Ketones: Metabolism's ugly duckling

Nutrition Reviews

Volumn 61, Issue 10, 2003, Pages 327-341

  VanItallie, Theodore B ^a   Nufert, Thomas H ^a  

^a ST LUKE S ROOSEVELT HOSPITAL CENTER   (United States)

Author keywords

Alzheimer's disease; Hyperketonemia; Ketogenic diet; Ketone metabolism; Mitochondriopathies; Parkinson's disease; Seizure disorders

Indexed keywords

ADENOSINE TRIPHOSPHATE; FAT; FREE RADICAL; GLUCOSE; KETONE;

ALZHEIMER DISEASE; BIOENERGY; BRAIN; DEGENERATIVE DISEASE; DIABETES MELLITUS; DIET RESTRICTION; EPILEPSY; GENETIC DISORDER; HUMAN; KETOGENIC DIET; LIVER; METABOLISM; METABOLITE; MITOCHONDRION; NERVE CELL; OXIDATION; PARKINSON DISEASE; REVIEW; SEIZURE; STARVATION; URINE;

ALZHEIMER DISEASE; DIETARY CARBOHYDRATES; HUMANS; KETONES; PARKINSON DISEASE; STARVATION;

EID: 0141919698     PISSN: 00296643     EISSN: None     Source Type: Journal    
DOI: 10.1301/nr.2003.oct.327-341     Document Type: Review

References (90)

