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Does the Anti-Diabetic Agent Metformin Prevent the Beneficial Effects of Exercise?

This is an excerpt from Physiology of Sport and Exercise 9th Edition With HKPropel Access by W. Larry Kenney,Jack H. Wilmore & David L. Costill.

Research Perspective 2.2

It is well known that both reductions in cardiorespiratory fitness and impairments in glucose control and insulin sensitivity—both of which occur as a part of normal aging—predict the development of disease, disability, and death. The Diabetes Prevention Program has shown that habitual aerobic exercise and, independently, metformin each substantially lower the risk of progressing from prediabetes to type 2 diabetes mellitus (T2DM). Metformin is the most widely prescribed medication to treat T2DM. Although its precise mechanisms of action have not been definitively established, metformin appears to inhibit the mitochondria within skeletal muscle, which subsequently alters the energetic or redox status of the cell. Intriguingly, there is growing interest in using metformin to delay the onset of age-related cardiovascular disease, even in individuals without T2DM. However, most of the evidence suggests that adding metformin to exercise training not only does not have an additive effect but instead actually prevents the typical exercise training–induced improvements in cardiorespiratory fitness and insulin sensitivity. Konopka and colleagues (2019) attempted to understand the mechanism through which this inhibitory effect occurs. The investigators tested the hypothesis that metformin restricts improvements in cardiorespiratory fitness and insulin sensitivity by inhibiting the increase in skeletal muscle mitochondrial respiration and protein synthesis.

Similar to previous studies, the results clearly demonstrate that a clinical dose of metformin prevents the typical improvement in cardiorespiratory fitness and insulin sensitivity that occur after 12 weeks of aerobic exercise training in healthy older adults (see figure), as seen in skeletal muscle fiber biopsies from the vastus lateralis to evaluate mitochondrial respiration and protein synthesis rates. Metformin inhibited the increase in skeletal muscle mitochondrial respiration, which occurred in the absence of any effects of metformin on mitochondrial protein synthesis. These data add to the growing body of literature raising serious concerns about the broad recommendations for metformin as a treatment to target diseases of aging adults without T2DM. The results highlight the need for additional studies to examine how metformin interacts with exercise training to potentially produce both positive and negative effects before it is adopted for widespread use by adults without overt clinical disease.

Konopka, A.R., Laurin, J.L., Schoenberg, H.M., et al. (2019). Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell, 18(1), e12880.

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