Miro1 protein linked to insulin resistance in type 2 diabetes

A protein called Miro1 found at elevated levels in the skeletal muscle of people with Type 2 diabetes may contribute to insulin resistance, potentially making it a target for future treatments that help the body regulate blood sugar, according to a study published today in Nature Communications. Researchers found that removing Miro1 restored the muscles' response to insulin in preclinical models, while exercise reduced the protein's levels in people with Type 2 diabetes.

The study was led by senior author Dr. John P. Kirwan, recently named executive director of the OU Health Harold Hamm Diabetes Center at the University of Oklahoma. He conducted the research while at LSU's Pennington Biomedical Research Center and now brings his internationally recognized translational research program to OU, where he will build on his work to advance the understanding and treatment of diabetes. The study's first author is Elizabeth Heintz, a doctoral candidate who worked in the Integrated Physiology and Molecular Medicine Laboratory at Pennington Biomedical, and the co-corresponding author is Christopher Axelrod, who has since joined Kirwan at the Harold Hamm Diabetes Center.

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. 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."

Dr. Jennifer Rood, Interim Senior Vice Chancellor and Executive Director, Pennington Biomedical

Miro1 (Mitochondrial Rho GTPase1) is a protein found on the outer membrane of mitochondria, the structures inside cells that produce energy. To better understand its role in diabetes, Kirwan and his team examined the protein in cells, preclinical models and people with Type 2 diabetes. This approach allowed the researchers to investigate Miro1's effects on muscle function from the cellular level to its potential relevance in people with the disease.

"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," Dr. Kirwan said. He also serves as Vice Provost for Diabetes Programs at the University of Oklahoma and holds the Chickasaw Nation Endowed Chair in Diabetes Research.

The role of exercise was established through a randomized controlled trial involving people with obesity and Type 2 diabetes, during which researchers compared aerobic exercise with standard medical care. Participants in the exercise group experienced reductions in muscle Miro1 levels, along with improvements in insulin sensitivity and the muscles' ability to produce energy.

Although more research is needed to determine whether targeting Miro1 could lead to new treatments, the findings provide a foundation for further investigation into the causes of insulin resistance. At the Harold Hamm Diabetes Center, Kirwan will continue this translational research, connecting laboratory studies with studies in people to better understand the biological mechanisms underlying diabetes and identify potential new approaches to preventing and treating the disease.

"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."