On the metabolism of exogenous ketones in humans

Frontiers in Physiology

Volumn 8, Issue OCT, 2017, Pages

  Stubbs, Brianna J ^a   Cox, Pete J ^a   Evans, Rhys D ^a   Santer, Peter ^a   Miller, Jack J ^a,b   Faull, Olivia K ^a   Magor Elliott, Snapper ^a   Hiyama, Satoshi ^c   Stirling, Matthew ^d   Clarke, Kieran ^a  

^a UNIVERSITY OF OXFORD   (United Kingdom)

^b UNIVERSITY OF OXFORD   (United Kingdom)

^c NTT DOCOMO   (Japan)

^d UNIVERSITY OF HUDDERSFIELD   (United Kingdom)

Author keywords

(R) 3 hydroxybutyl (R) 3 hydroxybutyrate; D hydroxybutyrate; Exogenous ketones; Ketone ester; Ketone salt; Ketones

Indexed keywords

3 HYDROXYBUTYRIC ACID; FATTY ACID; GLUCOSE; KETONE DERIVATIVE; KETONE ESTER; KETONE SALT; TRIACYLGLYCEROL; UNCLASSIFIED DRUG;

ADULT; AREA UNDER THE CURVE; ARTICLE; BLOOD PH; CONTROLLED STUDY; FATTY ACID BLOOD LEVEL; FEMALE; GLUCOSE BLOOD LEVEL; HUMAN; HUMAN EXPERIMENT; INFORMED CONSENT; KETONE METABOLISM; LIMIT OF QUANTITATION; MALE; METABOLISM; NORMAL HUMAN; TRIACYLGLYCEROL BLOOD LEVEL; URINARY EXCRETION; URINE PH;

EID: 85032685119     PISSN: None     EISSN: 1664042X     Source Type: Journal    
DOI: 10.3389/fphys.2017.00848     Document Type: Article

References (71)

