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Exercise-stimulated glucose uptake — regulation and implications for glycaemic control

Key Points

  • Exercise-stimulated signal transduction can restore glucose metabolism in insulin-resistant muscle through both acute activation of glucose transport and by improving insulin sensitivity for up to 48 hours after exercise

  • Glucose is a major fuel source during exercise and glucose uptake by skeletal muscle can increase by up to 50-fold during bouts of exercise

  • In excess of 1,000 phosphorylation sites in human skeletal muscle are regulated by exercise, which suggests that many regulators of muscle glucose uptake have yet to be discovered

  • Regulation of exercise-stimulated glucose uptake by skeletal muscle requires three major steps (delivery, transport and intramyocellular metabolism), any of which could be rate-limiting during various exercise conditions

  • Intensity and duration of exercise are key determinants of glucose uptake by skeletal muscle

  • Exercise-stimulated glucose transport is regulated by two major pathways that sense either alterations in the intracellular metabolic milieu (probably mediated by AMPK) or mechanical stress (partly mediated by RAC1)

Abstract

Skeletal muscle extracts glucose from the blood to maintain demand for carbohydrates as an energy source during exercise. Such uptake involves complex molecular signalling processes that are distinct from those activated by insulin. Exercise-stimulated glucose uptake is preserved in insulin-resistant muscle, emphasizing exercise as a therapeutic cornerstone among patients with metabolic diseases such as diabetes mellitus. Exercise increases uptake of glucose by up to 50-fold through the simultaneous stimulation of three key steps: delivery, transport across the muscle membrane and intracellular flux through metabolic processes (glycolysis and glucose oxidation). The available data suggest that no single signal transduction pathway can fully account for the regulation of any of these key steps, owing to redundancy in the signalling pathways that mediate glucose uptake to ensure maintenance of muscle energy supply during physical activity. Here, we review the molecular mechanisms that regulate the movement of glucose from the capillary bed into the muscle cell and discuss what is known about their integrated regulation during exercise. Novel developments within the field of mass spectrometry-based proteomics indicate that the known regulators of glucose uptake are only the tip of the iceberg. Consequently, many exciting discoveries clearly lie ahead.

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Figure 1: Exercise enhances insulin sensitivity.
Figure 2: Molecular mechanisms of exercise-regulated glucose uptake by skeletal muscle.
Figure 3: An integrated view of exercise-stimulated glucose uptake.

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Acknowledgements

E.A.R is supported by grants from the Danish Council for Independent Research Natural Sciences (grant 4002-00492B), the Danish Council for Independent Research Medical Sciences (grant 0602-02273B), the Novo Nordisk Foundation (grant 1015429) and the University of Copenhagen Excellence Program for Interdisciplinary Research (“Physical activity and nutrition for improvement of health”). L.S. and M.K. are supported by Postdoctoral Fellowships from the Danish Council for Independent Research Medical Sciences (grants 5053–00155 and 4004–00233, respectively). T.E.J. is supported by an excellence grant from the Novo Nordisk Foundation (grant 15182).

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L.S., M.K., E.A.R. and T.E.J. researched the data for the article. L.S., M.K., E.A.R. and T.E.J. provided a substantial contribution to discussions of the content. L.S., M.K., E.A.R. and T.E.J. contributed equally to writing the article and to review and/or editing of the manuscript before submission.

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Correspondence to Erik A. Richter.

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Sylow, L., Kleinert, M., Richter, E. et al. Exercise-stimulated glucose uptake — regulation and implications for glycaemic control. Nat Rev Endocrinol 13, 133–148 (2017). https://doi.org/10.1038/nrendo.2016.162

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