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
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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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).
The authors declare no competing financial interests.
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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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