1. Ari, C., Kovács, Z., Juhasz, G., Murdun, C., Goldhagen, C. R., and Koutnik, A. P. (2016). Exogenous Ketone supplements reduce anxiety-related behavior in Sprague-Dawley and Wistar Albino Glaxo/Rijswijk Rats. Front. Mol. Neurosci. 9:137. doi: 10.3389/fnmol.2016.00137
2. Balasse, E. O. (1979). Kinetics of ketone body metabolism in fasting humans. Metab. Clin. Exp. 28, 41-50. doi: 10.1016/0026-0495(79)90166-5
3. Balasse, E. O., and Fery, F. (1989). Ketone-body production and disposal - effects of fasting, diabetes, and exercise. Diabetes Metab. Rev. 5, 247-270. doi: 10.1002/dmr.5610050304
4. Balasse, E., and Ooms, H. A. (1968). Changes in the concentrations of glucose, free fatty acids, insulin and ketone bodies in the blood during sodium hydroxybutyrate infusions in man. Diabetologia 4, 133-135. doi: 10.1007/BF01219433
5. Bates, D., M. M., Bolker, B. M., and Walker, S. (2015). _lme4: linear mixed-effects models using Eigen and S4_. R package version 1.1-8, J. Stat. Softw. 67, 1-48. doi: 10.18637/jss.v067.i01
6. Bergmeyer, H. U. (1965). Methods of Enzymatic Analysis. Weinheim: Verlag Chemie.
7. Biden, T. J., and Taylor, K. W. (1983). Effects of ketone bodies on insulin release and islet-cell metabolism in the rat. Biochem. J. 212, 371-377. doi: 10.1042/bj2120371
8. Bueno, N. B., Melo, I. S., Oliveira, S. L., and Rocha Ataide, T. (2013). Very-low-carbohydrate ketogenic diet v. low-fat diet for long-term weight loss: a meta-analysis of randomized controlled trials. Br. J. Nutr. 110, 1178-1187. doi: 10.1017/S0007114513000548
9. Burke, L. M., Ross, M. L., Garvican-Lewis, L. A., Welvaert, M., Heikura, I. A., Forbes, S. G., et al. (2016). A low-carbohydrate, high-fat diet impairs exercise economy and negates the performance benefit from intensified training in elite race walkers. J. Physiol. 595, 2785-2807. doi: 10.1113/JP273230
10. Cahill, G. F. Jr. (1970). Starvation in man. New Engl. J. Med. 282, 668-675. doi: 10.1056/NEJM197003192821209
11. Cahill, G. F., Herrera, M. G., Morgan, A. P., Soeldner, J. S., Steinke, J., Levy, P. L., et al. (1966). Hormone-fuel interrelationships during fasting. J. Clin. Invest. 45, 1751-1769. doi: 10.1172/JCI105481
12. Cai, Q. Y., Zhou, Z. J., Luo, R., Gan, J., Li, S. P., Mu, D. Z., et al. (2017). Safety and tolerability of the ketogenic diet used for the treatment of refractory childhood epilepsy: a systematic review of published prospective studies. World J. Pediatr. 13, 528-536. doi: 10.1007/s12519-017-0053-2
13. Caminhotto, R. O., Komino, A. C. M., de Fatima Silva, F., Andreotti, S., Sertié, R. A. L., Lima, F.B. et al. (2017). Oral ß-hydroxybutyrate increases ketonemia, decreases visceral adipocyte volume and improves serum lipid profile in Wistar rats. Nutr. Metab. 14:31. doi: 10.1186/s12986-017-0184-4
14. Chung, Y., Rabe-Hesketh, S., Dorie, V., Gelman, A., and Liu, J. (2013). A nondegenerate penalized likelihood estimator for variance parameters in multilevel models. Psychometrika 78, 685-709. doi: 10.1007/s11336-013-9328-2
15. Clarke, K., Tchabanenko, K., Pawlosky, R., Carter, E., Knight, N. S., Murray, A. J., et al. (2012a). Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate. Regul. Toxicol. Pharm. 63, 196-208. doi: 10.1016/j.yrtph.2012.04.001
16. Clarke, K., Tchabanenko, K., Pawlosky, R., Carter, E., Todd King, M., Musa-Veloso, K., et al. (2012b). Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regul. Toxicol. Pharm. 63, 401-408. doi: 10.1016/j.yrtph.2012.04.008
17. Cox, P. J., Kirk, T., Ashmore, T., Willerton, K., Evans, R., Smith, A., et al. (2016). Nutritional ketosis alters fuel preference and thereby endurance performance in athletes. Cell Metab. 24, 1-13. doi: 10.1016/j.cmet.2016.07.010
18. Declaration of Helsinki (2008). "Ethical principles for medical research involving human subjects," in 18th WMA General Assembly, Helsinki, Finland, June 1964, and Amended by the: 59th WMA General Assembly, Seoul (Ferney-Voltaire: World Medical Association.
