Abstract
Much of the world's prominent and burdensome chronic diseases, such as diabetes, Alzheimer's, and heart disease, are caused by impaired metabolism. By acting as both an efficient fuel and a powerful signalling molecule, the natural ketone body, d-β-hydroxybutyrate (βHB), may help circumvent the metabolic malfunctions that aggravate some diseases. Historically, dietary interventions that elevate βHB production by the liver, such as high-fat diets and partial starvation, have been used to treat chronic disease with varying degrees of success, owing to the potential downsides of such diets. The recent development of an ingestible βHB monoester provides a new tool to quickly and accurately raise blood ketone concentration, opening a myriad of potential health applications. The βHB monoester is a salt-free βHB precursor that yields only the biologically active d-isoform of the metabolite, the pharmacokinetics of which have been studied, as has safety for human consumption in athletes and healthy volunteers. This review describes fundamental concepts of endogenous and exogenous ketone body metabolism, the differences between the βHB monoester and other exogenous ketones and summarises the disease-specific biochemical and physiological rationales behind its clinical use in diabetes, neurodegenerative diseases, heart failure, sepsis related muscle atrophy, migraine, and epilepsy. We also address the limitations of using the βHB monoester as an adjunctive nutritional therapy and areas of uncertainty that could guide future research.
Highlights
The human brain consumes between 100 and 120 grams of glucose daily
More than an efficient fuel, ketones regulate their own production by inhibiting lipolysis, spare glycogen and direct fuel oxidation in different tissues [5]. βHB acts as a signalling molecule in different tissues to co-ordinate a survival response during starvation; it increases histone acetylation, inducing the expression of genes that suppress oxidative stress [6], diminishes inflammation by blocking the NLRP3 inflammasome [7] and reduces sympathetic nervous system activity and total energy expenditure by inhibiting short-chain fatty acid signalling through GPR41 [8]
Ketone bodies themselves are a source of calories [62], βHB inhibits lipolysis via the PUMA-G receptor [16], reduces total energy expenditure by inhibiting short-chain fatty acid signalling through GPR41 [8] and most importantly, diminishes inflammation by blocking the NLRP3 inflammasome [7]
Summary
The human brain consumes between 100 and 120 grams of glucose daily. As 1.75 grams of muscle protein must be broken down to produce 1 gram of glucose, lean tissue mass would quickly atrophy in order to feed the glucose-deprived brain in early starvation [1], should no other adaptation take place. Ketogenic diets and intermittent fasting strategies for metabolic health have regained popularity in the last few years [25], research on the mechanisms behind their benefits is scarce and/or difficult to interpret because the interventions result in many physiological changes and because of the inherent limitations of animal models and diet studies [26] In this context, the βHB monoester offers the possibility of consistently, accurately, and singularly inducing high βHB blood concentrations in humans to allow the determination of results due to ketosis itself. Ketogenic diets have yielded positive results, to the point of reversing type 2 diabetes in 54% of patients in one 2-year study [49] It is unclear if the benefit arose from a reduced glucose load or a ketone specific mechanism. Having the most thoroughly studied safety profile so far ketone supplement so far, the βHB monoester offers an opportunity to advance research on novel nutritional strategies for this critical condition
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