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. 1982 Oct 15;208(1):53–60. doi: 10.1042/bj2080053

Effect of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid on pyruvate dehydrogenase complex activity in starved and alloxan-diabetic rats

Ian D Caterson 1,*, Stephen J Fuller 1, Philip J Randle 1
PMCID: PMC1153928  PMID: 7159398

Abstract

Intravenous administration of the fatty acid oxidation inhibitor 2-tetradecylglycidic acid had no effect on the proportion of pyruvate dehydrogenase complex in the active form in heart, diaphragm or gastrocnemius muscles or in liver, kidney or adipose tissue of fed normal rats. The compound reversed the effect of 48h starvation (which decreased the proportion of active complex) in heart muscle, partially reversed the effect of starvation in kidney, but had no effect in the other tissues listed. The compound failed to reverse the effect of alloxan-diabetes (which decreased the proportion of active complex) in any of these tissues. In perfused hearts of fed normal rats, 2-tetradecylglycidate reversed effects of palmitate (which decreased the proportion of active complex), but it had no effect in the absence of palmitate. In perfused hearts of 48h-starved rats the compound increased the proportion of active complex to that found in fed normal rats in the presence or absence of insulin. In perfused hearts of diabetic rats the compound normalized the proportion of active complex in the presence of insulin, but not in its absence. Palmitate reversed the effects of 2-tetradecylglycidate in perfused hearts of starved or diabetic rats. Evidence is given that 2-tetradecylglycidate only reverses effects of starvation and alloxan-diabetes on the proportion of active complex in heart muscle under conditions in which it inhibits fatty acid oxidation. It is concluded that effects of starvation and alloxan-diabetes on the proportion of active complex in heart muscle are dependent on fatty acid oxidation. Insulin had no effect on the proportion of active complex in hearts or diaphragms of fed or starved rats in vitro. In perfused hearts of alloxan-diabetic rats, insulin induced a modest increase in the proportion of active complex in the presence of albumin, but not in its absence.

