Exercise and diabetes: The role of reactive oxygen species

Some people in a scrum during a Rugby football match.
A new study in mice looks at the molecular mechanisms that underpin some of the health benefits of exercise. Ivo de Bruijn/Stocksy
  • The risks of type 2 diabetes and muscle wasting increase with age and decreased physical activity.
  • Researchers in Australia have isolated an enzyme associated with exercise that could be key to protecting against insulin resistance.
  • The same protective effect may be achievable through drugs that trigger the activation of this enzyme.

Our world’s population is getting older. The United Nations estimates that by 2050, 1 in 6 people will be over 65 years of age.

As we age, there is often a decrease in physical activity, which plays a role in the increased prevalence of type 2 diabetes and muscle wasting in older age.

While the benefits of physical activity are widely known and accepted, exactly how exercise promotes our metabolic health and reduces insulin resistance with age is less clear.

Discovery of exercise-related enzyme

A recent study in mice, which appears in Science Advances, points to an exercise-related enzyme that may help prevent the oxidative damage that occurs during the development of age-associated type 2 diabetes.

This enzyme is NADPH oxidase 4 (NOX4), and the levels of it in our skeletal muscles increase after exercise.

Skeletal muscles are the muscles connected to bones. Exercise exposes these muscles to stress that increases the body’s tolerance for future stressors.

As we exercise, reactive oxygen species (ROS) are generated in muscles. As the authors of the new study explain, ROS “generated during exercise are considered integral for the health-promoting effects of exercise.”

Lead study author Prof. Tony Tiganis, of the Monash University Biomedicine Discovery Institute, in Clayton, Australia, told Micro B Life about earlier findings that a ROS called hydrogen peroxide enhanced insulin sensitivity in mice.

In the new study, a team set out to investigate the relationship between ROS, exercise, and insulin resistance in more detail.

“Our findings provide insight into why and how exercise promotes insulin sensitivity and is beneficial for metabolic health,” Prof. Tiganis said.

Aging affects production of enzyme

As the lead author explained, the new study shows that ROS generated by NOX4 after exercise activate an enzyme. This enzyme, which is called NFE2L2, produces “a robust antioxidant defense response.”

This response does not immediately affect insulin sensitivity, Prof. Tiganis said, but it reduces “mitochondrial oxidative stress and the oxidative damage of proteins and lipids that otherwise lead to the decline in insulin sensitivity and the development of insulin resistance over time.”

ROS can damage cells through oxidative stress. Indeed, there is evidence that oxidative stress plays a role in the development of insulin resistance. Therefore, the body needs to deal with ROS swiftly.

During exercise, ROS are produced in greater amounts, so the body must learn to clear them right away. Exercise trains the body to remove ROS more quickly, thereby reducing the risk of damage caused by oxidative stress.

The authors conclude:

“In this study, we demonstrate that the generation of ROS by skeletal muscle NOX4 […] induces adaptive responses that prevent oxidative damage, maintain muscle function and exercise capacity, and attenuate the age- and obesity-associated development of insulin resistance.”

Importantly, the researchers also showed that NOX4 levels naturally decline with the age. So, as levels of NOX4 reduce over time, so do levels of ROS. And as ROS production drops, the body does not benefit from the “adaptive responses” that help maintain insulin sensitivity.

“Whereas NOX4 expression in mice or humans is increased in skeletal muscles after exercise, its abundance declines with age, at least in mice, and this contributes to the development of insulin resistance,” Prof. Tiganis said.

MBL asked Dr. Swapnil Khare, assistant professor of clinical medicine and medical director of inpatient diabetes at Indiana University’s Adult Academic Health Center, for her reaction to the Monash study.

“With aging and obesity, there are more problems with insulin resistance, glucose metabolism, and type 2 diabetes,” said Dr. Khare. “This is a very relevant study. We know we need a balance between the oxidative species in our bodies. Exercise helps that. Now we have a better picture of how it helps.”

Future research needed

Dr. Khare also noted that while it is important to promote exercise and healthy lifestyles, some people are not able to exercise due to physical limitations and other factors. She hopes that future studies on this topic will focus on those individuals.

The authors stress the need for further research into the beneficial effects of NOX4 in humans.

“If our findings in mice translate to humans,” said Prof. Tiganis, “such compounds and approaches may be useful for combatting the development of insulin resistance, and thereby type 2 diabetes, in aging and increasingly sedentary people.”

“Our next goal is to determine if skeletal muscle NOX4 also declines in aging humans and whether this is accompanied by diminished antioxidant defense and insulin resistance,” Prof. Tiganis concluded.

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