Top Line:

Metformin, a common medication for managing type 2 diabetes, shows a complex relationship with exercise. While it does not significantly affect overall exercise capacity, it may blunt muscle hypertrophy, alter metabolic responses, and influence fat oxidation during exercise. 

Why It Matters:

Understanding the interaction between metformin and exercise is crucial for optimizing treatment strategies for people with type 2 diabetes or those at risk for metabolic diseases. Exercise is vital in managing blood sugar levels, improving cardiovascular health, and boosting muscle strength. However, when combined with metformin, the effectiveness of these outcomes may change. Healthcare professionals and patients must be aware of these potential effects to tailor exercise and medication plans effectively.

Key Takeaways:

Exercise Capacity and Performance: Metformin does not significantly affect VO2, VO2peak, or anaerobic threshold but increases perceived exertion and lowers respiratory exchange ratio (RER)¹.

1. Muscle Hypertrophy and Strength: Metformin may blunt muscle growth and strength gains in older adults during resistance training².
2. Fat Oxidation: During exercise, metformin increases fat oxidation but reduces it after exercise, suggesting opposing effects pre- and post-workout (Malin et al., 2010)⁵.
3. Glycemic Control: Metformin can interfere with exercise’s glucose-lowering effects³, but overall, it does not significantly reduce the benefits of exercise on fitness or blood sugar control in type 2 diabetes patients¹⁰.
4. Muscle Protection: Metformin may protect muscles from exercise-induced damage without enhancing overall performance⁷.

Introduction

Metformin is one of the most commonly prescribed medications for managing type 2 diabetes. It is known for its ability to improve insulin sensitivity and lower blood sugar levels. Given the well-documented benefits of exercise in enhancing metabolic health, researchers have explored the interactions between metformin and exercise. This article will delve into how metformin influences exercise performance, muscle adaptation, fat oxidation, and glycemic control, focusing on how these factors impact individuals on the medication.

Impact on Exercise Capacity and Performance

Several studies indicate that metformin does not dramatically alter overall exercise performance markers like VO2 or the ventilatory anaerobic threshold (VAT). However, it can have subtle effects. Metformin reduces the heart rate and RER during exercise, which may signal increased fat utilization for energy¹. Conversely, individuals report a higher rating of perceived exertion (RPE), suggesting that exercise feels harder when taking metformin, even though physical performance metrics like time-to-exhaustion do not significantly change.

Metformin presents more noticeable effects in older adults, notably regarding muscle hypertrophy. Studies show that when older adults engage in resistance training while on metformin, their muscle strength and growth gains are less pronounced than those not taking the medication². This blunting of muscle growth could be due to metformin’s interference with mitochondrial function and protein synthesis in muscle tissues⁴.

Metabolic and Glycemic Responses

One of metformin's more significant effects during exercise is its impact on metabolic responses. Metformin has been shown to increase heart rate and plasma lactate levels during exercise, suggesting that it influences how the body utilizes energy substrates³. It also enhances fat oxidation during exercise, but this effect is reversed post-exercise, leading to slightly reduced fat burning after the workout⁵.

Interestingly, metformin can reduce the glucose-lowering effect of exercise. While exercise alone helps lower blood sugar levels by improving insulin sensitivity, this effect is less pronounced when combined with metformin³. However, the reduction in glycemic response does not mean that metformin cancels out the benefits of exercise; it only attenuates them slightly.

Substrate Oxidation and Exercise Intensity

The RPE increases when people take metformin during exercise, making workouts feel more challenging¹. Despite this, metformin does not lower the intensity of exercise individuals choose, indicating that while the effort feels harder, people can still maintain their usual exercise routines⁶.

On a metabolic level, metformin shifts the body towards greater fat oxidation during exercise⁵. This shift could benefit weight management or metabolic health, as higher fat oxidation may improve body composition. However, after exercise, the fat oxidation effect decreases, highlighting metformin’s dual-phase impact on metabolism.

Muscle Protection and Adaptation

In addition to its metabolic effects, metformin also appears to have protective effects on muscles. It reduces exercise-induced muscle damage, which may help individuals recover faster after intense physical activity⁷. However, despite these protective effects, metformin does not enhance overall exercise performance. Its role in muscle adaptation is more about preservation than augmentation, meaning that while muscles may not grow as much in strength or size, they may recover and function better over time.

In animal studies, such as those conducted on rats, metformin combined with exercise improved bone density and muscle function. However, the combination was not more effective than exercise alone⁸. These findings suggest that metformin may offer protective benefits to skeletal muscle and bones without providing additional performance gains.

