Bis Hexanoyl (R)-1,3-Butanediol, a Novel Ketogenic Ester, Acutely Increases Circulating <scp>r</scp>- and <scp>s</scp>-ß-Hydroxybutyrate Concentrations in Healthy Adults

Crabtree, Christopher D.; Blade, Thanh; Hyde, Parker N.; Buga, Alex; Kackley, Madison L.; Sapper, Teryn N.; Panda, Oishika; Roa-Diaz, Stephanie; Anthony, James R.; Newman, John C.; Volek, Jeff S.; Stubbs, Brianna J.

doi:10.1080/07315724.2021.2015476

Cited by 14 publications

(28 citation statements)

References 38 publications

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“…1), including being fasted or fed, and being at rest or exercising, such that large variations exist in the degree of ketosis (Table 1). Ingestion of EKS, therefore, provides an alternative method to increase [R-βHB], and to a lesser extent [AcAc] [34][35][36][37][38][39], without injections or intravenous infusions [40], both of which would be impractical or illegal in most athletic contexts.…”

Section: Introductionmentioning

confidence: 99%

“…Ingestion in the fed state produces a rapid and dose-responsive increase in plasma [R-βHB] [ 39 , 106 ] e.g…”

Section: Introductionmentioning

confidence: 99%

“…Ketone esters have been prominent in the exercise science literature [ 35 , 38 , 42 , 44 , 47 – 49 , 54 , 58 – 60 , 66 – 68 , 70 – 72 , 78 , 81 , 86 , 87 , 99 ], and include the R-3-hydroxybutyl R-3-hydroxybutyrate (R-BD R-βHB) ketone monoester (KME) [ 34 , 44 , 100 ], originally developed to improve the physical and cognitive performance in warfighters [ 101 ], and the R,S-1,3-butanediol acetoacetate (R,S-BD AcAc) ketone diester (KDE) [ 35 , 102 , 103 ]. Other ketone esters that have been reported in the peer-reviewed literature to date include a compound of βHB and the short chain fatty acid butyrate (βHB-BA) [ 104 ], and a diester of hexanoic acid (a ketogenic MCFA) and R-1,3 butanediol (BH-BD) [ 39 , 105 , 106 ]. Given the numerous possible combinations of AcAc and βHB with ketogenic precursors (including BD, MCFAs, glycerol, and ketogenic amino acids), it is likely that additional forms of EKS will be developed in the future.…”

Section: Introductionmentioning

confidence: 99%

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Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

Evans

McClure²,

Koutnik³

et al. 2022

Sports Med

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The ketone bodies acetoacetate (AcAc) and β-hydroxybutyrate (βHB) have pleiotropic effects in multiple organs including brain, heart, and skeletal muscle by serving as an alternative substrate for energy provision, and by modulating inflammation, oxidative stress, catabolic processes, and gene expression. Of particular relevance to athletes are the metabolic actions of ketone bodies to alter substrate utilisation through attenuating glucose utilisation in peripheral tissues, anti-lipolytic effects on adipose tissue, and attenuation of proteolysis in skeletal muscle. There has been long-standing interest in the development of ingestible forms of ketone bodies that has recently resulted in the commercial availability of exogenous ketone supplements (EKS). These supplements in the form of ketone salts and ketone esters, in addition to ketogenic compounds such as 1,3-butanediol and medium chain triglycerides, facilitate an acute transient increase in circulating AcAc and βHB concentrations, which has been termed ‘acute nutritional ketosis’ or ‘intermittent exogenous ketosis’. Some studies have suggested beneficial effects of EKS to endurance performance, recovery, and overreaching, although many studies have failed to observe benefits of acute nutritional ketosis on performance or recovery. The present review explores the rationale and historical development of EKS, the mechanistic basis for their proposed effects, both positive and negative, and evidence to date for their effects on exercise performance and recovery outcomes before concluding with a discussion of methodological considerations and future directions in this field.

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Section: Introductionmentioning

confidence: 99%

“…Ingestion in the fed state produces a rapid and dose-responsive increase in plasma [R-βHB] [ 39 , 106 ] e.g…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

Evans

McClure²,

Koutnik³

et al. 2022

Sports Med

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“…There was a statistically significant correlation between β-OHB exposure and overall glucose-lowering effect for "KE4" (r (10) = -0.61, 95% CI: -0.88 to -0.06, p = 0.03) (Figure 4). In contrast, there were no statistically significant relationships between the two measures for "Ketone-IQ" (r (10) = -0.23, 95% CI: -0.71 to 0.40, p = 0.47) or "Kenetik" (r (10) = -0.33, 95% CI: -0.76 0.30, p = 0.29).…”

