A Novel Powder Formulation of the Ketone Ester, Bis Hexanoyl (R)-1,3-Butanediol, Rapidly Increases Circulating ß-Hydroxybutyrate Concentrations in Healthy Adults

References

• Cahill GF.Jr., Fuel metabolism in starvation. Annu Rev Nutr. 2006;26:1–22. doi:10.1146/annurev.nutr.26.061505.111258.
   PubMed Web of Science ®Google Scholar
• Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab. 2014;25(1):42–52. doi:10.1016/j.tem.2013.09.002.
   PubMed Web of Science ®Google Scholar
• Mikkelsen KH, Seifert T, Secher NH, Grøndal T, van Hall G. Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-beta-hydroxybutyratemia in post-absorptive healthy males. J Clin Endocrinol Metab. 2015;100(2):636–43. doi:10.1210/jc.2014-2608.
   PubMed Web of Science ®Google Scholar
• Shaw DM, Merien F, Braakhuis A, Maunder E, Dulson DK. Exogenous ketone supplementation and keto-adaptation for endurance performance: disentangling the effects of two distinct metabolic states. Sports Med. 2020;50(4):641–56. doi:10.1007/s40279-019-01246-y.
   PubMed Web of Science ®Google Scholar
• Volek JS, Noakes T, Phinney SD. Rethinking fat as a fuel for endurance exercise. Eur J Sport Sci. 2015;15(1):13–20. doi:10.1080/17461391.2014.959564.
   PubMed Web of Science ®Google Scholar
• Poff AM, Koutnik AP, Egan B. Nutritional ketosis with ketogenic diets or exogenous ketones: features, convergence, and divergence. Curr Sports Med Rep. 2020;19(7):251–9. doi:10.1249/JSR.0000000000000732.
   PubMed Web of Science ®Google Scholar
• Cahill GF.Jr., Starvation in man. N Engl J Med. 1970;282(12):668–75. doi:10.1056/NEJM197003192821209.
   PubMedGoogle Scholar
• Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, Campbell WW, Hazbun TL, Volk BM, McCarter JP, Phinney SD, et al. Effectiveness and safety of a novel care model for the management of type 2 diabetes at 1 year: an open-label, non-randomized, controlled study. Diabetes Ther. 2018;9(2):583–612. doi:10.1007/s13300-018-0373-9.
   PubMed Web of Science ®Google Scholar
• Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15(6):412–26. doi:10.1002/(SICI)1520-7560(199911/12)15:6<412::AID-DMRR72>3.0.CO;2-8.
   PubMed Web of Science ®Google Scholar
• Robinson AM, Williamson DH. Physiological roles of ketone-bodies as substrates and signals in mammalian-tissues. Physiol Rev. 1980;60(1):143–87. doi:10.1152/physrev.1980.60.1.143.
   PubMed Web of Science ®Google Scholar
• Crabtree CD, Blade T, Hyde PN, Buga A, Kackley ML, Sapper TN, Panda O, Roa-Diaz S, Anthony JC, Newman JC, et al. Bis hexanoyl (R)-1,3-butanediol, a novel ketogenic ester, acutely increases circulating R- and S- ß-hydroxybutyrate concentra-tions in healthy adults. J Am Coll Nutr. 2022:1–9. doi:10.1080/07315724.2021.2015476.
   Google Scholar
• Poffe C, et al. Ketone ester supplementation blunts overreaching symptoms during endurance training overload. J Physiol. 2019;597(12):3009–27.
   PubMed Web of Science ®Google Scholar
• Poffe C, et al. Bicarbonate unlocks the ergogenic action of ketone monoester intake in endurance exercise. Med Sci Sports Exerc. 2021;53(2):431–41.
   PubMed Web of Science ®Google Scholar
• EVANS MARK, MCSWINEY FT, BRADY AJ, EGAN B. No benefit of ingestion of a ketone monoester supplement on 10-km running performance. Med Sci Sports Exerc. 2019;51(12):2506–15. doi:10.1249/MSS.0000000000002065.
