Advertisement

Metabolic Brain Disease

, Volume 1, Issue 1, pp 63–82 | Cite as

β-Hydroxybutyrate reverses insulin-induced hypoglycemic coma in suckling-weanling mice despite low blood and brain glucose levels

  • Jean Holowach Thurston
  • Richard E. Hauhart
  • James A. Schiro
Original Contributions

Abstract

In normal suckling-weanling mice,dl-β-hydroxybutyrate (30 mmol/kg ip) stimulated insulin secretion and reduced plasma glucose levels. In the brains of these animals, glucose levels were tripled due to a reduced rate of glucose utilization (determined by deoxyglucose phosphorylation). Other metabolite changes were compatible with inhibition of hexokinase, phosphofructokinase, glyceraldehyde-P-dehydrogenase, and pyruvate dehydrogenase activities. In contrast to the decrease in cerebral glycolysis, metabolite changes were compatible with an increase in the Krebs citric acid metabolic flux. The brain energy charge was also elevated. While it is generally believed that ketone bodies cannot sustain normal brain metabolism and function in theabsence of glucose,dl-β-hydroxybutyrate (20 or 30 mmol/kg ip) reversed insulin (100 U/kg sc)-induced hypoglycemia despite the persistence of a critically reduced plasma glucose concentration and near-zero brain glucose levels. Metabolic correlates of possible significance in the behavioral recovery from coma were reductions of the elevated levels of brain aspartate to below normal and ammonia levels to normal. Levels of acetyl CoA were unchanged both before and after treatment withβ-Hydroxybutyrate.

