The hidden key in muscles to lowering blood sugar

For millions of people with diabetes or prediabetes, keeping blood sugar stable is a daily challenge. Exercise helps, as does medication – but for many, getting the body to respond is still difficult.

An international review of scientific articles on glucose metabolism in muscles – conducted by Erik Richter from the University of Copenhagen in Denmark together with Philip J. Bilan and Amira Klip from the University of Toronto in Canada – brings together more than 40 years of research. It spans experiments with humans and animals, cell studies and modern methods.

“It is important to periodically conduct a comprehensive review of a field of research so that we can say where we stand today. This is what we know, this is what we do not know. In this way, a review becomes a resource for people who want to enter the field of research but also for those who already work in the field and may want to update their knowledge,” says Erik Richter. “But of course, such a body of work should also lead to new insights.”

But why are researchers specifically interested in muscle glucose uptake?

“It turns out that muscles play a very important role in glucose metabolism. After a mixed meal, carbohydrate is broken down into glucose in the intestine, which is then released into the bloodstream. This causes blood sugar – blood glucose – levels to rise, stimulating the pancreas to release insulin. Insulin increases glucose uptake in the muscles, which account for about half of all glucose from food, making them the body’s biggest consumer of sugar,” explains Erik Richter, Professor at the Department of Nutrition, Exercise and Sports at the University of Copenhagen.

People with type 2 diabetes have impaired glucose uptake, and this contributes significantly to the regulation of blood glucose not functioning normally. Understanding the mechanisms that regulate glucose uptake in the muscles is therefore crucial.

“This provides insight into what goes wrong in type 2 diabetes and improves understanding of how to prevent type 2 diabetes and treat the people who have it,” continues Erik Richter.

Two keys – one door: how insulin and exercise unlock glucose in the muscles

Insulin is not the only way to get glucose into the muscles. Physical activity does the same thing – but via a different signalling pathway. Both pathways end at GLUT4, a transporter protein that moves to the cell surface to open the door for glucose.

“Our research shows that moderate physical activity can double the amount of glucose taken up by muscles compared with after a meal – an effect that is especially important for people for whom insulin is less effective.”

This shows how crucial physical activity is for regulating blood glucose – especially when insulin does not work properly because of insulin resistance.

“Muscle activity is even more intriguing because, for people with type 2 diabetes, glucose uptake still increases during activity, whereas insulin works poorly because they are more or less insulin resistant. The chemical signalling pathways in the cells that muscles use to absorb glucose are therefore interesting as possible alternatives to those that insulin normally activates – also when developing medicines.”

But of course, understanding how insulin itself works in the muscles is also important, and in the review the researchers attempted to map the molecular signalling pathways that insulin is currently known to use to increase muscle glucose uptake.

New discoveries: the secret route glucose takes into cells

For many years, it was believed that exercise and insulin affected the body in roughly the same way. But it turns out that they actually take different routes – and only meet at the end, when the glucose needs to enter the cells.

“We know that insulin and exercise each have their own motorway into muscle cells,” explains Erik Richter. “They start from very different points, but both converge at GLUT4 – the transport molecule usually hidden in the cell, which can quickly move to the surface to let glucose in. If the signal does not get through – for example, in the case of insulin resistance – GLUT4 remains in place and the glucose stays in the bloodstream.”

Today, researchers can peer much deeper into muscle cells. New technologies give them a map showing not only the mountain peaks but also the small tracks in between – revealing both the broad landscape and its tiniest details.

“We understand much more today. Before, we only saw the mountain peaks – now we are beginning to see the paths between them,” says Erik Richter. “It is not either–or,” he explains. “It is a network in which small signals control how much glucose the cell absorbs – and when.”

Researchers have discovered that muscle proteins can be switched on and off by small chemical signals – like flicking a light switch. Until recently, these redox reactions were seen only as harmful; now they are known to help cells fine-tune their response to both insulin and exercise.

“For example, we are currently investigating to what extent redox modifications of proteins help explain why physical activity increases the effect of insulin in muscles. Increased insulin sensitivity after physical activity is a very important property of muscle contractions. Physical activity benefits glucose metabolism in two ways: first, because muscle contractions themselves increase the muscles’ glucose uptake, and second, because muscle contractions increase the effect of insulin for many hours after physical activity.”

This new knowledge offers hope for better treatments, especially for those for whom medication does not work, and that exercise may be the key, even in cells that do not respond normally to insulin.

When the body finds the key itself: exercise’s path to glucose in the muscles

For the more than 500 million people worldwide living with type 2 diabetes or other forms of insulin resistance, this research is about something as concrete as understanding why exercise works – and how its effects might be mimicked with medication.

For a person with type 2 diabetes, this means that even when insulin treatment does not work as desired, exercise can still open the door for glucose – and thus lower blood sugar. This means that physical activity can sidestep some of the problems medication cannot always fix.

“We have patients who respond poorly to insulin treatment but still achieve better blood sugar control when they start exercising more,” he says. “It is not magic. It is biology.”

Could the effects of exercise one day be available on prescription?

In the long term, researchers hope that understanding these mechanisms will lead to new drugs that mimic exercise signalling – especially for people who cannot be physically active because of illness or old age.

“We dream of one day creating an exercise in a bottle that could mimic some of exercise’s most powerful effects. But it can never replace movement – the best thing will always be to use your body.”

In addition, the new knowledge offers hope for better ways to prevent complications such as cardiovascular disease and metabolic dysfunction–associated steatotic liver disease – diseases that often accompany diabetes and are closely tied to how the body handles sugar and fat.

“It starts with insulin resistance and leads to a number of problems,” says Erik Richter. “If we can break the chain early, we may be able to prevent serious disease.”

As technology has improved, researchers have gained new opportunities to study what actually happens in the muscles during and after exercise. This has opened up a whole new chapter in understanding the body’s metabolism.

“Previously, we could only measure one protein at a time. Now we can map thousands of signals and proteins simultaneously,” says Erik Richter. “This has significantly changed research.”

Joint quest to crack the diabetes code

Today, research is conducted in close collaboration between biologists, doctors and data experts. Biologists, doctors and data scientists are now working together to understand the complex network of signals that control glucose uptake and energy metabolism in the body.

“It is not just one pathway but a large network of signals that influence each other,” he says. “That is why we need to work together.”

“Physical activity is not just a good idea – it is an important treatment,” says Erik Richter. “And now we know why.”

Many questions remain unanswered – such as how age and genetics play a role – but one thing is clear: exercise is not just healthy; it is a biological key that can both prevent and remedy disease – and now gives researchers a new map to navigate by in the quest for better treatments.

“We have only scratched the surface,” he says. “But every step brings us closer to using this to prevent, treat – and perhaps one day even cure – some of the world’s most widespread diseases.”