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Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus

Nature Reviews Endocrinology volume 12, pages 633–645 (2016)Cite this article

Subjects

Key Points

  • Type 2 diabetes mellitus (T2DM) is associated with reduced mitochondrial function in the skeletal muscle and metabolic inflexibility

  • Healthy mitochondria require a tight balance between mitochondrial biogenesis and mitophagy, as well as between mitochondrial ATP and reactive oxygen species production

  • Exercise training is the intervention that most comprehensively improves the diverse aspects of mitochondrial function, along with whole-body and skeletal muscle insulin sensitivity

  • Calorie restriction and calorie restriction mimetics are strong nonexercise tools to boost mitochondrial function, probably via the activation of an AMPK–NAD+–SIRT pathway

  • Novel environmental and lifestyle factors, such as sleep and ambient temperature, might also affect mitochondrial function and insulin sensitivity in humans

Abstract

Low levels of physical activity and the presence of obesity are associated with mitochondrial dysfunction. In addition, mitochondrial dysfunction has been associated with the development of insulin resistance and type 2 diabetes mellitus (T2DM). Although the evidence for a causal relationship between mitochondrial function and insulin resistance is still weak, emerging evidence indicates that boosting mitochondrial function might be beneficial to patient health. Exercise training is probably the most recognized promoter of mitochondrial function and insulin sensitivity and hence is still regarded as the best strategy to prevent and treat T2DM. Animal data, however, have revealed several new insights into the regulation of mitochondrial metabolism, and novel targets for interventions to boost mitochondrial function have emerged. Importantly, many of these targets seem to be regulated by factors such as nutrition, ambient temperature and circadian rhythms, which provides a basis for nonpharmacological strategies to prevent or treat T2DM in humans. Here, we will review the current evidence that mitochondrial function can be targeted therapeutically to improve insulin sensitivity and to prevent T2DM, focusing mainly on human intervention studies.

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Figure 1: The conversion of acetyl-CoA to acetylcarnitine by carnitine-acyltransferase.
Figure 2: Mitochondrial network morphology.
Figure 3: Schematic overview of the role of NAD+ in the regulation of mitochondrial metabolism.
Figure 4: Circadian clock and mitochondrial function.

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Acknowledgements

M.K.C.H. is supported by a VIDI Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 917.66.359). V.S.-H. is supported by a VENI Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 916.11.136). P.S. is supported by a VICI Research Grant for innovative research from the Netherlands Organization for Scientific Research (Grant 918.96.618).

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Authors and Affiliations

  1. Department of Human Biology and Human Movement Sciences, Maastricht University Medical Center, Universiteitsingel 50, Maastricht, 6229 ER, Netherlands

    Matthijs K. C. Hesselink, Vera Schrauwen-Hinderling & Patrick Schrauwen

  2. NUTRIM, School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Center, Universiteitsingel 50, Maastricht, 6229 ER, Netherlands

    Matthijs K. C. Hesselink, Vera Schrauwen-Hinderling & Patrick Schrauwen

  3. Department of Radiology, Maastricht University Medical Center, P. Debyelaan 25, Maastricht, 6229 HX, Netherlands

    Vera Schrauwen-Hinderling

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M.K.C.H. researched data and wrote the manuscript. All authors contributed to discussion of the content and reviewed and/or edited the article before submission.

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Correspondence to Patrick Schrauwen.

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Hesselink, M., Schrauwen-Hinderling, V. & Schrauwen, P. Skeletal muscle mitochondria as a target to prevent or treat type 2 diabetes mellitus. Nat Rev Endocrinol 12, 633–645 (2016). https://doi.org/10.1038/nrendo.2016.104

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