- People with type 2 diabetes or fatty liver disease produce less energy from ketone bodies
- Mitochondria in heart, muscle and liver tissue are less able to use ketones as fuel
- Raising ketone levels alone may not improve metabolism unless the underlying defect is addressed
The liver sits at the centre of the body’s energy economy.
When glucose is in short supply, it converts fatty acids into small molecules called ketone bodies, which can be used as fuel by the heart, muscles, kidneys and other organs.
In healthy people, this flexibility allows the body to switch between fuels depending on diet, activity and fasting.
In type 2 diabetes and metabolic dysfunction associated steatotic liver disease (MASLD, often called fatty liver disease), that flexibility is impaired.
Mitochondria, the cell’s energy producers, struggle to change efficiently between fuel sources.
A closer look at mitochondrial ketone use
Scientists at the German Diabetes Center, Heinrich Heine University Düsseldorf and University Hospital Düsseldorf set out to measure, directly for the first time, how well mitochondria in different human tissues can use ketone bodies to produce energy.
They examined tissue samples from obese people:
- With and without type 2 diabetes
- With and without MASLD
Using high resolution respirometry, a technique that measures oxygen consumption, they quantified mitochondrial energy production when ketone bodies were supplied as the main fuel.
Unlike earlier work that only measured ketone levels in blood or tissue, this approach captured the actual energy output from ketone metabolism in the cellular environment, albeit ex vivo rather than inside the living body.
Ketone metabolism is particularly fragile in insulin resistance
Across all insulin resistant states studied, mitochondria produced less energy from ketone bodies than in control tissue.
The pattern was consistent:
- Heart and skeletal muscle cells from overweight individuals with type 2 diabetes showed impaired ketone driven energy production
- Liver cells from overweight individuals with MASLD were similarly less efficient at using ketones
Strikingly, the defect in ketone oxidation was greater than the overall decline in mitochondrial function. This suggests ketone metabolism is especially vulnerable in insulin resistant conditions, rather than simply reflecting a general drop in mitochondrial performance.
Implications for treatment and diets
These findings have direct implications for people with diabetes and fatty liver disease.
Approaches that simply raise ketone levels, such as low carbohydrate diets, fasting or ketone supplements, may not deliver the expected metabolic benefits if mitochondria are unable to use ketones efficiently.
Future therapies may need to focus on:
- Restoring mitochondrial ketone oxidation capacity
- Improving metabolic flexibility so tissues can switch between fuels
- Targeting the specific molecular pathways that govern ketone metabolism in insulin resistant states
Follow up work from the same group aims to uncover the mechanisms driving this defect and to identify interventions that could restore normal ketone use.
