Skip to main content
Transactions of the American Clinical and Climatological Association logoLink to Transactions of the American Clinical and Climatological Association
. 2003;114:149–163.

Ketoacids? Good medicine?

George F Cahill Jr, Richard L Veech
PMCID: PMC2194504  PMID: 12813917

Abstract

D-beta-hydroxybutyrate, the principal "ketone" body in starving man, displaces glucose as the predominating fuel for brain, decreasing the need for glucose synthesis in liver (and kidney) and accordingly spares its precursor, muscle-derived amino acids. Thus normal 70 kg. man survives 2-3 months of starvation instead of several weeks, and obese man many months to over a year. Without this metabolic adaptation, H. sapiens could not have evolved such a large brain. Recent studies have shown that D-beta-hydroxybutyrate, the principal "ketone", is not just a fuel, but a "superfuel" more efficiently producing ATP energy than glucose or fatty acid. In a perfused rat heart preparation, it increased contractility and decreased oxygen consumption. It has also protected neuronal cells in tissue culture against exposure to toxins associated with Alzheimer's or Parkinson's. In a rodent model it decreased the death of lung cells induced by hemorrhagic shock. Also, mice exposed to hypoxia survived longer. These and other data suggest a potential use of beta-hydroxybutyrate in a number of medical and non-medical conditions where oxygen supply or substrate utilization may be limited. Efforts are underway to prepare esters of beta-hydroxybutyrate which can be taken orally or parenterally to study its potential therapeutic applications.