19. Desrochers, S., David, F., Garneau, M., Jette, M., and Brunengraber, H. (1992). Metabolism of R-1,3-Butanediol and S-1,3-Butanediol in perfused livers from meal-fed and starved rats. Biochem. J. 285, 647-653. doi: 10.1042/bj2850647
20. Desrochers, S., Dubreuil, P., Brunet, J., Jette, M., David, F., Landau, B. R., et al. (1995a). Metabolism of (R,S)-1,3-Butanediol acetoacetate esters, potential parenteral and enteral nutrients in conscious pigs. Am. J. Physiol. 268, E660-E667.
21. Desrochers, S., Quinze, K., Dugas, H., Dubreuil, P., Bomont, C., David, F., et al. (1995b). R,S-1,3-Butanediol acetoacetate esters, potential alternates to lipid emulsions for total parenteral-nutrition. J. Nutr. Biochem. 6, 111-118. doi: 10.1016/0955-2863(94)00011-A
22. Edwards, L. M., Murray, A. J., Holloway, C. J., Carter, E. E., Kemp, G. J., Codreanu, I., et al. (2011). Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men. FASEB J. 25, 1088-1096. doi: 10.1096/fj.10-171983
23. Evans, M., Cogan, K. E., and Egan, B. (2017). Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation. J. Physiol. 595, 2857-2871. doi: 10.1113/JP273185
24. Feinman, R. D., Pogozelski, W. K., Astrup, A., Bernstein, R. K., Fine, E. J., Westman, E. C., et al. (2015). Dietary carbohydrate restriction as the first approach in diabetes management: critical review and evidence base. Nutrition 31, 1-13. doi: 10.1016/j.nut.2014.06.011
25. Forster, H. V., Dempsey, J. A., Thomson, J., Vidruk, E., and DoPico, G. A. (1972). Estimation of arterial PO2, PCO2, pH, and lactate from arterialized venous blood. J. Appl. Physiol. 32, 134-137.
26. Fraser, A. G., Rosalki, S. B., Gamble, G. D., and Pounder, R. E. (1995). Inter-individual and intra-individual variability of ethanol concentration-time profiles: comparison of ethanol ingestion before or after an evening meal. Br. J. Clin. Pharmacol. 40, 387-392. doi: 10.1111/j.1365-2125.1995.tb04561.x
27. Gilbert, D. L., Pyzik, P. L., and Freeman, J. M. (2000). The ketogenic diet: Seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J. Child Neurol. 15, 787-790. doi: 10.1177/088307380001501203
28. Guimont, M. C., Desjobert, H., Fonfrede, M., Vitoux, D., Benoist, J. F., Launay, J. M., et al. (2015). Multicentric evaluation of eight glucose and four ketone blood meters. Clin. Biochem. 48, 1310-1316. doi: 10.1016/j.clinbiochem.2015.07.032
29. Haces, M. L., Hernández-Fonseca, K., Medina-Campos, O. N., Montiel, T., Pedraza-Chaverri, J., and Massieu, L. (2008). Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Exp. Neurol. 211, 85-96. doi: 10.1016/j.expneurol.2007.12.029
30. Hall, S. E., Wastney, M. E., Bolton, T. M., Braaten, J. T., and Berman, M. (1984). Ketone body kinetics in humans: the effects of insulin-dependent diabetes, obesity, and starvation. J. Lipid Res. 25, 1184-1194.
31. Himwich, H. E., Bowman, K. M., Wortis, J., and Fazekas, J. F. (1937). Brain metabolism during the hypoglycemic treatment of Schizophrenia. Science 86, 271-272. doi: 10.1126/science.86.2229.271
32. Holdsworth, D. A., Cox, P. J., Kirk, T., Stradling, H., Impey, S. G., and Clarke, K. (2017). A ketone ester drink increases postexercise muscle glycogen synthesis in humans. Med. Sci. Sports Exerc. 49, 1789-1795. doi: 10.1249/MSS.0000000000001292
33. Holloway, C. J., Emmanuel, Y., Cochlinl, L. E., Szmigielski, C., Edwards, L. M., Francis, J. M., et al. (2009). A short-term, high fat diet impairs cardiac high energy phosphate metabolism, without change in cardiac function. J. Cardiovasc. Magn. Reson. 11:O72. doi: 10.1186/1532-429X-11-S1-O72
34. Horowitz, M., Maddox, A., Bochner, M., Wishart, J., Bratasiuk, R., Collins, P., et al. (1989). Relationships between gastric-emptying of solid and caloric liquid meals and alcohol absorption. Am. J. Physiol. 257, G291-G298.
35. Kesl, S. L., Poff, A. M., Ward, N. P., Fiorelli, T. N., Ari, C., Van Putten, A. J., et al. (2016). Effects of exogenous ketone supplementation on blood ketone, glucose, triglyceride, and lipoprotein levels in Sprague-Dawley rats. Nutr. Metab. 13:9. doi: 10.1186/s12986-016-0069-y