1. Gerhardt J. Diabetes mellitus und aceton. Wiener Medizinische Presse. 1865;6:672.
2. Hirschfeld F. Beobachtungen über die Acentonurie und das Coma diabeticum. Z klin Med. 1895;28: 176-209.
3. Peters JP, Van Slyke DD. Quantitative Clinical Chemistry: Interpretations. Volume 1, 2nd edition. Baltimore: Williams & Wilkins; 1946:439.
4. Cohen PP. Studies in ketogenesis. J Biol Chem. 1937;119:333-346.
5. Cohen PP, Stark IE. Hepatic ketogenesis and ketolysis in different species. J Biol Chem. 1938;126:97-107.
6. Jowett M, Quastel JH. Fat metabolism III. The formation and breakdown of acetoacetic acid in animal tissues. Biochem J. 1935;29:2181-2191.
7. Chaikoff IL, Soskin S. The utilization of acetoacetic acid by normal and diabetic dogs before and after evisceration. Am J Physiol. 1928;87:58-72.
8. Barnes RH, Drury DR, Greeley PO, Wick AN. Utilization of the ketone bodies in normal animals and in those with ketosis. Am J Physiol. 1940;130:144-150.
9. Mirsky IA, Broh-Kahn RH. The influence of increased metabolism on β-hydroxybutyric acid utilization. Am J Physiol. 1937;120:446-450.
10. Waters ET, Fletcher JP, Mirsky IA. The relation between carbohydrate and β-hydroxybutyric acid utilization by the heart-lung preparation. Am J Physiol. 1938;122:542-546.
11. Johnson RE, Sargent F II, Passmore R. Normal variations in total ketone bodies in serum and urine of healthy young men. Q J Exp Physiol. 1958;43: 339-344.
12. Cahill GF Jr. Starvation. Trans Am Clin Climatol Assoc. 1982;94:1-21.
13. Foster DW. Diabetes mellitus. In: Wilson JD, Braunwald E, Isselbacher KJ, eds. Harrison's Principles of Internal Medicine. 12th edition. New York: McGraw-Hill; 1991:1750.
14. Crandall DI, Gurin S. Studies of acetoacetate formation with labeled carbon I. Experiments with pyruvate, acetate, and fatty acids in washed liver homogenates. J Biol Chem. 1949;181:829-843.
15. Lynen F, Henning U, Bublitz C, Sorbo B, Kröplin-Rueff L. Der chemische Mechanismus der Acetes-sigsäurebildung in der Leber. Biochem Ztschr. 1958;330:269-295.
16. Robinson AM, Williamson DH. Physiological roles of ketone bodies as substrates and signals in mammalian tissues. Physiol Rev. 1980;60:143-187.
17. Wastney ME, Hall SEH, Berman M. Ketone body kinetics in humans: a mathematical model. J Lipid Res. 1984;25:160-174.
18. Hall SEH, Wastney ME, Bolton TM, Braaten JT, Berman M. Ketone body kinetics in humans: the effects of insulin-dependent diabetes, obesity, and starvation. J Lipid Res. 1984;25:1184-1194.
19. Williamson DH, Mellanby J, Krebs HA. Enzymic determination of D(-)β-hydroxybutyric acid and acetoacetic acid in blood. Biochem J. 1962;82:90-96.
20. Krebs HA. The physiological role of the ketone bodies. Biochem J. 1961;80:225-233.
21. Cahill GF Jr. Starvation in man. N Engl J Med. 1970;282:668-675.
22. Laffel L. Ketone bodies: a review of physiology, pathophysiology and application of monitoring to diabetes. Diabetes Metab Res Rev. 1999;15:412-426.
23. Courtice FC, Douglas CG. The effects of prolonged muscular exercise on the metabolism. Proc R Soc. 1936;119B:381-439.
24. Owen OE, Reichard GAJ. Human forearm metabolism during progressive starvation. J Clin Invest. 1971;50:1538-1545.
25. Cahill GF Jr. Starvation in man. Clin Endocrinol Metab. 1975;5:397-417.
26. Behre JA. Studies in ketone body excretion. I. Daily variations in the ketone bodies of normal urine and the ketonuria of short fasts, with a note on diabetic ketonuria during insulin treatment. J Biol Chem. 1931;92:679-697.
27. Kartin BL, Man EB, Winkler AW, Peters JP. Blood ketones and serum lipids in starvation and water deprivation. J Clin Invest. 1944;23:824-835.
28. Johnson RE, Passmore R, Sargent F. Multiple factors in experimental human ketosis. Arch Intern Med. 1961;107:43-50.
29. Bach SJ, Hibbitt KG. Biochemical aspects of bovine ketosis. Biochem J. 1959;72:87-92.
30. Paterson P, Sheath J, Taft P, Wood C. Maternal and foetal ketone concentrations in plasma and urine. Lancet. 1967;1:862-865.
31. Aoki TT, Muller WA, Brennan MR, Cahill GF Jr. The metabolic effects of glucose in brief and prolonged fasted man. Am J Clin Nutr. 1975;28:507-511.