Key words

brain ketone-body metabolism insulin hypoglycemia β-hydroxybutyrate brain carbohydrate, amino acid, ammonia, energy, and coenzyme A metabolism cerebral rate of glucose utilization 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Atkinson, D. E. (1968). The energy charge of the adenylate pool as a regulatory parameter. Interaction with feedback modifiers.Biochemistry 7: 4030–4034.Google Scholar
  2. 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 β-hydroxybutyrate infusions in man.Diabetologia 4: 133–135.Google Scholar
  3. Binkiewicz, A., Sadeghi-Nejad, A., Hochman, H., Loridan, L., and Senior, B. (1974). An effect of ketones on the concentration of glucose and of free fatty acids in man independent of the release of insulin.J. Pediat. 84: 226–231.Google Scholar
  4. Blass, J. P., and Lewis, C. A. (1973). Kinetic properties of the partially purified pyruvate dehydrogenase complex of ox brain.Biochem. J. 131: 31–37.Google Scholar
  5. Browning, E. T., and Schulman, M. P. (1968). [14C]Acetylcholine synthesis by cortex slices of rat brain.J. Neurochem. 15: 1391–1405.Google Scholar
  6. Butterworth, R. F., Markel, A. D., and Landreville, F. (1982). Regional amino acid distribution in relation to function in insulin hypoglycemia.J. Neurochem. 38: 1483–1489.Google Scholar
  7. Crane, P. D., Braun, L. D., Cornford, E. M., Cremer, J. E., Glass, J. M., and Oldendorf, W. H. (1978). Dose dependent reduction of glucose utilization by pentobarbital in rat brain.Stroke 9: 12–18.Google Scholar
  8. Crossland, J., Elliot, K. A. C., and Pappius, H. M. (1955). Acetylcholine content of brain during insulin hypoglycemia.Am. J. Physiol. 183: 23–25.Google Scholar
  9. Ferrendelli, J. A., and Chang, M.-M. (1973). Brain metabolism during hypoglycemia: Effect of insulin on regional central nervous system glucose and energy reserves in mice.Arch. Neurol. 28: 173–177.Google Scholar
  10. Folbergrová, J., Passonneau, J. V., Lowry, O. H., and Schulz, D. W. (1969). Glycogen, ammonia and related metabolites in the brain during seizures evoked by methionine sulphoximine.J. Neurochem. 16: 191–203.Google Scholar
  11. Ghajar, J. B. G., Plum, F., and Duffy, T. E. (1982). Cerebral oxidative metabolism and blood flow during acute hypoglycemia and recovery in unanesthetized rats.J. Neurochem. 38: 397–409.Google Scholar
  12. Gibson, G. E., and Blass, J. P. (1976). Impaired synthesis of acetylcholine in brain accompanying mild hypoxia and hypoglycemia.J. Neurochem. 27: 37–42.Google Scholar
  13. Goldberg, N. D., Passonneau, J. V., and Lowry, O. H. (1966). Effects of changes in brain metabolism on the levels of citric acid cycle intermediates.J. Biol. Chem. 241: 3997–4003.Google Scholar
  14. Gorell, J. M., Dolkart, P. H., and Ferrendelli, J. A. (1976). Regional levels of glucose, amino acids, high energy phosphates, and cyclic nucleotides in the central nervous system during hypoglycemic stupor and behavioral recovery.J. Neurochem. 27: 1043–1049.Google Scholar
  15. Gorell, J. M., Law, M. M., Lowry, O. H., and Ferrendelli, J. A. (1977). Levels of cerebral cortical glycolytic and citric acid cycle metabolites during hypoglycemic stupor and its reversal.J. Neurochem. 29: 187–191.Google Scholar
  16. Gorell, J. M., Navarro, C. P., and Schwendner, S. P. W. (1981). Regional CNS levels of acetylcholine and choline during hypoglycemic stupor and recovery.J. Neurochem. 36: 321–324.Google Scholar
  17. Grewaal, D. S., and Quastel, J. H. (1973). Control of synthesis and release of radioactive acetylcholine in brain slices from the rat. Effect of neurotropic drugs.Biochem. J. 132: 1–14.Google Scholar
  18. Hansford, R. G., and Johnson, R. N. (1975). The steady state concentrations of coenzyme A-SH and coenzyme A thioester, citrate, and isocitrate during tricarboxylate cycle oxidations in rabbit heart mitochondria.J. Biol. Chem. 250: 8361–8375.Google Scholar
  19. Hawkins, R. A., Williamson, D. H., and Krebs, H. A. (1971). Ketone-body utilization by adult and suckling rat brain in vivo.Biochem. J. 122: 13–18.Google Scholar