Glycemic Control and Fitness in Type 2 Diabetes

One of the critical concerns about metformin and exercise is whether the drug diminishes the glycemic control benefits of physical activity in people with type 2 diabetes. Contrary to some earlier short-term studies, more recent research suggests that metformin does not significantly reduce the positive effects of exercise on blood sugar control or overall fitness levels in individuals with type 2 diabetes¹⁰. This is important because although metformin may slightly alter how the body responds to exercise, it does not negate the long-term benefits of combining medication with regular physical activity.

Conclusion:

Metformin’s interaction with exercise presents a unique blend of beneficial and inhibitory effects. While it does not significantly impact overall exercise capacity or performance, it can affect muscle growth, fat oxidation, and metabolic responses during and after physical activity. Metformin may blunt muscle hypertrophy for older adults, but it also protects against muscle damage. Significantly, for people with type 2 diabetes, metformin does not drastically diminish the beneficial effects of exercise on glycemic control or fitness, supporting the continued use of exercise as a cornerstone of diabetes management, even while on the medication.

In summary, healthcare providers and patients should consider these interactions when designing exercise and medication plans, ensuring both are optimized for individual health goals.

References:

1. Das, S., Behera, S., Srinivasan, A., Xavier, A., Selvarajan, S., Kamalanathan, S., Sahoo, J., & Nair, N. (2018). Effect of metformin on exercise capacity: A meta-analysis.. Diabetes research and clinical practice, 144, 270-278. https://doi.org/10.1016/j.diabres.2018.08.022.
2. Walton, R., Dungan, C., Long, D., Tuggle, S., Kosmac, K., Peck, B., Bush, H., Tezanos, A., McGwin, G., Windham, S., Ovalle, F., Bamman, M., Kern, P., & Peterson, C. (2019). Metformin blunts muscle hypertrophy in response to progressive resistance exercise training in older adults: A randomized, double‐blind, placebo‐controlled, multicenter trial: The MASTERS trial. Aging Cell, 18. https://doi.org/10.1111/acel.13039.
3. Boulé, N., Robert, C., Bell, G., Johnson, S., Bell, R., Lewanczuk, R., Gabr, R., & Brocks, D. (2011). Metformin and Exercise in Type 2 Diabetes. Diabetes Care, 34, 1469 - 1474. https://doi.org/10.2337/dc10-2207.
4. Konopka, A., Laurin, J., Schoenberg, H., Reid, J., Castor, W., Wolff, C., Musci, R., Safairad, O., Linden, M., Biela, L., Bailey, S., Hamilton, K., & Miller, B. (2018). Metformin inhibits mitochondrial adaptations to aerobic exercise training in older adults. Aging Cell, 18. https://doi.org/10.1111/acel.12880.
5. Malin, S., Stephens, B., Sharoff, C., Hagobian, T., Chipkin, S., & Braun, B. (2010). Metformin's effect on exercise and postexercise substrate oxidation.. International journal of sport nutrition and exercise metabolism, 20 1, 63-71 . https://doi.org/10.1123/IJSNEM.20.1.63.
6. Pilmark, N., Petersen-Bønding, C., Holm, N., Johansen, M., Pedersen, B., Hansen, K., & Karstoft, K. (2021). The Effect of Metformin on Self-Selected Exercise Intensity in Healthy, Lean Males: A Randomized, Crossover, Counterbalanced Trial. Frontiers in Endocrinology, 12. https://doi.org/10.3389/fendo.2021.599164.
7. Abbadessa, G., Maniscalco, E., Grasso, L., Popara, J., Scipio, F., Franco, F., Mancardi, D., Pigozzi, F., Borrione, P., Berta, G., & Racca, S. (2023). Metformin Protects Rat Skeletal Muscle from Physical Exercise-Induced Injury. Biomedicines, 11. https://doi.org/10.3390/biomedicines11092334.
8. Stunes, A., Erben, R., Schüler, C., Eriksen, E., Tice, M., Vashishth, D., Syversen, U., & Mosti, M. (2019). Skeletal effects of plyometric exercise and metformin in ovariectomized rats.. Bone, 115193 . https://doi.org/10.1016/j.bone.2019.115193.
9. Boulé, N., Kenny, G., Larose, J., Khandwala, F., Kuzik, N., & Sigal, R. (2013). Does metformin modify the effect on glycaemic control of aerobic exercise, resistance exercise or both?. Diabetologia, 56, 2378-2382. https://doi.org/10.1007/s00125-013-3026-6.

Jon Esposito PhD, CSCS, CISSN, USAW