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. 1975 Jun;148(3):353–362. doi: 10.1042/bj1480353b

The effects of inhibition of gluconeogenesis on ketogenesis in starved and diabetic rats.

P J Blackshear, P A Holloway, K G Aberti
PMCID: PMC1165552  PMID: 128351

Abstract

Experiments were performed in which the effects of inhibiting gluconeogenesis on ketone-body formation were examined in vivo in starved and severely streptozotocin-diabetic rats. The infusion of 3-mercaptopicolinate, an inhibitor of gluconeogenesis (DiTullio et al., 1974), caused decreases in blood [glucose] and increases in blood [lactate] and [pyruvate] in both normal and ketoacidotic rats. Patterns of liver gluconeogenic intermediates after 3-mercaptopicolinate infusion suggested inhibition at the level of phosphoenolpyruvate carboxykinase. This was confirmed by measurement of hepatic oxaloacetate concentrations which were increased 5-fold after 3-mercaptopicolinate administration. The infusion of 3-mercaptopicolinate caused a decrease in total ketone-body concentrations of 30% in starved rats and 73% in the diabetic animals. Blood glycerol and hepatic triglyceride concentrations remained unchanged. The decreases in ketone-body concentrations were associated with increases in the calculated hepatic cytosolic and mitochondrial [NADH]/[NAD+] ratios. The decrease in ketogenesis seen after inhibition of gluconeogenesis may have resulted from an inhibition of hepatic fatty acid oxidation by the more reduced mitochondrial redox state. It was concluded that gluconeogenesis may stimulate ketogenesis by as much as 30% in severe diabetic ketoacidosis.