32. Heinbecker P. Studies on the metabolism of Eskimos. J Biol Chem. 1928;80:461-475.
33. Astrand P-O, Rodahl K. Textbook of Work Physiology. Physiological Bases of Exercise. 3rd edition. New York: McGraw-Hill; 1986:317.
34. McClellan WS, DuBois EF. Clinical calorimetry. XLV. Prolonged meat diets with a study of kidney function and ketosis. J Biol Chem. 1930;87:651-667.
35. Krebs HA. The metabolic fate of amino acids, In: Munro HN, Allison JB, eds. Mammalian Protein Metabolism. New York: Academic Press; 1964:126-176.
36. Jungas RL, Halperin ML, Brosnan JT. Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans. Physiol Rev. 1992;72: 419-448.
37. Swink TD, Vining EPG, Freeman JM. The ketogenic diet: 1997. Adv Pediatr. 1997;44:297-329.
38. VanItallie TB, Bergen SS Jr. Ketogenesis and hyperketonemia. Am J Med. 1961;31:909-918.
39. Cahill GF Jr, Herrera G, Morgan AP et al. Hormone-fuel interrelationships during fasting. J Clin Invest. 1966;45:1751-1769.
40. Sokoloff L. Metabolism of the central nervous system in vivo. In: Field J, ed. Handbook of Physiology, Section I. Neurophysiology. Baltimore: American Physiological Society, Williams and Wilkins; 1960: 1843-1864.
41. Benedict FG. A study of prolonged fasting. Washington, DC: The Carnegie Institute; 1915: Publication 203.
42. Gamble JL, Ross GS, Tisdall FF. The metabolism of fixed base during fasting. J Biol Chem. 1923;57: 633-695.
43. Leiter LA, Marliss EB. Survival during fasting may depend on fat as well as protein stores. JAMA. 1982;248:2306-2307.
44. Owen OE, Morgan AP, Kemp HG, et al. Brain metabolism during fasting. J Clin Invest. 1967;46: 1589-1595.
45. Lardy HA, Hansen RG, Phillips PH: The metabolism of bovine epididymal spermatozoa. Arch Biochem. 1945;6:41-51.
46. Lardy HA, Phillips PH. Studies of fat and carbohydrate oxidation in mammalian spermatozoa. Arch Biochem. 1945;6:53-61.
47. Kashiwaya Y, Sato K, Tsuchiya S, et al. Control of glucose utilization in working perfused rat heart. J Biol Chem. 1994;269:25502-25514.
48. Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9:651-658.
49. Kashiwaya Y, King MT, Veech RL. Substrate signaling by insulin: a ketone bodies ratio mimics insulin action in heart. Am J Cardiol. 1997;80:50A-64A.
50. Veech RL, Chance B, Kashiwaya Y, Lardy HA, Cahill GF Jr. Ketone bodies, potential therapeutic uses. IUBMB Life. 2001;51:241-247.
51. McHenry LC Jr. Cerebral blood flow. N Engl J Med. 1966;274:82-91.
52. Woodyatt RT. Objects and method of diet adjust ment in diabetics. Arch Intern Med. 1921;28:125-141.
53. Wilder RM. The effect of ketonemia on the course of epilepsy. Mayo Clin Bull. 1921;2:307-8.
54. Peterman MG. The ketogenic diet in the treatment of epilepsy. A preliminary report. Am J Dis Child. 1924;28:28-33.
55. Huttenlocher PR, Wilbourn AJ, Signore JM. Medium-chain triglycerides as a therapy for intractable childhood epilepsy. Neurology. 1971;21:1097-1103.
56. Gordon N. Medium-chain triglycerides in a ketogenic diet. Dev Med Child Neurol. 1977;19:535-544.
57. Bergen SS Jr, Hashim SA, Vanltallie TB. Hyperketonemia induced in man by medium-chain triglyceride. Diabetes. 1966;15:723-725.
58. Schwartz RH, Eaton J, Bower BD, Aynsley-Green A. Ketogenic diets in the treatment of epilepsy. Short-term clinical effects. Dev Med Child Neurol. 1989; 31:145-151.
59. Al-Mudallal AS, LaManna JC, Lust WD, Harik SL. Diet-induced ketosis does not cause cerebral acidosis. Epilepsia. 1996;37:258-261.
60. Uhleman ER, Neims AH. Anticonvulsant properties of the ketogenic diet in mice. J Pharmacol Exp Ther. 1972;180:231-238.
61. DeVivo DC, Malas KL, Leckie MP. Starvation and seizures. Arch Neurol. 1974;32:755-760.
62. 31P spectroscopic imaging at 4.1 T. Epilepsia. 1999;40:703-707.
63. Thavendiranathan P, Chow C, Cunnane S, McIntyre BW. The effect of the 'classic' ketogenic diet on animal seizure models. Brain Res. 2003;959:206-213.
64. Janigro D. Blood-brain barrier, ion homeostasis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. Epilepsy Res. 1999;37:223-232.
65. Leino RL, Gerhart DZ, Duelli R, Enerson BE, Drewes LR. Diet-induced ketosis increases monocarboxylate transporter (MCT1) levels in rat brain. Neurochem Int. 2001;38:519-527.