  20. Hucho, F. (1974). Regulation of the mammalian pyruvate dehydrogenase mutlienzyme complex by Mg++ and the adenine nucleotide pool.Eur. J. Biochem. 46: 499–505.Google Scholar
  21. Ide, T., Steinke, J., and Cahill, G. F., Jr. (1969). Metabolic interactions of glucose, lactate and β-hydroxybutyrate in rat brain slices.Am. J. Physiol. 217: 784–792.Google Scholar
  22. Itoh, T., and Quastel, J. H. (1970). Acetoacetate metabolism in infant and adult rat brain in vitro.Biochem. J. 116: 641–655.Google Scholar
  23. Jope, R., and Blass, J. P. (1975). A comparison of the regulation of pyruvate dehydrogenase in mito-chondria from rat brain and liver.Biochem. J. 150: 397–403.Google Scholar
  24. Jope, R., and Blass, J. P. (1976). The regulation of pyruvate dehydrogenase in brain in vivo.J. Neurochem. 26: 709–714.Google Scholar
  25. Kato, T. (1975). CoA cycling: An enzymatic amplification method for determination of CoASH and acetyl CoA.Anal. Biochem. 66: 372–392.Google Scholar
  26. Konitzer, K., Solle, M., and Voigt, S. (1965). Wirkung von insulin auf den hirnstoffwechsel. I. Veranderungen einiger phosphor-und stickstoff-metaboliten des rattenhirns in vivo nach insulinapplikation.Acta Biol. Med. Germ. 15: 461–479.Google Scholar
  27. Krebs, H. A.,and Veech, R. L. (1970). Regulation of the redox state of the pyridine nucleotides in rat liver. In Sund, H. (ed.),Pyridine Nucleotide-Dependent Dehydrogenases, Springer-Verlag, New York, pp. 413–438.Google Scholar
  28. LaNoue, K. F., Bryla, J., and Williamson, J. R. (1972). Feedback interactions in the control of citric acid cycle activity in rat heart mitochondria.J. Biol. Chem. 247: 667–679.Google Scholar
  29. Lewis, L. D., Ljunggren, B., Ratcheson, R. A., and Siesjö, B. K. (1974) Cerebral energy state in insulininduced hypoglycemia, related to blood glucose and to EEG.J. Neurochem. 23: 673–679.Google Scholar
  30. Lowry, O. H., and Passonneau, J. V. (1972).A Flexible System of Enzymatic Analysis, Academic Press, New York, pp. 120–128, 146–222.Google Scholar
  31. Lowry, O. H., Passonneau, J. V., Hasselberger, F. X., and Schulz, D. W. (1964). Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain.J. Biol. Chem. 239: 18–30.Google Scholar
  32. Madison, L. L., Mebane, D., Unger, R. H., and Lochner, A. (1964). The hypoglycemic action of ketones. II. Evidence for a stimulating feedback of ketones on the pancreatic beta cells.J. Clin. Invest. 43: 408–415.Google Scholar
  33. McDougal, D. B., Jr., and Dargar, R. V. (1979). A spectrophotometric cycling assay for reduced coenzyme A and its esters in small amounts of tissue.Anal. Biochem. 97: 103–115.Google Scholar
  34. Miller, A. L., Hawkins, R. A., and Veech, R. L. (1973). The mitochondrial redox state of rat brain.J. Neurochem. 20: 1393–1400.Google Scholar
  35. Miller, A. L., Kiney, C. A., Corddry, D. H., and Staton, D. M. (1982). Interactions between glucose and ketone body use by developing brain.Dev. Brain Res. 4: 443–450.Google Scholar
  36. Openshaw, H., and Bortz, W. M. (1968). Oxidation of glucose, acetoacetate, and palmitate in brain mince of normal and ketotic rats.Diabetes 17: 90–95.Google Scholar
  37. Owen, O. E., Morgan, A. P., Kemp, H. G., Sullivan, J. M., Herrera, M. G., and Cahill, G. F., Jr. (1967). Brain metabolism during fasting.J. Clin. Invest. 46: 1589–1595.Google Scholar
  38. Pagliara, A. S., Stillings, S. N., Hover, B., Martin, D. M., and Matschinsky, F. M. (1974). Glucose modulation of amino acid induced glucagon and insulin release in the perfused rat pancreas.J. Clin. Invest. 54: 819–832.Google Scholar
  39. Passonneau, J. V., and Lauderdale, V. R. (1974). A comparison of three methods of glycogen measurement in tissues.Anal. Biochem. 60: 405–412.Google Scholar
  40. Passonneau, J. V., and Lowry, O. H. (1964). The role of phosphofructokinase in metabolic regulation.Adv. Enzyme Regul. 2: 265–274.Google Scholar
  41. Portenhauser, R., and Wieland, O. (1972). Regulation of pyruvate dehydrogenase in mitochondria of rat liver.Eur. J. Biochem. 31: 308–314.Google Scholar
  42. Quastel, J. H., Tennenbaum, M., Wheatley, A. H. M. (1936). Choline ester formation in, and choline esterase activities of, tissues in vitro.Biochem. J. 30: 1668–1681.Google Scholar
