Surprising discovery about how exercise training prevents diabetes

Diet and lifestyle 11. dec 2020 4 min Professor Erik A. Richter, Professor Jørgen Wojtaszewski +1 Written by Morten Busch

Physical activity is a way to prevent insulin resistance and type 2 diabetes. Researchers are therefore carrying out extensive studies to understand what types of exercise training optimally improve insulin action and why exercise is so beneficial. People’s muscles are part of the answer. Two new studies identify some of the key aspects of the benefits and indicate a surprising new candidate to increase insulin action after physical activity.

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Today, most people intuitively know that exercise is healthy, but no one fully understands why it is so healthy and how it can actually prevent disease. Type 2 diabetes is one of the diseases that is triggered by unhealthy lifestyles, but healthy lifestyles can also cure or at least significantly improve it. Determining the benefits of exercise training at the molecular level can therefore provide important information on how to optimize treatment, whether this comprises actual exercise training or the equivalent administered as a drug.

“A key element in understanding how exercise affects insulin action is understanding how physical activity affects muscles and how sensitive they are to insulin. Our latest studies show that physical activity improves insulin action in both the slow-twitch type I human muscle fibres and the fast-twitch type II muscle fibres. In addition, we conclude that the metabolic product succinate, which is formed in the body when carbohydrate and fat are metabolized, may be the key to the increased insulin action,” explains Jørgen Wojtaszewski, Professor, Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen.

Important observation for future strategies

The type I muscle fibres are better at creating energy through aerobic (with oxygen) processes over a long period of time; type II muscle fibres can conversely work faster anaerobically (without oxygen) but are far less useful for activity requiring endurance. The researchers tried to determine whether both types of muscle fibres improve insulin action during physical activity.

“This is really important to know, because if only one type of muscle fibre improves insulin action, then people who have or are at risk of developing type 2 diabetes should focus on a type of physical activity that activates this particular fibre type . Experiments in rodents have previously indicated such a difference between the types of muscle fibre, so we wanted to determine whether this also applies to humans,” says Jørgen Wojtaszewski.

To investigate this, the researchers asked nine young, lean and healthy untrained men with normal blood glucose to perform a bout of one-legged knee-extension exercise. Insulin action markedly improved after this exercise – but only in the muscles that performed the work. To examine muscular adaptation to the physical work, the researchers took biopsies from the thigh muscle of both the active and inactive legs, and further analysed the type I and type II muscle fibres.

“We found the expected differences in the concentrations of key proteins – metabolic enzymes and signal proteins that are important for insulin action. But more importantly, these proteins were regulated similarly in the context of insulin stimulation in type I and type II muscle fibres. This applied to fibres from both the inactive and previously active muscles, and we interpret this as the insulin-induced regulation of key proteins that increase insulin action being similar in the two types of muscle fibres,” explains Jørgen Wojtaszewski.

The new study may turn out to be extremely important. Earlier this year, the same research team very surprisingly showed that improvement in insulin action depends on the type, intensity and duration of physical activity.

“Now we have found that this is apparently not caused by training different muscle fibres. This therefore helps us to understand how to train to increase insulin action. This may also be an important observation for future pharmacological strategies targeting the effect of insulin on insulin action in human muscles – observations from animals indicate muscle fibre–specific mechanisms, which is apparently not true for humans,” adds Jørgen Wojtaszewski.

Searching for factors for many years

In a brand new study, the researchers also succeeded in uncovering a molecular mechanism that is key to how exercise improves insulin action. The Danish researchers and researchers at Harvard Medical School studied a molecule that leads to exercise benefitting metabolism and muscles.

“We have long been searching for substances with specific physiochemical properties that can explain this beneficial effect. In the new study, we found a substance that looks promising: succinate, a mitochondrial metabolite formed in the body when carbohydrate and fat are metabolized into energy in muscle mitochondria,” explains co-author Erik A. Richter, Professor, Deputy Head and Head of the Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen.

To investigate how succinate affects humans, the researchers recruited 25- to 35-year-old, healthy, non-obese, non-smoking men who were catheterized in the femoral artery and vein to allow local sampling of blood from the leg muscles during exercise training. After 2 hours of rest, insulin action was measured

“What we are actually measuring is insulin’s ability to affect how muscles take up glucose, and we were very surprised that the release of succinate from muscles during exercise was so clearly connected with increased insulin action after exercise. We have long been searching for factors that might explain increased insulin action after exercise . Succinate may be part of the explanation,” says Erik A. Richter.

Does not directly affect muscle cells

The experiments had two purposes. The researchers wanted to determine how succinate affects insulin action. In addition, they wanted to determine whether succinate regulates muscle remodelling. They therefore investigated how strength training affects normal mice versus mice lacking a receptor for succinate. Mice ran on a special resistance wheel, which leads to muscle growth and greater strength in ordinary mice, and the researchers collected blood s and harvested muscles.

“Exercise training causes muscles to release succinate, but in the mice without the succinate receptor, the succinate released did not cause their muscles to grow even though they trained, because succinate could not function when the receptor was missing,” explains co-author Bente Kiens, Professor, Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen.

Muscles comprise muscle cells surrounded by different types of tissue. Growing muscles require that different types of tissues, including connective tissue, tendons, blood vessels and nerves, react, develop and strengthen.

“The interesting part is that succinate does not affect the muscle cells themselves but instead affects the other tissues in muscle such as tendons and nerve tissue, which have been shown to be important for muscles to become stronger after exercising,” says Bente Kiens.

This new and surprising finding suggests that succinate is not only required to regulate insulin action in muscles but also to increase muscle strength. In addition to existing naturally in the human body, succinate is frequently used in foods and supplements to regulate acidity and enhance flavour because it creates part of the umami taste.

“However, it is unrealistic to imagine that using succinate as an actual dietary supplement or as a treatment for type 2 diabetes would be able to create physiological effects. In addition, the amounts consumed would be simply too great. So this new knowledge will primarily advance our understanding of why exercise is so healthy, even though we do not have the complete picture yet,” concludes Bente Kiens.

The insulin‐sensitizing effect of a single exercise bout is similar in type I and type II human muscle fibres” has been published in the Journal of Physiology. “pH-Gated Succinate Secretion Regulates Muscle Remodeling in Response to Exercise” has been published in Cell. In 2016, the Novo Nordisk Foundation awarded a grant to Jørgen Wojtaszewski for the project Exercising with Muscle Insulin Sensitivity. The Foundation also awarded a grant to Erik A. Richter in 2017 for the project Defining the AMPK-mediated Signalling Network and its Function.

My primary research interests are regulation of muscle metabolism, particularly during and following exercise. This includes acute exercise and exerci...

Our research focus on the mechanism(s) by which physical activity promotes metabolic health. Our studies have focused on the role of the energy sensor...

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