Cellular quality control contributes to insulin resistance related to T2DM

Pennington Biomedical Research Center researchers have revealed critical insights into how impaired mitochondrial dynamics and quality control mechanisms in skeletal muscle influence insulin sensitivity in patients with T2DM.

John Kirwan

The research team, led by Pennington Biomedical Executive Director, Dr John Kirwan, focused on the significance of deubiquitinating enzymes (DUBs), in regulating mitochondrial dynamics within skeletal muscle. The findings suggest that mitochondrial fragmentation can bypass defects in mitophagy, the process by which cells remove damaged mitochondria, to sustain skeletal muscle quality control in patients with T2D. This adaptation may help maintain mitochondrial function despite impaired mitophagy.​

Therefore, people with T2D have fewer healthy mitochondria, the parts of the cell that produce energy, because dynamin-related protein 1 (DRP1) is working too much. In addition, another group of proteins – DUBs – are shown to interfere with a process that helps the body clean up damaged mitochondria. This interference makes it harder for muscles to use insulin properly, which is a key issue in diabetes.

The research findings advance the understanding of how impaired mitochondrial dynamics and quality control may contribute to skeletal muscle insulin resistance and the manifestation of T2DM, and also provides key evidence that DUB antagonists may play an important role in preventing or treating T2DM.

“Our research team examined how certain enzymes affect mitochondria in muscle cells of people with diabetes," said Dr Kirwan, Executive Director and George A Bray, Jr Endowed Super Chair in Nutrition at Pennington Biomedical. "We found that when the normal cleanup process for damaged mitochondria isn't working well, the cells adapt by breaking mitochondria into smaller pieces. This alternative approach helps maintain muscle function despite the metabolic challenges of Type 2 diabetes. Our study highlights the complex interplay between mitochondria and insulin, paving the way for future interventions aimed at improving metabolic health.”

The findings were featured in the paper, ‘Deubiquitinating Enzymes Regulate Skeletal Muscle Mitochondrial Quality Control and Insulin Sensitivity in Patients With Type 2 Diabetes’, published in the Journal of Cachexia, Sarcopenia and Muscle. To access this paper, please click here