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

Abstract

SummaryMetformin 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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“…Similarly, metformin-induced GLUT1 expression in the colon and ileum, secondary to increased expression of activating transcription factor 4, might also contribute to the metformin-mediated basolateral intestinal glucose uptake in HFD-fed mice 37 . After uptake into enterocytes, glucose anaerobic metabolism resulted in lactate and acetate accumulation in the wall of the small intestine and release into the circulation; this finding is supported by preclinical 37,55,56 (note that ref. 56 is a preprint and has not yet been peer-reviewed) and clinical studies 57 .…”

“…After uptake into enterocytes, glucose anaerobic metabolism resulted in lactate and acetate accumulation in the wall of the small intestine and release into the circulation; this finding is supported by preclinical 37,55,56 (note that ref. 56 is a preprint and has not yet been peer-reviewed) and clinical studies 57 . Intestinal lactate and acetate production establishes a gut-liver crosstalk to blunt hepatic glucose production, possibly through reduction in the activity of the hepatic pyruvate carboxylase by reducing pH in the portal vein (a consequence of increased lactate) and of the hepatic mitochondrial pyruvate carriers 1 and 2 by acetylation (a consequence of increased acetate) 37 .…”

“…However, AMPK-independent mechanisms of metformin action have also been documented extensively 26,74,75 . Of note, the acute glucose-lowering effect of metformin is preserved in liver-specific, intestine-specific and skeletal musclespecific AMPK-knockout mouse models, which indicates that at least some direct effects of metformin are AMPK-independent 56,76,77 . By contrast, intestinal AMPK is required for the therapeutic effects of chronic metformin administration in HFD-fed mice 35,36 .…”

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“…These observations led to the conclusion that, by inhibiting complex I and activating AMPK, metformin promotes glucose uptake in muscle [93] and enhances insulin sensitivity [141]. However, this hypothesis has been challenged by a very recent study on the muscle-specific knockout of AMPKα1/α2 mouse models, where it was shown that lack of AMPK activity in skeletal muscle of lean and diet-induced obese mice does not affect the ability of metformin to lower blood glucose levels or improve whole-body glucose tolerance [142]. Moreover, in T2DM patients rendered normoglycemic with 4 weeks of insulin treatment, metformin had no effect on insulin-stimulated peripheral glucose metabolism [143], suggesting that the ability of metformin to increase insulin-stimulated muscle glucose uptake could be secondary to improved glucose homeostasis and reduction of glucose toxicity rather than due to a direct effect.…”

Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review

“…The study indicated that metformin targets PEN2, thereby interrupting the PEN2-ATP6AP1 axis, which disrupts the glucose-sensing pathway to activate AMPK. Another study by Kjobsted et al [13] indicated that in a lean and diet-induced obese mouse model, metformin increased intestinal glucose clearance without involving skeletal muscle AMPK activation. This study also indicated that chronic metformin increases skeletal muscle AMPK activity in type-2 diabetic patients, which is not associated with increased peripheral insulin sensitivity.…”