Mitochondrial Dysfunction linked to Insulin Resistance: New Insights into Diabetes and Fatty Liver Disease Treatment
A groundbreaking new study reveals that individuals with type 2 diabetes and fatty liver disease may struggle to effectively utilize ketone bodies – an alternative energy source – due to impaired mitochondrial function, perhaps opening new avenues for therapeutic intervention.
(Metabolic Dysfunction-Associated Steatotic liver Disease, commonly known as fatty liver disease), the mitochondria – the powerhouses of cells – lose their ability to efficiently switch between energy sources. Researchers from the German Diabetes Center, the Heinrich Heine University Düsseldorf, and the University Hospital Düsseldorf have, for the first time, comprehensively investigated how well mitochondria in various organs harness ketone bodies for energy production. their findings, published in EBioMedicine, suggest that restricted ketone body metabolism in the face of insulin resistance represents a promising new target for diabetes therapies.
The body’s ability to flexibly adapt its energy source based on nutrient availability is crucial for maintaining metabolic health. Ketone bodies are produced by the liver from fatty acids when glucose is scarce, serving as an alternative fuel for organs like the heart, skeletal muscles, and kidneys. While elevated ketone levels can support energy production in healthy individuals, the study emphasizes that the mitochondria’s capacity to utilize these ketone bodies is paramount. “Ketone bodies are more than just an alternative fuel under certain conditions – they are an crucial energy supplier for all forms of life,” stated a senior researcher involved in the study. “We examined whether the mitochondria of people with diabetes or fatty liver disease can continue to use them effectively.”
Researchers analyzed tissue samples from overweight individuals, both with and without type 2 diabetes or MASLD. Employing a novel technique called high-resolution respirometry, they directly measured mitochondrial energy production from ketone bodies within the cells’ natural environment – a significant advancement over previous studies that only assessed ketone body concentrations in blood or organs. “our approach maps the ketone body-driven energy production of the mitochondria…and thus provides a much more representative picture of metabolic changes,” explained a lead author of the study. Data was drawn from several ongoing studies, including the BARIA-DDZ study, the German Diabetes Study (GDS), and the METAB-HTx study.
The results were conclusive: mitochondrial energy production from ketone bodies was demonstrably lower in both type 2 diabetes and MASLD. Specifically, heart and skeletal muscle cells from overweight individuals with type 2 diabetes, and liver cells from those with MASLD, exhibited impaired ketone body utilization compared to their respective control groups. “Interestingly, this defect was more pronounced than the general decline in mitochondrial function,” noted a researcher. “This suggests that ketone body metabolism is particularly vulnerable in insulin resistance.”
The findings indicate that simply increasing ketone body levels may not be sufficient to improve energy production if the mitochondria are unable to effectively process them.Future therapeutic strategies shoudl therefore focus on enhancing mitochondrial utilization of ketone bodies and restoring overall metabolic adaptability. The research team plans to further investigate the underlying mechanisms driving this altered ketone body metabolism to identify potential therapeutic targets.
Scientific contacts: Dr.Elric Zweck, DDZ/UKD/HHU; Dr. Cesare Granata, DDZ.
Original publication: Impaired mitochondrial ketone body oxidation in insulin resistant states, EBioMedicine, Ziel, E., Piel, S., Schmidt, JW et al.DOI: https://doi.org/10.1016/j.ebiom.2025.106007.