   PubMed Web of Science ®Google Scholar
• Cox PJ, Kirk T, Ashmore T, Willerton K, Evans R, Smith A, Murray AJ, Stubbs B, West J, McLure SW, et al. Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 2016;24(2):256–68. doi:10.1016/j.cmet.2016.07.010.
   PubMed Web of Science ®Google Scholar
• Mujica-Parodi LR, Amgalan A, Sultan SF, Antal B, Sun X, Skiena S, Lithen A, Adra N, Ratai E-M, Weistuch C, et al. Diet modulates brain network stability, a biomarker for brain aging, in young adults. Proc Natl Acad Sci USA. 2020;117(11):6170–7. doi:10.1073/pnas.1913042117.
   PubMed Web of Science ®Google Scholar
• Evans M, Egan B. Intermittent running and cognitive performance after ketone ester ingestion. Med Sci Sports Exerc. 2018;50(11):2330–8. doi:10.1249/MSS.0000000000001700.
   PubMed Web of Science ®Google Scholar
• Coleman K, Phillips J, Sciarini M, Stubbs B, Jackson O, Kernagis D. A Metabolic intervention for improving human cognitive performance during hypoxia. Aerosp Med Hum Perform. 2021;92(7):556–62. doi:10.3357/AMHP.5767.2021.
   PubMed Web of Science ®Google Scholar
• Walsh JJ, Neudorf H, Little JP. 14-Day ketone supplementation lowers glucose and improves vascular function in obesity: a randomized crossover trial. J Clin Endocrinol Metab. 2021;106(4):e1738–e1754. doi:10.1210/clinem/dgaa925.
   PubMed Web of Science ®Google Scholar
• Myette-Cote E, et al. Prior ingestion of exogenous ketone monoester attenuates the glycaemic response to an oral glucose tolerance test in healthy young individuals. J Physiol. 2018;596(8):1385–95.
   PubMed Web of Science ®Google Scholar
• Myette-Côté É, Caldwell HG, Ainslie PN, Clarke K, Little JP. A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial. The American Journal of Clinical Nutrition. 2019;110(6):1491–501. doi:10.1093/ajcn/nqz232.
   PubMed Web of Science ®Google Scholar
• Greaves G, Xiang R, Rafiei H, Malas A, Little JP. Prior ingestion of a ketone monoester supplement reduces postprandial glycemic responses in young healthy-weight individuals. Appl Physiol Nutr Metab. 2021;46(4):309–17. doi:10.1139/apnm-2020-0644.
   PubMed Web of Science ®Google Scholar
• Selvaraj S, et al. Acute echocardiographic effects of exogenous ketone administration in healthy participants. J Am Soc Echocardiogr. 2021;35:305–311.
   PubMed Web of Science ®Google Scholar
• Monzo L, Sedlacek K, Hromanikova K, Tomanova L, Borlaug BA, Jabor A, Kautzner J, Melenovsky V. Myocardial ketone body utilization in patients with heart failure: The impact of oral ketone ester. Metabolism. 2021;115:154452. doi:10.1016/j.metabol.2020.154452.
   PubMed Web of Science ®Google Scholar
• Dearlove DJ, Harrison OK, Hodson L, Jefferson A, Clarke K, Cox PJ. The effect of blood ketone concentration and exercise intensity on exogenous ketone oxidation rates in athletes. Med Sci Sports Exerc. 2021;53(3):505–16. doi:10.1249/MSS.0000000000002502.
   PubMed Web of Science ®Google Scholar
• Stubbs BJ, Blade T, Mills S, Thomas J, Yufei X, Nelson FR, Higley N, Nikiforov AI, Rhiner MO, Verdin E, et al. In vitro stability and in vivo pharmacokinetics of the novel ketogenic ester, bis hexanoyl (R)-1,3-butanediol. Food Chem Toxicol. 2021;147:111859. doi:10.1016/j.fct.2020.111859.
   PubMed Web of Science ®Google Scholar
• Traul KA, Driedger A, Ingle DL, Nakhasi D. Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol. 2000;38(1):79–98. doi:10.1016/S0278-6915(99)00106-4.
