Glucose-sparing action of ketones boosts functions exclusive to glucose in the brain

Abstract

The ketogenic diet (KD) has been successfully used for a century for treating refractory epilepsy and is currently seen as one of the few viable approaches to the treatment of a plethora of metabolic and neurodegenerative diseases. Empirical evidence notwithstanding, there is still no universal understanding of KD mechanism(s). An important fact is that the brain is capable of utilizing ketone bodies for fuel. Another critical point is that glucose's functions span beyond its role as an energy substrate, and in most of these functions glucose is irreplaceable. By acting as a supplementary fuel, ketone bodies may free up glucose for its other crucial and exclusive function. We propose that this glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and major neurodegenerative diseases, which are all characterized by brain glucose hypometabolism.

Significance Statement The ketogenic diet (KD) was created in the 1920s as a therapy for refractory epilepsy. Since then, evidence accumulated showing its potential for other major neurodegenerative disorders. The exact mechanism of KD's protective activity still remains unknown, nonetheless. In the brain, ketone bodies can be utilized for cellular energy, at least partially substituting glucose as brain fuel. However, glucose has essential functions beyond those of just energy supply that cannot be provided by alternative substrates. We propose that the glucose-sparing effect of ketone bodies may underlie the effectiveness of KD in epilepsy and other major neurodegenerative diseases which are all characterized by brain glucose hypometabolism.