On the Metabolism of Exogenous Ketones in Humans

Abstract

Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate “ketogenic” diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB) concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE); (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, or ketone salts (KS); sodium plus potassium βHB.Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001), which returned to baseline within 3–4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001), but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12) or a continuous nasogastric infusion (n = 4) to maintain blood D-βHB concentrations greater than 1 mM. Both drinks and infusions gave identical D-βHB AUC of 1.3–1.4 moles.min.Conclusion: We conclude that exogenous ketone drinks are a practical, efficacious way to achieve ketosis.

DietaryR, S‐1,3‐butanediol diacetoacetate reduces body weight and adiposity in obese mice fed a high‐fat diet

“…These findings support work by Webber and Edmond (49) which showed lower oxidation of S-bHB than the R isomer and superior substrate utilization for sterol and fatty acid synthesis in brain, spinal cord, and kidney. A more recent study by Stubbs et al (50), in which they used using racemic mixtures of Rand S-bHB, showed that the S enantiomer is oxidized to a lesser extent than the R enantiomer and is not a major oxidative fuel in humans at rest (50). In contrast, we showed that the major fate of exogenous R-bHB was oxidation in peripheral tissues.…”

Ketone ester supplementation blunts overreaching symptoms during endurance training overload

“…), but ketone esters allow blood ketones to reach ∼3‐fold higher levels than salts, with less incidence of gastrointestinal problems (Stubbs et al . ; Sansone et al . ).…”

“…However, exogenous ketone supplements recently emerged as a novel approach to induce ketosis. Exogenous supplements are available either in the form of ketone salts or ketone esters (Cox et al 2016;Brownlow et al 2017;Leckey et al 2017), but ketone esters allow blood ketones to reach ß3-fold higher levels than salts, with less incidence of gastrointestinal problems (Stubbs et al 2017;Sansone et al 2018). Recent studies in our and other laboratories have shown that post-exercise ingestion of the ketone monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate (KE) stimulates markers of protein synthesis and potentially also muscle glycogen repletion following exercise (Holdsworth et al 2017;Vandoorne et al 2017).…”

Inhibition of adenosine A1 receptors abolished the nutritional ketosis-evoked delay in the onset of isoflurane-induced anesthesia in Wistar Albino Glaxo Rijswijk rats

“…It has been demonstrated that exogenous ketone (ketogenic) supplements, such as ketone ester (KE), not only increase the level of ketone bodies (e.g., β-hydroxybutyrate/ βHB) [1][2][3][4][5], but also maintain blood levels of ketone bodies in both animals and humans [2,3,6]. Ketone bodies, such as βHB, enter into the brain through blood-brain barrier and provide fuel to brain cells [7,8] improving cell energy metabolism (e.g., enhance mitochondrial ATP synthesis) [9].…”

“…It was suggested that these effects of ketosis may have therapeutic potential in the treatment of several central nervous system (CNS) diseases, such as Alzheimer's disease, Parkinson's disease, epilepsy and psychiatric disorders (e.g., anxiety, schizophrenia and depression) [1,3,8,16]. It was also demonstrated that exogenous ketone supplements, such as KE and ketone salt (KS) are relatively well-tolerated without (or with minimal) adverse effects [1,2,6,16,17]. However, exact mechanism(s) of action of exogenous ketone supplement-generated ketosis on CNS diseases and other pathophysiological and physiological processes are largely unknown.…”