A new study suggests that people with type 2 diabetes or fatty liver disease may have a harder time using ketones for energy. The research, published in EBioMedicine, offers fresh insight into how insulin resistance affects the way cells switch between fuels and why some metabolic pathways work differently in diabetes.
Ketone bodies are small molecules the liver makes when glucose is scarce. They rise during fasting, exercise and low-carbohydrate eating patterns and can serve as an alternative fuel for the heart, muscles, kidneys and other organs. But the new findings suggest that in insulin-resistant states, mitochondria are less able to turn ketones into usable energy.
The research team, based at the German Diabetes Center and collaborating institutions, analyzed tissue samples from people with and without type 2 diabetes or metabolic dysfunction-associated steatotic liver disease (MASLD). Using a high-resolution method that measures how mitochondria process different fuels, they evaluated how well cells from the heart, skeletal muscle and liver used ketone bodies.
“Ketone bodies are more than just an alternative fuel in specific conditions — they serve as important fuels for all domains of life to produce energy,” said Professor Michael Roden, senior author of the study. “In our study, we investigated if mitochondria in people with diabetes or fatty liver disease can still use them effectively.”
Across all insulin-resistant groups, mitochondrial energy production from ketones was reduced. Heart and skeletal muscle cells from participants with type 2 diabetes, and liver cells from participants with MASLD, showed lower ketone-driven energy output compared with those from people without these conditions. The impairment was more pronounced than the overall decline in mitochondrial function, suggesting that ketone metabolism may be particularly sensitive to insulin resistance.
“Interestingly, this defect was greater than the overall decline in mitochondrial function, suggesting that ketone body metabolism is particularly vulnerable in insulin resistance,” said lead author Dr. Elric Zweck.
These findings may help explain why raising ketone levels, through fasting or low-carbohydrate diets, does not affect everyone the same way. The researchers emphasize that the study was conducted ex vivo, meaning the fuel use was measured in tissue samples outside the body. This provides important mechanistic insight but does not directly measure how ketones function in a living person.
Still, the work points toward potential future therapies aimed at improving how mitochondria use ketones and restoring metabolic flexibility. Follow-up studies will explore why ketone processing is altered in insulin resistance and whether it can be improved.
This research was supported by national and regional science agencies in Germany, including the German Research Foundation, the German Diabetes Center and the German Federal Ministry of Health. Additional support came from the German Federal Ministry of Education and Research, the Ministry of Culture and Science of North Rhine-Westphalia, the German Center for Diabetes Research and several nonprofit foundations.