A little-known protein could be a major culprit in type 2 diabetes

The protein, known as Miro1, was found at higher levels in the skeletal muscles of people with Type 2 diabetes. In preclinical experiments, scientists discovered that removing Miro1 restored the muscles' response to insulin. They also found that exercise lowered Miro1 levels in people with the disease, offering new insight into how physical activity improves insulin sensitivity.

The findings were published in Nature Communications and could help researchers better understand the biological processes behind insulin resistance, a central feature of Type 2 diabetes.

How a Hidden Muscle Protein Affects Insulin Resistance

Miro1 (Mitochondrial Rho GTPase1) is located on the outer membrane of mitochondria, the tiny structures inside cells responsible for producing energy. Researchers believe that excessive amounts of this protein may interfere with how muscles respond to insulin, making it more difficult for the body to regulate blood sugar effectively.

To investigate this connection, the research team studied Miro1 in laboratory cells, preclinical models, and people living with Type 2 diabetes. By examining the protein across these different settings, they were able to explore its effects on muscle function and determine whether the findings could be relevant to human disease.

The results showed that Miro1 buildup impaired the muscles' response to insulin. When researchers removed the protein in preclinical models, insulin responsiveness returned, providing evidence that Miro1 contributes directly to this process.

Exercise Reduces a Protein Linked to Type 2 Diabetes

The researchers also investigated whether exercise could influence Miro1 levels in people with diabetes. In a randomized controlled trial involving participants with obesity and Type 2 diabetes, they compared the effects of aerobic exercise with those of standard medical care.

People assigned to the exercise group experienced a decline in Miro1 levels in their muscles. These changes occurred alongside improvements in insulin sensitivity and the muscles' capacity to produce energy.

The findings suggest that reducing Miro1 may be one of the ways exercise helps the body respond more effectively to insulin. They also raise the possibility that treatments designed to target the protein could eventually provide additional benefits alongside physical activity.

"Insulin resistance in muscle is at the heart of Type 2 diabetes, and its molecular causes have remained frustratingly unclear. This study, the product of years of work, identifies Miro1 as a key part of the answer. By tracing Miro1 from cells to preclinical models to patients, we show that Miro1 accumulation impairs the muscle's response to insulin, that removing it causally restores that response in our models, and that exercise reverses its buildup in people. For the field, this is a new therapeutic target. For patients, it deepens our understanding of why exercise is so effective and opens a path toward treatments that could one day complement it," said Dr. John P. Kirwan, the study's senior author.

A Promising New Direction for Diabetes Treatment

Kirwan recently became executive director of the OU Health Harold Hamm Diabetes Center at the University of Oklahoma. He carried out the research while working at LSU's Pennington Biomedical Research Center and has since brought his internationally recognized translational research program to the University of Oklahoma.

He also serves as Vice Provost for Diabetes Programs at the university and holds the Chickasaw Nation Endowed Chair in Diabetes Research.

The study's first author, Elizabeth Heintz, is a doctoral candidate who worked in the Integrated Physiology and Molecular Medicine Laboratory at Pennington Biomedical. Christopher Axelrod, the study's co-corresponding author, has also moved to the Harold Hamm Diabetes Center, joining Kirwan in continuing this line of research.

Dr. Jennifer Rood, Interim Senior Vice Chancellor and Executive Director of Pennington Biomedical, emphasized the importance of connecting laboratory discoveries with research involving patients and broader populations.

"This research exemplifies the breadth of scientific discovery at Pennington Biomedical, where research spans all levels, from basic science that reveals the biological mechanisms underlying disease to clinical studies and population-based research that informs public health," said Dr. Jennifer Rood, Interim Senior Vice Chancellor and Executive Director of Pennington Biomedical. "Dr. Kirwan and his team's findings on Miro1 demonstrate the value of this integrated approach, connecting fundamental discoveries about muscle function with insights into insulin resistance and the benefits of exercise in people with Type 2 diabetes. This work is advancing our understanding of diabetes and helping lay the foundation for future approaches to prevention and treatment."

Could Targeting Miro1 Lead to New Diabetes Therapies?

Although the results are encouraging, scientists still need to establish whether directly targeting Miro1 can produce safe and effective treatments for people with Type 2 diabetes. The restoration of insulin responsiveness was demonstrated in preclinical models, while the human trial showed that exercise reduced Miro1 levels alongside improvements in insulin sensitivity.

Kirwan plans to continue investigating these findings at the Harold Hamm Diabetes Center. His research will combine laboratory experiments with studies involving people to uncover more of the biological mechanisms responsible for diabetes and explore new strategies for preventing and treating the condition.

"Type 2 diabetes is an affliction in Oklahoma and nationally," he said. "Ultimately, we are looking for cures, and we hope these recent findings could be part of the solution."

The study received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute on Aging, the National Center for Complementary and Integrative Health, the National Heart, Lung, and Blood Institute, and the National Institute of General Medical Sciences.