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Selected References

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  1. 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]
  2. 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]
  3. Chase J. F. pH-dependence of carnitine acetyltransferase activity. Biochem J. 1967 Aug;104(2):503–509. doi: 10.1042/bj1040503. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chen R. F. Removal of fatty acids from serum albumin by charcoal treatment. J Biol Chem. 1967 Jan 25;242(2):173–181. [PubMed] [Google Scholar]
  5. Cooper R. H., Randle P. J., Denton R. M. Stimulation of phosphorylation and inactivation of pyruvate dehydrogenase by physiological inhibitors of the pyruvate dehydrogenase reaction. Nature. 1975 Oct 30;257(5529):808–809. doi: 10.1038/257808a0. [DOI] [PubMed] [Google Scholar]
  6. Coore H. G., Denton R. M., Martin B. R., Randle P. J. Regulation of adipose tissue pyruvate dehydrogenase by insulin and other hormones. Biochem J. 1971 Nov;125(1):115–127. doi: 10.1042/bj1250115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Denton R. M., Randle P. J. Concentrations of glycerides and phospholipids in rat heart and gastrocnemius muscles. Effects of alloxan-diabetes and perfusion. Biochem J. 1967 Aug;104(2):416–422. doi: 10.1042/bj1040416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Denton R. M., Randle P. J. Measurement of flow of carbon atoms from glucose and glycogen glucose to glyceride glycerol and glycerol in rat heart and epididymal adipose tissue. Effects of insulin, adrenaline and alloxan-diabetes. Biochem J. 1967 Aug;104(2):423–434. doi: 10.1042/bj1040423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Garland P. B., Randle P. J. Regulation of glucose uptake by muscles. 10. Effects of alloxan-diabetes, starvation, hypophysectomy and adrenalectomy, and of fatty acids, ketone bodies and pyruvate, on the glycerol output and concentrations of free fatty acids, long-chain fatty acyl-coenzyme A, glycerol phosphate and citrate-cycle intermediates in rat heart and diaphragm muscles. Biochem J. 1964 Dec;93(3):678–687. doi: 10.1042/bj0930678. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hagg S. A., Taylor S. I., Ruberman N. B. Glucose metabolism in perfused skeletal muscle. Pyruvate dehydrogenase activity in starvation, diabetes and exercise. Biochem J. 1976 Aug 15;158(2):203–210. doi: 10.1042/bj1580203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hennig G., Löffler G., Wieland O. H. Active and inactive forms of pyruvatedehydrogenase in skeletal muscle as related to the metabolic and functional state of the muscle cell. FEBS Lett. 1975 Nov 15;59(2):142–145. doi: 10.1016/0014-5793(75)80361-9. [DOI] [PubMed] [Google Scholar]
  12. Hutson N. J., Randle P. J. Enhanced activity of pyruvate dehydrogenase kinase in rat heart mitochondria in alloxan-diabetes or starvation. FEBS Lett. 1978 Aug 1;92(1):73–76. doi: 10.1016/0014-5793(78)80724-8. [DOI] [PubMed] [Google Scholar]
  13. Idell-Wenger J. A., Grotyohann L. W., Neely J. R. Coenzyme A and carnitine distribution in normal and ischemic hearts. J Biol Chem. 1978 Jun 25;253(12):4310–4318. [PubMed] [Google Scholar]
  14. Jungas R. L. Hormonal regulation of pyruvate dehydrogenase. Metabolism. 1971 Jan;20(1):43–53. doi: 10.1016/0026-0495(71)90058-8. [DOI] [PubMed] [Google Scholar]
  15. Kerbey A. L., Radcliffe P. M., Randle P. J. Diabetes and the control of pyruvate dehydrogenase in rat heart mitochondria by concentration ratios of adenosine triphosphate/adenosine diphosphate, of reduced/oxidized nicotinamide-adenine dinucleotide and of acetyl-coenzyme A/coenzyme A. Biochem J. 1977 Jun 15;164(3):509–519. doi: 10.1042/bj1640509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kerbey A. L., Radcliffe P. M., Randle P. J., Sugden P. H. Regulation of kinase reactions in pig heart pyruvate dehydrogenase complex. Biochem J. 1979 Aug 1;181(2):427–433. doi: 10.1042/bj1810427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kerbey A. L., Randle P. J., Cooper R. H., Whitehouse S., Pask H. T., Denton R. M. Regulation of pyruvate dehydrogenase in rat heart. Mechanism of regulation of proportions of dephosphorylated and phosphorylated enzyme by oxidation of fatty acids and ketone bodies and of effects of diabetes: role of coenzyme A, acetyl-coenzyme A and reduced and oxidized nicotinamide-adenine dinucleotide. Biochem J. 1976 Feb 15;154(2):327–348. doi: 10.1042/bj1540327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kerbey A. L., Randle P. J. Pyruvate dehydrogenase kinase/activator in rat heart mitochondria, Assay, effect of starvation, and effect of protein-synthesis inhibitors of starvation. Biochem J. 1982 Jul 15;206(1):103–111. doi: 10.1042/bj2060103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kerbey A. L., Randle P. J. Thermolabile factor accelerates pyruvate dehydrogenase kinase reaction in heart mitochondria of starved or alloxan-diabetic rats. FEBS Lett. 1981 May 18;127(2):188–192. doi: 10.1016/0014-5793(81)80201-3. [DOI] [PubMed] [Google Scholar]
  20. Neely J. R., Denton R. M., England P. J., Randle P. J. The effects of increased heart work on the tricarboxylate cycle and its interactions with glycolysis in the perfused rat heart. Biochem J. 1972 Jun;128(1):147–159. doi: 10.1042/bj1280147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ohlen J., Siess E. A., Löffler G., Wieland O. H. The effect of insulin on pyruvate dehydrogenase interconversion in heart muscle of alloxan-diabetic rats. Diabetologia. 1978 Feb;14(2):135–139. doi: 10.1007/BF01263452. [DOI] [PubMed] [Google Scholar]