36. Koeslag, J. H., Noakes, T. D., and Sloan, A. W. (1980). Post-Exercise Ketosis. J. Physiol. 301, 79-90. doi: 10.1113/jphysiol.1980.sp013190
37. Kossoff, E. H., Krauss, G. L., McGrogan, J. R., and Freeman, J. M. (2003). Efficacy of the Atkins diet as therapy for intractable epilepsy. Neurology 61, 1789-1791. doi: 10.1212/01.WNL.0000098889.35155.72
38. Kwiterovich, P. O. Jr., Vining, E. P., Pyzik, P., Skolasky, R. Jr., and Freeman, J. M. (2003). Effect of a high-fat ketogenic diet on plasma levels of lipids, lipoproteins, and apolipoproteins in children. JAMA 290, 912-920. doi: 10.1001/jama.290.7.912
39. Lincoln, B. C., Desrosiers, C., and Brunengraber, H. (1987). Metabolism of S-3-Hydroxybutyrate in the Perfused-Rat-Liver. Arch. Biochem. Biophys. 259, 149-156. doi: 10.1016/0003-9861(87)90480-2
40. Madison, L. L., Mebane, D., Unger, R. H., and Lochner, A. (1964). The hypoglycemic action of ketones II. Evidence for a stiulatory effect of ketones on the pancreatic beta cells. J. Clin. Invest. 43, 408-415. doi: 10.1172/JCI104925
41. Marshall, D. M. (2010). Starvation physiology: reviewing the different strategies animals use to survive a common challenge. Comp. Biochem. Physiol. A 156, 1-18. doi: 10.1016/j.cbpa.2010.01.002
42. Martin, H. E., and Wick, A. N. (1943). Quantitative relationships between blood and urine ketone levels in diabetic ketosis. J. Clin. Invest. 22:235. doi: 10.1172/JCI101388
43. Melander, A. (1978). Influence of food on the bioavailability of drugs. Clin. Pharmacokinet. 3, 337-351. doi: 10.2165/00003088-197803050-00001
44. Mikkelsen, K. H., Seifert, T., Secher, N. H., Grondal, T., and van Hall, G. (2015). 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. 100, 636-643. doi: 10.1210/jc.2014-2608
45. Miles, J. M., Haymond, M. W., and Gerich, J. E. (1981). Suppression of glucose production and stimulation of insulin secretion by physiological concentrations of ketone bodies in man. J. Clin. Endocrinol. Metab. 52, 34-37. doi: 10.1210/jcem-52-1-34
46. Nakagawa, S., and Schielzeth, H. (2013). A general and simple method for obtaining R2 from generalized linear mixed-effects models. Methods Ecol. Evol. 4, 133-142. doi: 10.1111/j.2041-210x.2012.00261.x
47. Nebeling, L. C., Miraldi, F., Shurin, S. B., and Lerner, E. (1995). Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: two case reports. J. Am. Coll. Nutr. 14, 202-208. doi: 10.1080/07315724.1995.10718495
48. Newman, J. C., and Verdin, E. (2014). Ketone bodies as signaling metabolites. Trends Endocrin. Met. 25, 42-52. doi: 10.1016/j.tem.2013.09.002
49. O'Malley, T., Myette-Cote, E., Durrer, C., and Little, J. P. (2017). Nutritional ketone salts increase fat oxidation but impair high-intensity exercise performance in healthy adult males. Appl. Phys. Nutr. Metab. 42, 1031-1035. doi: 10.1139/apnm-2016-0641
50. Owen, O. E., Morgan, A. P., Kemp, H. G., Sullivan, J. M., Herrera, M. G., and Cahill, G. F. (1967). Brain metabolism during fasting. J. Clin. Invest. 46, 1589-1595. doi: 10.1172/JCI105650
51. Palmer, B. F. (2015). Regulation of potassium homeostasis. Clin. J. Am. Soc. Nephrol. 10, 1050-1060. doi: 10.2215/CJN.08580813
52. Plecko, B., Stoeckler-Ipsiroglu, S., Schober, E., Harrer, G., Mlynarik, V., Gruber, S., et al. (2002). Oral beta-hydroxybutyrate supplementation in two patients with hyperinsulinemic hypoglycemia: monitoring of beta-hydroxybutyrate levels in blood and cerebrospinal fluid, and in the brain by in vivo magnetic resonance spectroscopy. Pediatr. Res. 52, 301-306. doi: 10.1203/01.PDR.0000019439.27135.2B
53. Rodger, S., Plews, D., Laursen, P., and Driller, M. (2017). The effects of an oral ß-hydroxybutyrate supplement on exercise metabolism and cycling performance. J. Sci. Cycl. 6, 26-31. Available online at: http://www.jsc-journal.com/ojs/index.php?journal=JSC&page=article&op=view&path%5B%5D=304
54. Sato, K., Kashiwaya, Y., Keon, C. A., Tsuchiya, N., King, M. T., Radda, G. K., et al. (1995). Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 9, 651-658.
