Mitochondria Lose Ability to Use Ketones for Energy in Diabetes and Obesity

This groundbreaking study reveals a critical metabolic defect in insulin-resistant conditions that could reshape our understanding of diabetes, obesity, and fatty liver disease. Researchers discovered that mitochondria—the cellular powerhouses—lose their ability to efficiently use ketone bodies as fuel in these conditions.

Using gold-standard high-resolution respirometry, scientists measured ketone oxidation capacity in heart, skeletal muscle, kidney, and liver tissues from humans with type 2 diabetes, obesity, and metabolic dysfunction-associated steatotic liver disease (MASLD), comparing them to healthy controls. The results were striking: mitochondria from diabetic hearts and muscles showed 30% lower ketone-driven energy production, while obese kidneys had 15% reduced capacity.

Ketone bodies—β-hydroxybutyrate and acetoacetate—normally serve as crucial backup fuels when glucose is scarce. This study is the first to directly measure their contribution to mitochondrial ATP production in disease states, rather than relying on indirect markers like blood ketone levels or enzyme activity.

The findings suggest that metabolic inflexibility—the inability to switch between fuel sources—occurs earlier in disease progression than previously thought. This could explain why ketone-based therapies, despite showing promise in animal studies, often yield disappointing results in human trials for diabetes and obesity.

The research has immediate clinical implications. Reduced ketone oxidation capacity could serve as an early biomarker for mitochondrial dysfunction, potentially identifying at-risk individuals before overt diabetes develops. It also suggests that therapeutic strategies should focus on restoring mitochondrial flexibility rather than simply increasing ketone availability.