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. 1978 Nov 15;176(2):495–504. doi: 10.1042/bj1760495

Hyperglycaemic activity and metabolic effects of 3-aminopicolinic acid

Michael J MacDonald 1, Ming-Ta Huang 1, Henry A Lardy 1
PMCID: PMC1186258  PMID: 743255

Abstract

Administering 3-aminopicolinate to rats starved for 24h immediately initiated a progressive increase in blood glucose concentration. Hyperglycaemia was not the result of glycogenolysis, nor was it due to an inhibition of insulin release, since it caused marked hyperinsulinaemia. The rate of [6-3H]glucose disappearance from the blood of the intact rat was not altered by 3-aminopicolinate, indicating that it does not cause hyperglycaemia by inhibiting glucose utilization or by causing a redistribution of total body glucose. 3-Aminopicolinate increased the rate of fall in the specific radioactivity of blood [6-3H]-glucose, indicating dilution of the glucose pool by newly synthesized glucose. The rate of 14C incorporation into blood glucose from [14C]alanine and [14C]lactate was increased 90 and 35% respectively, whereas that from [14C]glycerol and [14C]xylitol was either unaffected or slightly decreased by 3-aminopicolinate administration. Liver phosphoenolpyruvate of rats was increased to four to seven times the normal concentration 10min to 1h after injections of 50–300mg of 3-aminopicolinate/kg body wt. and the amounts of 2-phosphoglycerate and 3-phosphoglycerate were increased to three to four times normal. The high concentrations of liver phosphoenolpyruvate, 2-phosphoglycerate and 3-phosphoglycerate, as well as the enhancement of gluconeogenesis from lactate and alanine, but not from glycerol or xylitol, is compatible with an enhancement of gluconeogenesis at a step between pyruvate and the triose phosphates. After injections of 3-aminopicolinate, liver malate, citrate, aspartate, alanine, lactate and pyruvate were also increased, but to lesser extents than was phosphoenolpyruvate. The increases in some of these metabolites were approximated after an intravenous infusion of glucose, so their elevated concentration after 3-aminopicolinate administration could have been, in part, a consequence of the hyperglycaemia. The possibility is considered that 3-aminopicolinate stimulates gluconeogenesis in vivo by facilitating Fe2+ activation of phosphoenolpyruvate carboxykinase as it does with the purified enzyme in vitro [MacDonald & Lardy (1978) J. Biol. Chem. 253, 2300–2307]. In this effect 3-aminopicolinate may simulate the physiological role of the naturally occurring ferroactivator protein [Bentle & Lardy (1977) J. Biol. Chem. 252, 1431–1440].

