Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance
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Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance. / Kjøbsted, Rasmus; Kristensen, Jonas Møller; Birk, Jesper Bratz; Jørgensen, Nicolas Oldenburg; Kido, Kohei; Andersen, Nicoline Resen; Larsen, Jeppe K; Foretz, Marc; Viollet, Benoit; Nielsen, Flemming; Brøsen, Kim; Jessen, Niels; Hellsten, Ylva; Højlund, Kurt; Wojtaszewski, Jørgen.
bioRxiv, 2022. p. 1-33.Research output: Working paper › Preprint › Research
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TY - UNPB
T1 - Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance
AU - Kjøbsted, Rasmus
AU - Kristensen, Jonas Møller
AU - Birk, Jesper Bratz
AU - Jørgensen, Nicolas Oldenburg
AU - Kido, Kohei
AU - Andersen, Nicoline Resen
AU - Larsen, Jeppe K
AU - Foretz, Marc
AU - Viollet, Benoit
AU - Nielsen, Flemming
AU - Brøsen, Kim
AU - Jessen, Niels
AU - Hellsten, Ylva
AU - Højlund, Kurt
AU - Wojtaszewski, Jørgen
N1 - (Preprint)
PY - 2022/5/24
Y1 - 2022/5/24
N2 - 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 importantrole of the intestine for the anti-hyperglycemic effect of metformin.
AB - 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 importantrole of the intestine for the anti-hyperglycemic effect of metformin.
KW - Faculty of Science
KW - Metformin
KW - Anti-hyperglycemic effect
KW - Intestinal glucose clearance
U2 - 10.1101/2022.05.22.492936
DO - 10.1101/2022.05.22.492936
M3 - Preprint
SP - 1
EP - 33
BT - Metformin improves glycemia independently of skeletal muscle AMPK via enhanced intestinal glucose clearance
PB - bioRxiv
ER -
ID: 328694811