55. Scofield, R. F., Brady, P. S., Schumann, W. C., Kumaran, K., Ohgaku, S., Margolis, J. M., et al. (1982). On the lack of formation of L-(+)-3-hydroxybutyrate by liver. Arch. Biochem. Biophys. 214, 268-272. doi: 10.1016/0003-9861(82)90030-3
56. Shivva, V., Cox, P. J., Clarke, K., Veech, R. L., Tucker, I. G., and Duffull, S. B. (2016). The population pharmacokinetics of d-ß-hydroxybutyrate following administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate. AAPS J. 18, 1-11. doi: 10.1208/s12248-016-9879-0
57. Taboulet, P., Deconinck, N., Thurel, A., Haas, L., Manamani, J., Porcher, R., et al. (2007). Correlation between urine ketones (acetoacetate) and capillary blood ketones (3-beta-hydroxybutyrate) in hyperglycaemic patients. Diabetes Metab. 33, 135-139. doi: 10.1016/j.diabet.2006.11.006
58. Taggart, A. K. P., Kero, J., Gan, X. D., Cai, T. Q., Cheng, K., Ippolito, M., et al. (2005). (D)-beta-hydroxybutyrate inhibits adipocyte lipolysis via the nicotinic acid receptor PUMA-G. J. Biol. Chem. 280, 26649-26652. doi: 10.1074/jbc.C500213200
59. Thompson, J. R., and Wu, G. (1991). The effect of ketone bodies on nitrogen metabolism in skeletal muscle. Comp. Biochem. Physiol. B 100, 209-216. doi: 10.1016/0305-0491(91)90363-I
60. Toothaker, R. D., and Welling, P. G. (1980). The effect of food on drug bioavailability. Annu. Rev. Pharmacol. 20, 173-199. doi: 10.1146/annurev.pa.20.040180.001133
61. Toyooka, T., Hiyama, S., and Yamada, Y. (2013). A prototype portable breath acetone analyzer for monitoring fat loss. J. Breath Res. 7:036005. doi: 10.1088/1752-7155/7/3/036005
62. Tsai, Y., Chou, Y., Wu, A., Hu, C., Chen, C., Chen, F., et al. (2006). Stereoselective effects of 3-hydroxybutyrate on glucose utilization of rat cardiomyocytes. Life Sci. 78, 1385-1391. doi: 10.1016/j.lfs.2005.07.013
63. Valayannopoulos, V., Bajolle, F., Arnoux, J. B., Dubois, S., Sannier, N., Baussan, C., et al. (2011). Successful treatment of severe cardiomyopathy in glycogen storage disease type III With D,L-3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr. Res. 70, 638-641. doi: 10.1203/PDR.0b013e318232154f
64. Vandoorne, T., De Smet, S., Ramaekers, M., Van Thienen, R., De Bock, K., Clarke, K., et al. (2017). Intake of a ketone ester drink during recovery from exercise promotes mTORC1 signaling but not glycogen resynthesis in human muscle. Front. Physiol. 8:310. doi: 10.3389/fphys.2017.00310
65. Vangel, M. G. (1996). Confidence intervals for a normal coefficient of variation. Am. Stat. 50, 21-26.
66. Van Hove, J. L. K., Grunewald, S., Jaeken, J., Demaerel, P., Declercq, P. E., Bourdoux, P., et al. (2003). D,L-3-hydroxybutyrate treatment of multiple acyl-CoA dehydrogenase deficiency (MADD). Lancet 361, 1433-1435. doi: 10.1016/S0140-6736(03)13105-4
67. Vanitallie, T. B., Nonas, C., Di Rocco, A., Boyar, K., Hyams, K., and Heymsfield, S. B. (2005). Treatment of Parkinson disease with diet-induced hyperketonemia: a feasibility study. Neurology 64, 728-730. doi: 10.1212/01.WNL.0000152046.11390.45
68. Veech, R. L. (2004). The therapeutic implications of ketone bodies: the effects of ketone bodies in pathological conditions: ketosis, ketogenic diet, redox states, insulin resistance, and mitochondrial metabolism. Prostaglandins Leukot. Essent. Fatty Acids 70, 309-319. doi: 10.1016/j.plefa.2003.09.007
69. Veech, R. L., and King, M. T. (2016). "Chapter 26: Alzheimer's disease: causes and treatment," in Ketogenic Diet and Metabolic Therapies: Expanded Roles in Health and Disease, ed A. S. Masino (Oxford, UK: Oxford University Press), 241-253. doi: 10.1093/med/9780190497996.003.0026
70. Wastney, M.E., Hall, S.E., and Berman, M. (1984). Ketone body kinetics in humans: a mathematical model. J. Lipid Res. 25, 160-174.
71. Webber, R. J., and Edmond, J. (1977). Utilization of L(+)-3-Hydroxybutyrate, D(-)-3-Hydroxybutyrate, acetoacetate, and glucose for respiration and lipid-synthesis in 18-day-old rat. J. Biol. Chem. 252, 5222-5226.