   PubMed Web of Science ®Google Scholar
• Miller SA, Dymsza HA. Utilization by rat of 1,3-butanediol as a synthetic source of dietary energy. J Nutr. 1967;91(1):79–88. &. doi:10.1093/jn/91.1.79.
   PubMed Web of Science ®Google Scholar
• Mehlman MA, Tobin RB, Hahn HK, Kleager L, Tate RL. Metabolic fate of 1,3-butanediol in rat – liver tissue slices metabolism. J Nutr. 1971;101(12):1711–8. &. doi:10.1093/jn/101.12.1711.
   PubMed Web of Science ®Google Scholar
• Chen O, Blonquist T, Mah E, Sanoshy K, Beckman D, Nieman K, Winters B, Anthony J, Verdin E, Newman J, et al. Tolerability and safety of a novel ketogenic ester, bis-hexanoyl (R)-1,3-butanediol: a randomized controlled trial in healthy adults. Nutrients. 2021;13(6):2066. doi:10.3390/nu13062066.
   PubMed Web of Science ®Google Scholar
• Hoag SW, Hussain AS. The impact of formulation on bioavailability: summary of workshop discussion. J Nutr. 2001;131(4 Suppl):1389S–91S. doi:10.1093/jn/131.4.1389S.
   PubMedGoogle Scholar
• Livesey G, Tagami H. Interventions to lower the glycemic response to carbohydrate foods with a low-viscosity fiber (resistant maltodextrin): meta-analysis of randomized controlled trials. Am J Clin Nutr. 2009;89(1):114–25. doi:10.3945/ajcn.26842.
   PubMed Web of Science ®Google Scholar
• Kishimoto Y, Oga H, Tagami H, Okuma K, Gordon DT. Suppressive effect of resistant maltodextrin on postprandial blood triacylglycerol elevation. Eur J Nutr. 2007;46(3):133–8. doi:10.1007/s00394-007-0643-1.
   PubMed Web of Science ®Google Scholar
• Assembly WG. Declaration of Helsinki. Ethical principles for medical research involving human subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended by the: 56th WMA General Assembly, Tokyo, October 2004. 2004. Ferney-Voltaire, France: World Medical Association.
   Google Scholar
• Moore AR, Holland-Winkler AM, Ansley JK, Boone EDH, Schulte MKO. Reliability and diagnostic performance of a new blood ketone and glucose meter in humans. J Int Soc Sports Nutr. 2021;18(1):6. doi:10.1186/s12970-020-00404-2.
   PubMed Web of Science ®Google Scholar
• How Accurate are Glucose & Ketone Meters? [accessed 2022 Aug 5]. https://keto-mojo.com/testing-how-accurate-are-glucose-ketone-meters/.
   Google Scholar
• Blood Glucose Monitoring System Comparison Report (Keto-Mojo GK+, Keto-Mojo TD-4279, Abbott Precision Xtra, Accu-Chek Performa) [accessed 2022 Aug 5]. https://keto-mojo.com/wp-content/uploads/2021/02/Blood-Glucose-Monitoring-System-Accuracy-Comparison-Report.pdf.
   Google Scholar
• NCI. Automated Self-Administered 24-Hour (ASA24®) Dietary Assessment Tool. [cited 2022]. Available from: https://epi.grants.cancer.gov/asa24/.
   Google Scholar
• Ye Z, Arumugam V, Haugabrooks E, Williamson P, Hendrich S. Soluble dietary fiber (Fibersol-2) decreased hunger and increased satiety hormones in humans when ingested with a meal. Nutr Res. 2015;35(5):393–400. doi:10.1016/j.nutres.2015.03.004.
   PubMed Web of Science ®Google Scholar
• Stubbs BJ, et al. On the metabolism of exogenous ketones in humans. Front Physiol. 2017;8:848.
   PubMed Web of Science ®Google Scholar
• Shivva V, Cox PJ, Clarke K, Veech RL, Tucker IG, Duffull SB. The population pharmacokinetics of d-β-hydroxybutyrate following administration of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Aaps J. 2016;18(3):678–88. doi:10.1208/s12248-016-9879-0.
   PubMed Web of Science ®Google Scholar