Section: Exploratory Analysesmentioning

confidence: 70%

“…Using the outcome data from this study (N = 15) and assuming 80% power with an alpha level of 0.05 and a moderate correlation between repeated measures of 0.5, a total sample size of N = 6 would be sufficient to detect an increase in average blood β-OHB compared to baseline (calculated using G*Power v3.1). In order to allow for a more nuanced evaluation of differences between ketone supplements and to account for any dropouts or missing blood samples, we enrolled 12 participants (aiming for equal males and females), which is in line with the sample size of previous pharmacokinetic studies of ketone supplements (5,10).…”

Section: Methodsmentioning

confidence: 99%

The Effect of Novel Exogenous Ketone Supplements on Blood Beta-Hydroxybutyrate and Glucose

Falkenhain¹,

Daraei²,

Little³

2022

Preprint

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Background Recently developed exogenous ketone monoester supplements can acutely raise blood β-OHB and lower blood glucose without the need for other nutritional modifications or invasive procedures. However, unpleasant taste and the potential for gastrointestinal discomfort may make adherence to a supplement regimen challenging. Two novel ketone supplements have been developed that promise an improved consumer experience but differ in their chemical properties; it is currently unknown how these affect blood β-OHB and blood glucose compared to the original ketone monoester supplement. Methods In a double-blind randomized cross-over pilot study, N = 12 healthy individuals (29 +/- 5 years, BMI = 25 +/- 4 kg/m2, 42% female) participated in three experimental trials with a different ketone supplement providing 10 grams of active ingredient in each trial; (i) the monoester (R)-3-hydroxybutyl (R)-3-hydroxybutyrate, (ii) D-β-hydroxybutyric acid with R-1,3-butanediol, and (iii) R-1,3-butanediol. Blood β-OHB and glucose were measured via finger prick capillary blood samples at baseline and across 240 minutes post-supplementation. Supplement acceptability, hunger, and gastrointestinal distress were assessed via questionnaires. Results β-OHB was elevated compared to baseline in all conditions. Total and incremental area under the curve (both p < 0.05) and peak β-OHB (p < 0.001) differed between conditions with the highest values seen in the ketone monoester condition. Blood glucose concentration was reduced after consumption of each supplement, with no differences in total and incremental area under the curve across supplements. Supplement acceptability was greatest for D-β-hydroxybutyric acid with R-1,3-butanediol, with no effect on hunger or evidence of gastrointestinal distress across all supplements. Conclusions Despite differences in composition, all ketone supplements tested raised β-OHB with the highest values seen after ketone monoester ingestion. Blood glucose was lowered to a similar extent across the assessed time frame with all three supplements.

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A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy

Meeusen,

Romagnolo,

Holsink

et al. 2024

Sci Rep

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The classic ketogenic diet is an effective treatment option for drug-resistant epilepsy, but its high fat content challenges patient compliance. Optimizing liver ketone production guided by a method comparing substrates for their ketogenic potential may help to reduce the fat content of the diet without loss in ketosis induction. Here, we present a liver cell assay measuring the β-hydroxybutyrate (βHB) yield from fatty acid substrates. Even chain albumin-conjugated fatty acids comprising between 4 and 18 carbon atoms showed a sigmoidal concentration-βHB response curve (CRC) whereas acetate and omega-3 PUFAs produced no CRC. While CRCs were not distinguished by their half-maximal effective concentration (EC50), they differed by maximum response, which related inversely to the carbon chain length and was highest for butyrate. The assay also suitably assessed the βHB yield from fatty acid blends detecting shifts in maximum response from exchanging medium chain fatty acids for long chain fatty acids. The assay further detected a dual role for butyrate and hexanoic acid as ketogenic substrate at high concentration and ketogenic enhancer at low concentration, augmenting the βHB yield from oleic acid and a fatty acid blend. The assay also found propionate to inhibit ketogenesis from oleic acid and a fatty acid blend at low physiological concentration. Although the in vitro assay shows promise as a tool to optimize the ketogenic yield of a fat blend, its predictive value requires human validation.

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Bis Hexanoyl (R)-1,3-Butanediol, a Novel Ketogenic Ester, Acutely Increases Circulating r- and s-ß-Hydroxybutyrate Concentrations in Healthy Adults

Cited by 14 publications

References 38 publications

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

Exogenous Ketone Supplements in Athletic Contexts: Past, Present, and Future

The Effect of Novel Exogenous Ketone Supplements on Blood Beta-Hydroxybutyrate and Glucose

A novel hepatocyte ketone production assay to help the selection of nutrients for the ketogenic diet treatment of epilepsy

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