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Selected References

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

  1. Alvares F. L., Ray P. D. Lack of inhibition by L-tryptophan or quinolinate of gluconeogenesis in diabetic rats. J Biol Chem. 1974 Apr 10;249(7):2058–2062. [PubMed] [Google Scholar]
  2. Backshear P. J., Holloway P. A., Alberti K. G. Metabolic interactions of dichloroacetate and insulin in experimental diabetic ketoacidosis. Biochem J. 1975 Feb;146(2):447–456. doi: 10.1042/bj1460447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bieberdorf F. A., Chernick S. S., Scow R. O. Effect of insulin and acute diabetes on plasma FFA and ketone bodies in the fasting rat. J Clin Invest. 1970 Sep;49(9):1685–1693. doi: 10.1172/JCI106386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bizzi A., Tacconi M. T., Garattini S. Lowering of blood ketone bodies induced by drugs preventing free fatty acid mobilization. Experientia. 1966 Oct 15;22(10):664–664. doi: 10.1007/BF01902430. [DOI] [PubMed] [Google Scholar]
  5. Blackshear P. J., Alberti K. G. Experimental diabetic ketoacidosis. Sequential changes of metabolic intermediates in blood, liver, cerebrospinal fluid and brain after acute insulin deprivation in the streptozotocin-diabetic rat. Biochem J. 1974 Jan;138(1):107–117. doi: 10.1042/bj1380107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blackshear P. J., Holloway P. A., Alberti K. G. The metabolic effects of sodium dichloroacetate in the starved rat. Biochem J. 1974 Aug;142(2):279–286. doi: 10.1042/bj1420279. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bässler K. H., Brinkrolf H. Die Rolle von Oxalacetate bei der gesteigerten Ketogenese und beim antiketogenen Effekt. Z Gesamte Exp Med. 1971;156(1):52–60. [PubMed] [Google Scholar]
  8. Dale R. A. Effects of sampling procedures on the contents of some intermediate metabolities of glycolysis in rat tissues. J Physiol. 1965 Dec;181(4):701–711. doi: 10.1113/jphysiol.1965.sp007792. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. DiTullio N. W., Berkoff C. E., Blank B., Kostos V., Stack E. J., Saunders H. L. 3-mercaptopicolinic acid, an inhibitor of gluconeogenesis. Biochem J. 1974 Mar;138(3):387–394. doi: 10.1042/bj1380387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Eggstein M., Kreutz F. H. Eine neue Bestimmung der Neutralfette im Blutserum und Gewebe. I. Prinzip, Durchführung und Besprechung der Methode. Klin Wochenschr. 1966 Mar 1;44(5):262–267. doi: 10.1007/BF01747716. [DOI] [PubMed] [Google Scholar]
  11. Exton J. H., Corbin J. G., Harper S. C. Control of gluconeogenesis in liver. V. Effects of fasting, diabetes, and glucagon on lactate and endogenous metabolism in the perfused rat liver. J Biol Chem. 1972 Aug 25;247(16):4996–5003. [PubMed] [Google Scholar]
  12. FRITZ I. B. Factors influencing the rates of long-chain fatty acid oxidation and synthesis in mammalian systems. Physiol Rev. 1961 Jan;41:52–129. doi: 10.1152/physrev.1961.41.1.52. [DOI] [PubMed] [Google Scholar]
  13. Foster D. O., Ray P. D., Lardy H. A. A paradoxical in vivo effect of L-tryptophan on the phosphoenolpyruvate carboxykinase of rat liver. Biochemistry. 1966 Feb;5(2):563–569. doi: 10.1021/bi00866a023. [DOI] [PubMed] [Google Scholar]
  14. Krebs H. A., Wallace P. G., Hems R., Freedland R. A. Rates of ketone-body formation in the perfused rat liver. Biochem J. 1969 May;112(5):595–600. doi: 10.1042/bj1120595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Mayes P. A., Felts J. M. Regulation of fat metabolism of the liver. Nature. 1967 Aug 12;215(5102):716–718. doi: 10.1038/215716a0. [DOI] [PubMed] [Google Scholar]
  16. Ontko J. A. Effects of ethanol on the metabolism of free fatty acids in isolated liver cells. J Lipid Res. 1973 Jan;14(1):78–86. [PubMed] [Google Scholar]
  17. Ontko J. A., Zilversmit D. B. Correlation between concentrations of circulating free fatty acids and ketone bodies. Proc Soc Exp Biol Med. 1966 Feb;121(2):319–321. doi: 10.3181/00379727-121-30768. [DOI] [PubMed] [Google Scholar]
  18. Parrilla R., Goodman M. N. Nitrogen metabolism in the isolated perfused rat liver. Nitrogen balance, redox state and rates of proteolysis. Biochem J. 1974 Mar;138(3):341–348. doi: 10.1042/bj1380341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Ray P. D., Foster D. O., Lardy H. A. Paths of carbon in gluconeogenesis and lipogenesis. IV. Inhibition by L-tryptophan of hepatic gluconeogenesis at the level of phosphoenolpyruvate formation. J Biol Chem. 1966 Sep 10;241(17):3904–3908. [PubMed] [Google Scholar]
  20. Schein P. S., Alberti K. G., Williamson D. H. Effects of streptozotocin on carbohydrate and lipid metabolism in the rat. Endocrinology. 1971 Sep;89(3):827–834. doi: 10.1210/endo-89-3-827. [DOI] [PubMed] [Google Scholar]
  21. Van Harken D. R., Dixon C. W., Heimberg M. Hepatic lipid metabolism in experimental diabetes. V. The effect of concentration of oleate on metabolism of triglycerides and on ketogenesis. J Biol Chem. 1969 May 10;244(9):2278–2285. [PubMed] [Google Scholar]
  22. Veneziale C. M., Walter P., Kneer N., Lardy H. A. Influence of L-tryptophan and its metabolites on gluconeogenesis in the isolated, perfused liver. Biochemistry. 1967 Jul;6(7):2129–2138. doi: 10.1021/bi00859a034. [DOI] [PubMed] [Google Scholar]
  23. WILLIAMSON D. H., MELLANBY J., KREBS H. A. Enzymic determination of D(-)-beta-hydroxybutyric acid and acetoacetic acid in blood. Biochem J. 1962 Jan;82:90–96. doi: 10.1042/bj0820090. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. WOLLENBERGER A., RISTAU O., SCHOFFA G. [A simple technic for extremely rapid freezing of large pieces of tissue]. Pflugers Arch Gesamte Physiol Menschen Tiere. 1960;270:399–412. [PubMed] [Google Scholar]
  25. Wieland O., Weiss L., Eger-Neufeldt I. Enzymatic regulation of liver acetyl-CoA metabolism in relation to ketogenesis. Adv Enzyme Regul. 1964;2:85–99. doi: 10.1016/s0065-2571(64)80007-8. [DOI] [PubMed] [Google Scholar]
  26. Williamson D. H., Lopes-Vieira O., Walker B. Concentrations of free glucogenic amino acids in livers of rats subjected to various metabolic stresses. Biochem J. 1967 Aug;104(2):497–502. doi: 10.1042/bj1040497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Williamson D. H., Lund P., Krebs H. A. The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver. Biochem J. 1967 May;103(2):514–527. doi: 10.1042/bj1030514. [DOI] [PMC free article] [PubMed] [Google Scholar]

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