Jessen, N.; Hellsten, Y.; Hojlund, K.; Wojtaszewski, J. F. P.

doi:10.1101/2022.05.22.492936

bioRxiv · 10.1101/2022.05.22.492936

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

Kjobsted, R.·Kristensen, J. M.·Birk, J. B.·Jorgensen, N. O.·Kido, K.·Andersen, N. R.·Larsen, J. K.·Foretz, M.·Benoit, V.·Nielsen, F.·Brosen, K.·Jessen, N.·Hellsten, Y.·Hojlund, K.·Wojtaszewski, J. F. P.

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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 anti-hyperglycemic 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.

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Kjobsted, R., Kristensen, J. M., Birk, J. B., Jorgensen, N. O., Kido, K., Andersen, N. R., Larsen, J. K., Foretz, M., Benoit, V., Nielsen, F., Brosen, K., Jessen, N., Hellsten, Y., Hojlund, K., Wojtaszewski, J. F. P.. 2022-05-24. Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance. https://doi.org/10.1101/2022.05.22.492936

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