66. Seidner G, Garcia Alvarez M, Yeh J-I, et al. GLUT-1 deficiency syndrome caused by haploinsufficiency of the blood-brain-barrier hexose carrier. Nat Genet. 1998;18:166-191.
67. Klepper J, Voit T. Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain - a review. Eur J Pediatr. 2002;161:295-304.
68. Wexler ID, Hemalatha SG, McConnell J, et al. Outcome of pyruvate dehydrogenase deficiency treated with ketogenic diets. Studies in patients with identical mutations. Neurology. 1997;49: 1655-1661.
69. Wijburg FA, Barth PG, Bindoff LA, et al. Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet. Neuropediatrics. 1992;23:147-152.
70. Buckley BM, Williamson DH. Acetoacetate and brain lipogenesis: developmental pattern of acetoacetyl-coenzyme A synthetase in the soluble fraction of rat brain. Biochem J. 1973;132:653-656.
71. Patel MS, Owen OE. Lipogenesis from ketone bodies in rat brain. Evidence for conversion of acetoacetate into acetyl-coenzyme A in the cytosol. Biochem J. 1976;156:603-607.
72. Koper JW, Zeinstra EC, Lopes-Cardozo M, van Golde LM. Acetoacetate and glucose as substrates for lipid synthesis by rat brain oligodendrocytes and astrocytes in serum-free culture. Biochim Biophys Acta. 1984;796:20-26.
73. Minassian BA, Lee JR, Herbrick JA, Huizenga J, et al. Mutations in a gene encoding a novel protein tyrosine phosphatase cause progressive myoclonic epilepsy. Nat Genet. 1198;20:171-174.
74. Calabrese V, Scapagnini G, Giuffrida Stella AM, Bates TE, Clark JB. Mitochondrial involvement in brain function and dysfunction: relevance to aging, neurodegenerative disorders and longevity. Neurochem Res. 2001;26:739-764.
75. DiMauro S, Schon EA. Mitochondrial respiratory-chain diseases. N Engl J Med. 2003;348:2656-2668.
76. Schapira AH. Causes of neuronal death in Parkinson's disease. Adv Neurol. 2001;86:155-162.
77. Finsterer J. Parkinson's disease as a manifestation of mitochondriopathy. Acta Neurol Scand. 2002; 105:384-389.
78. Veech GA, Dennis J, Keeney PM, et al. Disrupted mitochondrial electron transport function increases expression of anti-apoptotic bcl-2 and bcl-XL proteins in SH-SY5Y neuroblastoma and in Parkinson's disease cybrid cells through oxidative stress. J Neurosci Res. 2000;61:693-700.
79. Kashiwaya Y, Takeshima T, Mori N, Nakashima K, Clarke K, Veech RL. D-β-Hydroxybutyrate protects neurons in models of Alzheimer's and Parkinson's disease. Proc Natl Acad Sci U S A. 2000;97:5440-5444.
80. Schon EA, Manfredi G. Neuronal degeneration and mitochondrial dysfunction. J Clin Invest. 2003;111: 303-312.
81. Ogawa M, Fukuyama H, Ouchi Y, Yamauchi H, Kimura J. Altered energy metabolism in Alzheimer's disease. J Neurol Sci. 1996;139:78-82.
82. Watson GS, Craft S. The role of insulin resistance in the pathogenesis of Alzheimer's disease: implications for treatment. CNS Drugs. 2003;17:27-45.
83. Molina JA, Jimenez-Jimenez FJ, Vargas C, et al. Cerebrospinal fluid levels of insulin in patients with Alzheimer's disease. Acta Neurol Scand. 2002;106: 347-350.
84. Hoshi M, Takashima K, Noguchi M, et al. Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in brain. Proc Natl Acad Sci U S A. 1996;93: 2719-2723.
85. Hoshi M, Takashima M, Murayama K, et al. Non-toxic amyloid beta peptide 1-42 suppresses acetylcholine synthesis. J Biol Chem. 1997;272:2038-2041.
86. Casley CS, Canevari L, Land JM, Clark JB, Sharpe MA. Beta-amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J Neurochem. 2002;80:91-100.
87. Sharman MJ, Kraemer WJ, Love DM, et al. A ketogenic diet favorably affects serum biomarkers for cardiovascular disease in normal-weight young men. J Nutr. 2002;132:1879-1885.
88. Furth SL, Casey JC, Pyzik PL, et al. Risk factors for urolithiasis in children on the ketogenic diet. Pediatr Nephrol. 2000;15:125-128.
89. Berry-Kravis E, Booth G, Taylor A, Valentino LA. Bruising and the ketogenic diet: evidence for diet-induced changes in platelet function. Ann Neurol. 2001;49:98-103.
90. Best TH, Franz DN, Gilbert DL, Nelson DP, Epstein MR. Cardiac complications in pediatric patients on the ketogenic diet. Neurology. 2000;54:2328-2330.