  43. Roche, T. E., and Lawlis, V. B. (1982). Structure and regulation of α-ketoglutarate dehydrogenase of bovine kidney.Ann. N.Y. Acad. Sci. 378: 236–249.Google Scholar
  44. Rolleston, F. S., and Newsholme, E. A. (1967). Effects of fatty acids, ketone bodies, lactate and pyruvate on glucose utilization by guinea-pig cerebral cortex slices.Biochem. J. 104: 519–523.Google Scholar
  45. Ruderman, N. B., Ross, P. S., Berger, M., and Goodman, M. N. (1974). Regulation of glucose and ketone-body metabolism in brain of anaesthetized rats.Biochem. J. 138: 1–10.Google Scholar
  46. Siesjö, B. K., Folbergrová, J., and MacMillan, V. (1972). The effect of hypercapnia upon the intracellular pH in the brain, evaluated by the bicarbonate-carbonic acid method and from the creatine phosphokinase equilibrium.J. Neurochem. 19: 2483–2495.Google Scholar
  47. Siess, E., Wittmann, J., and Wieland, O. (1971). Interconversion and kinetic properties of pyruvate dehydrogenase from brain.Hoppe-Seyler Z. Physiol. Chem. 352: 447–452.Google Scholar
  48. Smith, C. M., Bryla, J., and Williamson, J. R. (1974). Regulation of mitochondrial α-ketoglutarate metabolism by product inhibition at α-ketoglutarate dehydrogenase.J. Biol. Chem. 249: 1497–1505.Google Scholar
  49. Sokoloff, L. (1973). Metabolism of ketone bodies by the brain.Annu. Rev. Med. 24: 271–280.Google Scholar
  50. Söling, H.-D., and Seufert, C.-D. (eds.) (1978).Biochemical and Clinical Aspects of Ketone Body Metabolism, Georg Thieme, Stuttgart.Google Scholar
  51. Taylor, W. M., and Halperin, M. L. (1973). Regulation of pyruvate dehydrogenase in muscle.J. Biol. Chem. 248: 6080–6083.Google Scholar
  52. Tews, J. K., Carter, S. H., and Stone, W. E. (1965). Chemical changes in the brain during insulin hypoglycaemia and recovery.J. Neurochem. 12: 679–693.Google Scholar
  53. Thurston, J. H., Hauhart, R. E., Jones, E. M., and Ater, J. L. (1975a). Effects of alloxan diabetes, antiinsulin serum diabetes, and non-diabetic dehydration on brain carbohydrate and energy metabolism in young mice.J. Biol. Chem. 250: 1751–1758.Google Scholar
  54. Thurston, J. H., Hauhart, R. E., Jones, E. M., and Ater, J. L. (1975b). Effects of salt and water loading on carbohydrate and energy metabolism and levels of selected amino acids in the brains of young mice.J. Neurochem. 24: 953–957.Google Scholar
  55. Thurston, J. H., Hauhart, R. E., and Dirgo, J. A. (1976). Insulin and brain metabolism: Absence of direction action of insulin on K+ and Na+ transport in mouse brain.Diabetes 25: 758–763.Google Scholar
  56. Thurston, J. H., Hauhart, R. E., Dirgo, J. A., and Jones, E. M. (1980). Mechanisms of increased brain glucose and glycogen after hydrocortisone: Possible clinical significance.Ann. Neurol. 7: 515–523.Google Scholar
  57. Thurston, J. H., Hauhart, R. E., and Schiro, J. A. (1983). Lactate reverses insulin-induced hypoglycemic stupor in suckling-weanling mice: Biochemical correlates in blood, liver and brain.J. Cereb. Blood Flow Metab. 3: 498–506.Google Scholar
  58. Tukey, J. W. (1953).The Problem of Multiple Comparisons, Ditto, Princeton University, Princeton, N. J. [Cited by Kirk, R. E. (1968).Experimental Design: Procedures for the Behavioral Sciences, Brooks/Cole, Belmont, Calif., pp. 69–98].Google Scholar
  59. Weitzman, P. D. J., and Danson, M. J. (1976). Citrate synthase. In Horecker, B. L., and Stadtman, E. R. (eds.),Current Topics in Cellular Regulation, Academic Press, New York, pp. 161–204.Google Scholar
  60. Williamson, D. H., Mellanby, J., and Krebs, H. A. (1962). Enzymic determination of D(−)-β-hydroxybutyric acid and acetoacetic acid in blood.Biochem. J. 82: 90–98.Google Scholar
  61. Williamson, D. H., Lund, P., and Krebs, H. A. (1967). The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of the rat liver.Biochem. J. 103: 514–527.Google Scholar

Copyright information

© Plenum Publishing Corporation 1986

Authors and Affiliations

  • Jean Holowach Thurston
    • 1
  • Richard E. Hauhart
    • 1
  • James A. Schiro
    • 1
  1. 1.Department of Pediatrics, Children's HospitalWashington University School of MedicineSt. Louis

Personalised recommendations