  22. Pearce F. J., Forster J., DeLeeuw G., Williamson J. R., Tutwiler G. F. Inhibition of fatty acid oxidation and in normal and hypoxic perfused rat hearts by 2-tetradecylglycidic acid. J Mol Cell Cardiol. 1979 Sep;11(9):893–915. doi: 10.1016/0022-2828(79)90483-8. [DOI] [PubMed] [Google Scholar]
  23. Pettit F. H., Pelley J. W., Reed L. J. Regulation of pyruvate dehydrogenase kinase and phosphatase by acetyl-CoA/CoA and NADH/NAD ratios. Biochem Biophys Res Commun. 1975 Jul 22;65(2):575–582. doi: 10.1016/s0006-291x(75)80185-9. [DOI] [PubMed] [Google Scholar]
  24. Randle P. J., England P. J., Denton R. M. Control of the tricarboxylate cycle and its interactions with glycolysis during acetate utilization in rat heart. Biochem J. 1970 May;117(4):677–695. doi: 10.1042/bj1170677. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Randle P. J., Garland P. B., Hales C. N., Newsholme E. A., Denton R. M., Pogson C. I. Interactions of metabolism and the physiological role of insulin. Recent Prog Horm Res. 1966;22:1–48. doi: 10.1016/b978-1-4831-9825-5.50004-x. [DOI] [PubMed] [Google Scholar]
  26. Randle P. J., Sugden P. H., Kerbey A. L., Radcliffe P. M., Hutson N. J. Regulation of pyruvate oxidation and the conservation of glucose. Biochem Soc Symp. 1978;(43):47–67. [PubMed] [Google Scholar]
  27. Saggerson E. D. Carnitine acyltransferase activities in rat liver and heart measured with palmitoyl-CoA and octanoyl-CoA. Latency, effects of K+, bivalent metal ions and malonyl-CoA. Biochem J. 1982 Feb 15;202(2):397–405. doi: 10.1042/bj2020397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Sale G. J., Randle P. J. Occupancy of phosphorylation sites in pyruvate dehydrogenase phosphate complex in rat heart in vivo. Relation to proportion of inactive complex and rate of re-activation by phosphatase. Biochem J. 1982 Aug 15;206(2):221–229. doi: 10.1042/bj2060221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Sale G. J., Randle P. J. Occupancy of sites of phosphorylation in inactive rat heart pyruvate dehydrogenase phosphate in vivo. Biochem J. 1981 Mar 1;193(3):935–946. doi: 10.1042/bj1930935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Severson D. L., Denton R. M., Pask H. T., Randle P. J. Calcium and magnesium ions as effectors of adipose-tissue pyruvate dehydrogenase phosphate phosphatase. Biochem J. 1974 May;140(2):225–237. doi: 10.1042/bj1400225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Spector A. A., John K., Fletcher J. E. Binding of long-chain fatty acids to bovine serum albumin. J Lipid Res. 1969 Jan;10(1):56–67. [PubMed] [Google Scholar]
  32. Stansbie D., Denton R. M., Bridges B. J., Pask H. T., Randle P. J. Regulation of pyruvate dehydrogenase and pyruvate dehydrogenase phosphate phosphatase activity in rat epididymal fat-pads. Effects of starvation, alloxan-diabetes and high-fat diet. Biochem J. 1976 Jan 15;154(1):225–236. doi: 10.1042/bj1540225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sugden P. H., Hutson N. J., Kerbey A. L., Randle P. J. Phosphorylation of additional sites on pyruvate dehydrogenase inhibits its re-activation by pyruvate dehydrogenase phosphate phosphatase. Biochem J. 1978 Feb 1;169(2):433–435. doi: 10.1042/bj1690433. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Tutwiler G. F., Dellevigne P. Action of the oral hypoglycemic agent 2-tetradecylglycidic acid on hepatic fatty acid oxidation and gluconeogenesis. J Biol Chem. 1979 Apr 25;254(8):2935–2941. [PubMed] [Google Scholar]
  35. Tutwiler G. F., Kirsch T., Mohrbacher R. J., Ho W. Pharmacologic profile of methyl 2-tetradecylglycidate (McN-3716)--an orally effective hypoglycemic agent. Metabolism. 1978 Oct;27(10):1539–1556. doi: 10.1016/s0026-0495(78)80027-4. [DOI] [PubMed] [Google Scholar]
  36. Tutwiler G. F., Mohrbacher R., Ho W. Methyl 2-tetradecylglycidate, an orally effective hypoglycemic agent that inhibits long chain fatty acid oxidation selectively. Diabetes. 1979 Mar;28(3):242–248. doi: 10.2337/diab.28.3.242. [DOI] [PubMed] [Google Scholar]
  37. Weiss L., Löffler G., Schirmann A., Wieland O. Control of pyruvate dehydrogenase interconversion in adipose tissue by insulin. FEBS Lett. 1971 Jun 24;15(3):229–231. doi: 10.1016/0014-5793(71)80318-6. [DOI] [PubMed] [Google Scholar]
  38. Whitehouse S., Cooper R. H., Randle P. J. Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J. 1974 Sep;141(3):761–774. doi: 10.1042/bj1410761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Wieland O. H., Patzelt C., Löffler G. Active and inactive forms of pyruvate dehydrogenase in rat liver. Effect of starvation and refeeding and of insulin treatment on pyruvate-dehydrogenase interconversion. Eur J Biochem. 1972 Apr 11;26(3):426–433. doi: 10.1111/j.1432-1033.1972.tb01783.x. [DOI] [PubMed] [Google Scholar]
  40. Wieland O. H., Siess E. A., Weiss L., Löffler G., Patzelt C., Portenhauser R., Hartmann U., Schirmann A. Regulation of the mammalian pyruvate dehydrogenase complex by covalent modification. Symp Soc Exp Biol. 1973;27:371–400. [PubMed] [Google Scholar]
  41. Wieland O., Funcke H. v., Löffler G. Interconversion of pyruvate dehydrogenase in rat heart muscle upon perfusion with fatty acids or ketone bodies. FEBS Lett. 1971 Jul 1;15(4):295–298. doi: 10.1016/0014-5793(71)80641-5. [DOI] [PubMed] [Google Scholar]
  42. Wieland O., Siess E., Schulze-Wethmar F. H., von Funcke H. G., Winton B. Active and inactive forms of pyruvate dehydrogenase in rat heart and kidney: effect of diabetes, fasting, and refeeding on pyruvate dehydrogenase interconversion. Arch Biochem Biophys. 1971 Apr;143(2):593–601. doi: 10.1016/0003-9861(71)90244-x. [DOI] [PubMed] [Google Scholar]

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