Full text

PDF
149

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Cahill G. F., Jr, Aoki T. T., Ruderman N. B. Ketosis. Trans Am Clin Climatol Assoc. 1973;84:184–202. [PMC free article] [PubMed] [Google Scholar]
  2. Cahill G. F., Jr, Herrera M. G., Morgan A. P., Soeldner J. S., Steinke J., Levy P. L., Reichard G. A., Jr, Kipnis D. M. Hormone-fuel interrelationships during fasting. J Clin Invest. 1966 Nov;45(11):1751–1769. doi: 10.1172/JCI105481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cahill G. F., Jr Starvation in man. N Engl J Med. 1970 Mar 19;282(12):668–675. doi: 10.1056/NEJM197003192821209. [DOI] [PubMed] [Google Scholar]
  4. Chance B., Sies H., Boveris A. Hydroperoxide metabolism in mammalian organs. Physiol Rev. 1979 Jul;59(3):527–605. doi: 10.1152/physrev.1979.59.3.527. [DOI] [PubMed] [Google Scholar]
  5. Flatt J. P., Blackburn G. L., Randers G., Stanbury J. B. Effects of ketone body infusion on hypoglycemic reaction in postabsorptive dogs. Metabolism. 1974 Feb;23(2):151–158. doi: 10.1016/0026-0495(74)90112-7. [DOI] [PubMed] [Google Scholar]
  6. Gilbert D. L., Pyzik P. L., Freeman J. M. The ketogenic diet: seizure control correlates better with serum beta-hydroxybutyrate than with urine ketones. J Child Neurol. 2000 Dec;15(12):787–790. doi: 10.1177/088307380001501203. [DOI] [PubMed] [Google Scholar]
  7. Hemingway C., Freeman J. M., Pillas D. J., Pyzik P. L. The ketogenic diet: a 3- to 6-year follow-up of 150 children enrolled prospectively. Pediatrics. 2001 Oct;108(4):898–905. doi: 10.1542/peds.108.4.898. [DOI] [PubMed] [Google Scholar]
  8. Hiraide A., Katayama M., Sugimoto H., Yoshioka T., Sugimoto T. Effect of 3-hydroxybutyrate on posttraumatic metabolism in man. Surgery. 1991 Feb;109(2):176–181. [PubMed] [Google Scholar]
  9. Huttenlocher P. R., Wilbourn A. J., Signore J. M. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology. 1971 Nov;21(11):1097–1103. doi: 10.1212/wnl.21.11.1097. [DOI] [PubMed] [Google Scholar]
  10. Ide T., Steinke J., Cahill G. F., Jr Metabolic interactions of glucose, lactate, and beta-hydroxybutyrate in rat brain slices. Am J Physiol. 1969 Sep;217(3):784–792. doi: 10.1152/ajplegacy.1969.217.3.784. [DOI] [PubMed] [Google Scholar]
  11. Kashiwaya Y., Takeshima T., Mori N., Nakashima K., Clarke K., Veech R. L. D-beta-hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A. 2000 May 9;97(10):5440–5444. doi: 10.1073/pnas.97.10.5440. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kirsch J. R., D'Alecy L. G., Mongroo P. B. Butanediol induced ketosis increases tolerance to hypoxia in the mouse. Stroke. 1980 Sep-Oct;11(5):506–513. doi: 10.1161/01.str.11.5.506. [DOI] [PubMed] [Google Scholar]
  13. Kossoff Eric H., Pyzik Paula L., McGrogan Jane R., Vining Eileen P. G., Freeman John M. Efficacy of the ketogenic diet for infantile spasms. Pediatrics. 2002 May;109(5):780–783. doi: 10.1542/peds.109.5.780. [DOI] [PubMed] [Google Scholar]
  14. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999 Nov-Dec;15(6):412–426. doi: 10.1002/(sici)1520-7560(199911/12)15:6<412::aid-dmrr72>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  15. Lai C. S., Fisher S. E., Hurst J. A., Vargha-Khadem F., Monaco A. P. A forkhead-domain gene is mutated in a severe speech and language disorder. Nature. 2001 Oct 4;413(6855):519–523. doi: 10.1038/35097076. [DOI] [PubMed] [Google Scholar]
  16. Müller W. A., Aoki T. T., Flatt J. P., Blackburn G. L., Egdahl R. H., Cahill G. F., Jr Effects of beta-hydroxybutyrate, glycerol, and free fatty acid infusions on glucagon and epinephrine secretion in dogs during acute hypoglycemia. Metabolism. 1976 Oct;25(10):1077–1086. doi: 10.1016/0026-0495(76)90015-9. [DOI] [PubMed] [Google Scholar]
  17. Newsholme E. A., Randle P. J. Regulation of glucose uptake by muscle. 7. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, on the concentrations of hexose phosphates, nucleotides and inorganic phosphate in perfused rat heart. Biochem J. 1964 Dec;93(3):641–651. doi: 10.1042/bj0930641. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Owen O. E., Morgan A. P., Kemp H. G., Sullivan J. M., Herrera M. G., Cahill G. F., Jr Brain metabolism during fasting. J Clin Invest. 1967 Oct;46(10):1589–1595. doi: 10.1172/JCI105650. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Pan J. W., Telang F. W., Lee J. H., de Graaf R. A., Rothman D. L., Stein D. T., Hetherington H. P. Measurement of beta-hydroxybutyrate in acute hyperketonemia in human brain. J Neurochem. 2001 Nov;79(3):539–544. doi: 10.1046/j.1471-4159.2001.00575.x. [DOI] [PubMed] [Google Scholar]
  20. Pardridge W. M., Boado R. J., Farrell C. R. Brain-type glucose transporter (GLUT-1) is selectively localized to the blood-brain barrier. Studies with quantitative western blotting and in situ hybridization. J Biol Chem. 1990 Oct 15;265(29):18035–18040. [PubMed] [Google Scholar]
  21. Pardridge W. M. Brain metabolism: a perspective from the blood-brain barrier. Physiol Rev. 1983 Oct;63(4):1481–1535. doi: 10.1152/physrev.1983.63.4.1481. [DOI] [PubMed] [Google Scholar]
  22. Pawan G. L., Semple S. J. Effect of 3-hydroxybutyrate in obese subjects on very-low-energy diets and during therapeutic starvation. Lancet. 1983 Jan 1;1(8314-5):15–17. doi: 10.1016/s0140-6736(83)91560-x. [DOI] [PubMed] [Google Scholar]
  23. Pulsifer M. B., Gordon J. M., Brandt J., Vining E. P., Freeman J. M. Effects of ketogenic diet on development and behavior: preliminary report of a prospective study. Dev Med Child Neurol. 2001 May;43(5):301–306. doi: 10.1017/s0012162201000573. [DOI] [PubMed] [Google Scholar]
  24. Robinson A. M., Williamson D. H. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980 Jan;60(1):143–187. doi: 10.1152/physrev.1980.60.1.143. [DOI] [PubMed] [Google Scholar]
  25. Ruderman N. B., Ross P. S., Berger M., Goodman M. N. Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats. Biochem J. 1974 Jan;138(1):1–10. doi: 10.1042/bj1380001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Schwartzkroin P. A. Mechanisms underlying the anti-epileptic efficacy of the ketogenic diet. Epilepsy Res. 1999 Dec;37(3):171–180. doi: 10.1016/s0920-1211(99)00069-8. [DOI] [PubMed] [Google Scholar]
  27. Sherwin R. S., Hendler R. G., Felig P. Effect of ketone infusions on amino acid and nitrogen metabolism in man. J Clin Invest. 1975 Jun;55(6):1382–1390. doi: 10.1172/JCI108057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Simpson I. A., Appel N. M., Hokari M., Oki J., Holman G. D., Maher F., Koehler-Stec E. M., Vannucci S. J., Smith Q. R. Blood-brain barrier glucose transporter: effects of hypo- and hyperglycemia revisited. J Neurochem. 1999 Jan;72(1):238–247. doi: 10.1046/j.1471-4159.1999.0720238.x. [DOI] [PubMed] [Google Scholar]
  29. Stafstrom C. E., Spencer S. The ketogenic diet: a therapy in search of an explanation. Neurology. 2000 Jan 25;54(2):282–283. doi: 10.1212/wnl.54.2.282. [DOI] [PubMed] [Google Scholar]
  30. Suzuki M., Suzuki M., Sato K., Dohi S., Sato T., Matsuura A., Hiraide A. Effect of beta-hydroxybutyrate, a cerebral function improving agent, on cerebral hypoxia, anoxia and ischemia in mice and rats. Jpn J Pharmacol. 2001 Oct;87(2):143–150. doi: 10.1254/jjp.87.143. [DOI] [PubMed] [Google Scholar]
  31. Tower D. B., Young O. M. Interspecies correlations of cerebral cortical oxygen consumption, acetylcholinesterase activity and chloride content: studies on the brains of the fin whale (Balaenoptera physalus) and the sperm whale (Physeter catadon). J Neurochem. 1973 Feb;20(2):253–267. doi: 10.1111/j.1471-4159.1973.tb12125.x. [DOI] [PubMed] [Google Scholar]
  32. Veech R. L., Chance B., Kashiwaya Y., Lardy H. A., Cahill G. F., Jr Ketone bodies, potential therapeutic uses. IUBMB Life. 2001 Apr;51(4):241–247. doi: 10.1080/152165401753311780. [DOI] [PubMed] [Google Scholar]
  33. Wolfsdorf J. I., Sadeghi-Nejad A., Senior B. Fat-derived fuels during a 24-hour fast in children. Eur J Pediatr. 1982 Mar;138(2):141–144. doi: 10.1007/BF00441141. [DOI] [PubMed] [Google Scholar]

Articles from Transactions of the American Clinical and Climatological Association are provided here courtesy of American Clinical and Climatological Association

RESOURCES