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Selected References

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

  1. ANDREWS P., HOUGH L., PICKEN J. M. THE BIOSYNTHESIS OF POLYSACCHARIDES. INCORPORATION OF D-(1-14C)GLUCOSE AND D-(6-14C)GLUCOSE INTO PLUM-LEAF POLYSACCHARIDES. Biochem J. 1965 Jan;94:75–80. doi: 10.1042/bj0940075. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bentle L. A., Lardy H. A. Interaction of anions and divalent metal ions with phosphoenolpyruvate carboxykinase. J Biol Chem. 1976 May 25;251(10):2916–2921. [PubMed] [Google Scholar]
  3. Bentle L. A., Snoke R. E., Lardy H. A. A protein factor required for activation of phosphoenolpyruvate carboxykinase by ferrous ions. J Biol Chem. 1976 May 25;251(10):2922–2928. [PubMed] [Google Scholar]
  4. Blackshear P. J., Holloway P. A., Aberti K. G. The effects of inhibition of gluconeogenesis on ketogenesis in starved and diabetic rats. Biochem J. 1975 Jun;148(3):353–362. doi: 10.1042/bj1480353b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Blair J. B., Cook D. E., Lardy H. A. Interaction of propionate and lactate in the perfused rat liver. Effects of glucagon and oleate. J Biol Chem. 1973 May 25;248(10):3608–3614. [PubMed] [Google Scholar]
  6. Blank B., DiTullio N. W., Miao C. K., Owings F. F., Gleason J. G., Ross S. T., Berkoff C. E., Saunders H. L. Mercaptopyridinecarboxylic acids, synthesis and hypoglycemic activity. J Med Chem. 1974 Oct;17(10):1065–1071. doi: 10.1021/jm00256a008. [DOI] [PubMed] [Google Scholar]
  7. Burch H. B., Max P., Jr, Ghyu K., Lowry O. H. Metabolic intermediates in liver of rats given large amounts of fructose or dihydroxyacetone. Biochem Biophys Res Commun. 1969 Mar 10;34(5):619–626. doi: 10.1016/0006-291x(69)90783-9. [DOI] [PubMed] [Google Scholar]
  8. DAVIS B., SALTMAN P., BENSON S. The stability constants of the iron-transferrin complex. Biochem Biophys Res Commun. 1962 Jun 19;8:56–60. doi: 10.1016/0006-291x(62)90235-8. [DOI] [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. Exton J. H., Park C. R. Control of gluconeogenesis in liver. 3. Effects of L-lactate, pyruvate, fructose, glucagon, epinephrine, and adenosine 3',5'-monophosphate on gluconeogenic intermediates in the perfused rat liver. J Biol Chem. 1969 Mar 25;244(6):1424–1433. [PubMed] [Google Scholar]
  11. FELLER D. D., STRISOWER E. H., CHAIKOFF I. L. Turnover and oxidation of body glucose in normal and alloxan-diabetic rats. J Biol Chem. 1950 Dec;187(2):571–588. [PubMed] [Google Scholar]
  12. Fahien L. A., Strmecki M. Studies on gluconeogenic mitochondrial enzymes. II. The conversion of glutamate to alpha-ketoglutarate by bovine liver mitochondrial glutamate dehydrogenase and glutamate-oxaloacetate transaminase. Arch Biochem Biophys. 1969 Mar;130(1):456–467. doi: 10.1016/0003-9861(69)90058-7. [DOI] [PubMed] [Google Scholar]
  13. Foster D. O., Lardy H. A., Ray P. D., Johnston J. B. Alteration of rat liver phosphoenolpyruvate carboxykinase activity by L-tryptophan in vivo and metals in vitro. Biochemistry. 1967 Jul;6(7):2120–2128. doi: 10.1021/bi00859a033. [DOI] [PubMed] [Google Scholar]
  14. 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]
  15. Frieden E., Osaki S. Ferroxidases and ferrireductases: their role in iron metabolism. Adv Exp Med Biol. 1974;48(0):235–265. doi: 10.1007/978-1-4684-0943-7_12. [DOI] [PubMed] [Google Scholar]
  16. Friedmann N., Rasmussen H. Calcium, manganese and hepatic gluconeogenesis. Biochim Biophys Acta. 1970 Oct 27;222(1):41–52. doi: 10.1016/0304-4165(70)90349-1. [DOI] [PubMed] [Google Scholar]
  17. Goodman M. N. Effect of 3-mercaptopicolinic acid on gluconeogenesis and gluconeogenic metabolite concentrations in the isolated perfused rat liver. Biochem J. 1975 Jul;150(1):137–139. doi: 10.1042/bj1500137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. HORNBROOK K. R., BURCH H. B., LOWRY O. H. CHANGES IN SUBSTRATE LEVELS IN LIVER DURING GLYCOGEN SYNTHESIS INDUCED BY LACTATE AND HYDROCORTISONE. Biochem Biophys Res Commun. 1965 Jan 18;18:206–211. doi: 10.1016/0006-291x(65)90741-2. [DOI] [PubMed] [Google Scholar]
  19. HUGGETT A. S., NIXON D. A. Use of glucose oxidase, peroxidase, and O-dianisidine in determination of blood and urinary glucose. Lancet. 1957 Aug 24;273(6991):368–370. doi: 10.1016/s0140-6736(57)92595-3. [DOI] [PubMed] [Google Scholar]
  20. Hsu S. L., Fahien L. A. Effect of quinolinate on aminotransferases. Arch Biochem Biophys. 1976 Nov;177(1):217–225. doi: 10.1016/0003-9861(76)90431-8. [DOI] [PubMed] [Google Scholar]
  21. Jomain-Baum M., Schramm V. L., Hanson R. W. Mechanism of 3-mercaptopicolinic acid inhibition of hepatic phosphoenolpyruvate carboxykinase (GTP). J Biol Chem. 1976 Jan 10;251(1):37–44. [PubMed] [Google Scholar]
