Research Highlight: Ketone body metabolism and β-Hydroxybutyrate

Research Highlight: Ketone body metabolism and β-Hydroxybutyrate

Sarah M. Rice

Introduction

Recent research on ketone bodies, notably β-hydroxybutyrate (β-HB), has demonstrated its potential as a metabolic substrate and signalling molecule with broad implications for metabolic, neurological, and psychiatric disorders

Ketone bodies: physiology and mechanisms

Ketone bodies, primarily β-HB, acetoacetate, and acetone, are produced in the liver during periods of low carbohydrate availability, such as fasting, prolonged exercise, or ketogenic diets. They serve as alternative energy substrates for peripheral tissues and the brain, especially under conditions of low glucose supply. Beyond their metabolic role, ketone bodies act as signalling molecules, modulating gene expression, inflammation, oxidative stress, and cellular resilience (1).

Ketone bodies in type 2 diabetes 

Emerging evidence supports a protective role for β-HB in type 2 diabetes (T2D). β-HB may regulate glucose and lipid metabolism, preserve pancreatic β-cell integrity, and improve insulin resistance. It also reduces oxidative stress, inflammation, and endoplasmic reticulum stress, while promoting mitochondrial biogenesis and autophagy. These mechanisms collectively address core pathologies of T2DM and its complications (1).

A recent study examining β-HB levels in patients with early diabetic kidney disease found that higher baseline fasting serum β-HB levels were associated with a lower risk of proteinuria in newly diagnosed T2D patients (2). These findings suggest further research into the role of β-HB would be useful, especially in the context of ketogenic interventions, where blood glucose control generally improves in the setting of increased β-HB concentration.

Astrocyte responses to ketogenic interventions

Ketone bodies are increasingly recognised for their neuroprotective and procognitive effects, particularly in the context of neurodegenerative diseases and ageing. Ketogenic interventions, ranging from dietary modifications to exogenous ketone supplementation, preserve neuronal function, improve metabolic efficiency, and increase cellular resilience to stress (3). Recent studies have highlighted the dynamic and multifaceted role of astrocytes in mediating the effects of ketone therapies. Astrocytes support neuronal metabolism and undergo morphological, metabolic, and transcriptional changes in response to ketone bodies. These adaptations include modulation of calcium signalling, neurotransmitter uptake, and transporter regulation, all required for synaptic function and neuroprotection (3). More research is needed to determine the best way to apply these findings to clinical situations.  

Ketone bodies in anorexia nervosa: an alternative energy source for the brain

Recent genetic and metabolic research implicates metabolic dysfunction in the pathophysiology of anorexia nervosa. Despite this, current treatments rarely target metabolic pathways. Ketones and ketogenic interventions may offer alternative energy sources for the brain, potentially modulating behaviour and neurobiology in anorexia nervosa. The literature suggests that exogenous ketones and ketone precursors could be explored as adjunctive therapies, though more research is required (4).

Clinical implications and future directions

The recent research on ketone bodies reflects their potential across a spectrum of metabolic, neurological, and psychiatric conditions. Clinically, ketogenic interventions show promise as having a supportive role in disease management. Further clinical trials are needed to determine optimal protocols, safety profiles, and long-term outcomes.

References

1. Ding, X., Wu, J., Wang, L., Li, K., Gao, H., Wu, M., Zhang, Q., Han, R., Wang, W., & Xiao, W. β‑hydroxybutyric acid as a potential therapeutic metabolite for type 2 diabetes mellitus (Review). International Journal of Molecular Medicine. 2026. https://doi.org/10.3892/ijmm.2025.5683

2. Kim, S., Lee, M., Lee, Y., Kang, E., Cha, B., & Lee, B. Protective Role of Serum β‑Hydroxybutyrate in Early Diabetic Kidney Disease: A Longitudinal Study. Diabetes Therapy. 2025 https://doi.org/10.1007/s13300-025-01819-3

3. Coronado-Monroy, P., & Massieu, L. The versatile and multifacetic role of astrocytes in response to ketogenic interventions. Reviews in the Neurosciences. 2025 https://doi.org/10.1515/revneuro-2025-0096

4. Micali, N., Miletta, M., Clemmensen, C., Pappaianni, E., Lazeyras, F., Cuenoud, B., & Sandi, C. Providing alternative fuel for the brain in anorexia nervosa: a review of the literature on ketones and their effects on metabolism and the brain. Translational Psychiatry. 2025 https://doi.org/10.1038/s41398-025-03591-1

Further reading

5. Tabatabaei Dakhili, S.A. et al. (2025) ‘The multifaceted roles of ketones in physiology’, Experimental Physiology [Preprint]. Available at: https://doi.org/10.1113/EP092243.

6. Fante, C. et al. (2025) ‘The role of β-hydroxybutyrate testing in ketogenic metabolic therapies’, Frontiers in Nutrition, 12, p. 1629921. Available at: https://doi.org/10.3389/fnut.2025.1629921.

December 2025                                           © 2025 Sarah M. Rice. All rights reserved.