  22. Kalkhoff R. K., Hornbrook K. R., Burch H. B., Kipnis D. M. Studies of the metabolic effects of acute insulin deficiency. II. Changes in hepatic glycolytic and krebs-cycle intermediates and pyridine nucleotides. Diabetes. 1966 Jul;15(7):451–456. doi: 10.2337/diab.15.7.451. [DOI] [PubMed] [Google Scholar]
  23. Kostos V., DiTullio N. W., Rush J., Cieslinski L., Saunders H. L. The effect of 3-mercaptopicolinic acid on phosphoenolpyruvate carboxykinase (GTP) in the rat and guinea pig. Arch Biochem Biophys. 1975 Dec;171(2):459–465. doi: 10.1016/0003-9861(75)90054-5. [DOI] [PubMed] [Google Scholar]
  24. Krietsch W. K., Bücher T. 3-phosphoglycerate kinase from rabbit sceletal muscle and yeast. Eur J Biochem. 1970 Dec;17(3):568–580. doi: 10.1111/j.1432-1033.1970.tb01202.x. [DOI] [PubMed] [Google Scholar]
  25. MacDonald M. J., Lardy H. A. 3-Aminopicolinate: a synthetic metal-complexing activator of phosphoenolpyruvate carboxykinase. J Biol Chem. 1978 Apr 10;253(7):2300–2307. [PubMed] [Google Scholar]
  26. MacDonald M., Neufeldt N., Park B. N., Berger M., Ruderman N. Alanine metabolism and gluconeogenesis in the rat. Am J Physiol. 1976 Aug;231(2):619–626. doi: 10.1152/ajplegacy.1976.231.2.619. [DOI] [PubMed] [Google Scholar]
  27. Marcus F. Functional consequences of modifying highly reactive arginyl residues of fructose 1,6-bisphosphatase. Loss of monovalent cation activation. Biochemistry. 1975 Aug 26;14(17):3916–3921. doi: 10.1021/bi00688a029. [DOI] [PubMed] [Google Scholar]
  28. McClure W. R., Lardy H. A., Kneifel H. P. Rat liver pyruvate carboxylase. I. Preparation, properties, and cation specificity. J Biol Chem. 1971 Jun 10;246(11):3569–3578. [PubMed] [Google Scholar]
  29. POPOVIC V., POPOVIC P. Permanent cannulation of aorta and vena cava in rats and ground squirrels. J Appl Physiol. 1960 Jul;15:727–728. doi: 10.1152/jappl.1960.15.4.727. [DOI] [PubMed] [Google Scholar]
  30. Papavasiliou P. S., Miller S. T., Cotzias G. C. Functional interactions between biogenic amines, 3',5'-cyclic AMP and manganese. Nature. 1968 Oct 5;220(5162):74–75. doi: 10.1038/220074a0. [DOI] [PubMed] [Google Scholar]
  31. 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]
  32. SEIFTER S., DAYTON S. The estimation of glycogen with the anthrone reagent. Arch Biochem. 1950 Jan;25(1):191–200. [PubMed] [Google Scholar]
  33. SHRAGO E., LARDY H. A., NORDLIE R. C., FOSTER D. O. METABOLIC AND HORMONAL CONTROL OF PHOSPHOENOLPYRUVATE CARBOXYKINASE AND MALIC ENZYME IN RAT LIVER. J Biol Chem. 1963 Oct;238:3188–3192. [PubMed] [Google Scholar]
  34. Seubert W., Huth W. On the mechanism of gluconeogenesis and its regulation. II. The mechanism of gluconeogenesis from pyruvate and fumarate. Biochem Z. 1965 Nov 15;343(2):176–191. [PubMed] [Google Scholar]
  35. Snoke R. E., Johnston J. B., Lardy H. A. Response of phosphopyruvate carboxylase to tryptophan metabolites and metal ions. Eur J Biochem. 1971 Dec;24(2):342–346. doi: 10.1111/j.1432-1033.1971.tb19692.x. [DOI] [PubMed] [Google Scholar]
  36. Soeldner J. S., Slone D. Critical variables in the radioimmunoassay of serum insulin using the double antibody technic. Diabetes. 1965 Dec;14(12):771–779. doi: 10.2337/diab.14.12.771. [DOI] [PubMed] [Google Scholar]
  37. THIERS R. E., VALLEE B. L. Distribution of metals in subcellular fractions of rat liver. J Biol Chem. 1957 Jun;226(2):911–920. [PubMed] [Google Scholar]
  38. Taunton O. D., Stifel F. B., Greene H. L., Herman R. H. Rapid reciprocal changes in rat hepatic glycolytic enzyme and fructose diphosphatase activities following insulin and glucagon injection. J Biol Chem. 1974 Nov 25;249(22):7228–7239. [PubMed] [Google Scholar]
  39. Ui M., Claus T. H., Exton J. H., Park C. R. Studies on the mechanism of action of glucagon on gluconeogenesis. J Biol Chem. 1973 Aug 10;248(15):5344–5349. [PubMed] [Google Scholar]
  40. 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]
  41. Williamson J. R. Effects of fatty acids, glucagon and anti-insulin serum on the control of gluconeogenesis and ketogenesis in rat liver. Adv Enzyme Regul. 1967;5:229–255. doi: 10.1016/0065-2571(67)90019-2. [DOI] [PubMed] [Google Scholar]
  42. Williamson J. R., Jákob A., Scholz R. Energy cost of gluconeogenesis in rat liver. Metabolism. 1971 Jan;20(1):13–26. doi: 10.1016/0026-0495(71)90056-4. [DOI] [PubMed] [Google Scholar]
  43. YOUNG J. W., SHRAGO E., LARDY H. A. METABOLIC CONTROL OF ENZYMES INVOLVED IN LIPOGENESIS AND GLUCONEOGENESIS. Biochemistry. 1964 Nov;3:1687–1692. doi: 10.1021/bi00899a015. [DOI] [PubMed] [Google Scholar]
  44. Zakim D., Pardini R. S., Herman R. H., Sauberlich H. E. Mechanism for the differential effects of high carbohydrate diets on lipogenesis in rat liver. Biochim Biophys Acta. 1967 Oct 2;144(2):242–251. doi: 10.1016/0005-2760(67)90154-3. [DOI] [PubMed] [Google Scholar]

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