Skip to main content
NCBI home page
Proceedings of the National Academy of Sciences of the United States of America logoLink to Proceedings of the National Academy of Sciences of the United States of America
. 1986 Jan;83(2):290–294. doi: 10.1073/pnas.83.2.290

Antiketogenic and hypoglycemic effects of aminocarnitine and acylaminocarnitines.

D L Jenkins, O W Griffith
PMCID: PMC322843  PMID: 3455765

Abstract

DL-Aminocarnitine (DL-3-amino-4-trimethylaminobutyrate) is a potent, noncovalent inhibitor of carnitine palmitoyltransferase (palmitoyl-CoA:L-carnitine O-palmitoyltransferase, EC 2.3.1.21). Here we show that decanoyl-DL-aminocarnitine and palmitoyl-DL-aminocarnitine inhibit carnitine palmitoyltransferase in vitro about 7-fold and 100-fold more effectively than does aminocarnitine. Aminocarnitine and its decanoyl and palmitoyl derivatives are active in vivo following oral or parenteral administration and, at doses of 0.3 mmol/kg or less, inhibit the oxidation of [14C]palmitate to 14CO2 by 45-70% in mice. Larger doses do not significantly increase the extent of inhibition, a finding suggesting that substantial carnitine palmitoyltransferase-independent long-chain fatty acid oxidation may occur in vivo. Small doses of aminocarnitine and palmitoylaminocarnitine prevent the development of ketoacidemia in fasted, normal mice and reverse the ketoacidemia observed in diabetic mice. Aminocarnitine has a strong hypoglycemic effect in fasted diabetic mice; a single dose (0.3 mmol/kg) normalizes plasma glucose levels within 4-8 hr and remains effective for at least 12 hr.

Full text

PDF
290

Selected References

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

  1. BREMER J. CARNITINE IN INTERMEDIARY METABOLISM. THE BIOSYNTHESIS OF PALMITYLCARNITINE BY CELL SUBFRACTIONS. J Biol Chem. 1963 Aug;238:2774–2779. [PubMed] [Google Scholar]
  2. Clarke P. R., Bieber L. L. Isolation and purification of mitochondrial carnitine octanoyltransferase activities from beef heart. J Biol Chem. 1981 Oct 10;256(19):9861–9868. [PubMed] [Google Scholar]
  3. Delisle G., Fritz I. B. Interrelations between hepatic fatty acid oxidation and gluconeogenesis: a possible regulatory role of carnitine palmityltransferase. Proc Natl Acad Sci U S A. 1967 Aug;58(2):790–797. doi: 10.1073/pnas.58.2.790. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. FRITZ I. B., YUE K. T. LONG-CHAIN CARNITINE ACYLTRANSFERASE AND THE ROLE OF ACYLCARNITINE DERIVATIVES IN THE CATALYTIC INCREASE OF FATTY ACID OXIDATION INDUCED BY CARNITINE. J Lipid Res. 1963 Jul;4:279–288. [PubMed] [Google Scholar]
  5. Fletcher M. J. A colorimetric method for estimating serum triglycerides. Clin Chim Acta. 1968 Nov;22(3):393–397. doi: 10.1016/0009-8981(68)90041-7. [DOI] [PubMed] [Google Scholar]
  6. Foster D. W., McGarry J. D. The metabolic derangements and treatment of diabetic ketoacidosis. N Engl J Med. 1983 Jul 21;309(3):159–169. doi: 10.1056/NEJM198307213090307. [DOI] [PubMed] [Google Scholar]
  7. Fritz I. B., Marquis N. R. The role of acylcarnitine esters and carnitine palmityltransferase in the transport of fatty acyl groups across mitochondrial membranes. Proc Natl Acad Sci U S A. 1965 Oct;54(4):1226–1233. doi: 10.1073/pnas.54.4.1226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Furman E., Sonn J., Acad B. A., Dvir S., Kedem J. Relation between myocardial substrate utilization, oxygen consumption and regional oxygen balance in the dog heart in vivo. Arch Int Physiol Biochim. 1986 Dec;94(5):285–293. doi: 10.3109/13813458609071428. [DOI] [PubMed] [Google Scholar]
  9. Greenawalt J. W. The isolation of outer and inner mitochondrial membranes. Methods Enzymol. 1974;31:310–323. doi: 10.1016/0076-6879(74)31033-6. [DOI] [PubMed] [Google Scholar]
  10. Jenkins D. L., Griffith O. W. DL-aminocarnitine and acetyl-DL-aminocarnitine. Potent inhibitors of carnitine acyltransferases and hepatic triglyceride catabolism. J Biol Chem. 1985 Nov 25;260(27):14748–14755. [PubMed] [Google Scholar]
  11. Kanamaru T., Shinagawa S., Asai M., Okazaki H., Sugiyama Y., Fujita T., Iwatsuka H., Yoneda M. Emeriamine, an antidiabetic beta-aminobetaine derived from a novel fungal metabolite. Life Sci. 1985 Jul 22;37(3):217–223. doi: 10.1016/0024-3205(85)90647-2. [DOI] [PubMed] [Google Scholar]
  12. Kientsch-Engel R. I., Siess E. A., Wieland O. H. Measurement of ketone bodies in subcellular fractions using a spectrophotometric iron-chelate assay. Anal Biochem. 1982 Jul 1;123(2):270–275. doi: 10.1016/0003-2697(82)90445-6. [DOI] [PubMed] [Google Scholar]
  13. Kiorpes T. C., Hoerr D., Ho W., Weaner L. E., Inman M. G., Tutwiler G. F. Identification of 2-tetradecylglycidyl coenzyme A as the active form of methyl 2-tetradecylglycidate (methyl palmoxirate) and its characterization as an irreversible, active site-directed inhibitor of carnitine palmitoyltransferase A in isolated rat liver mitochondria. J Biol Chem. 1984 Aug 10;259(15):9750–9755. [PubMed] [Google Scholar]
  14. McGarry J. D., Foster D. W. Acute reversal of experimental diabetic ketoacidosis in the rat with (+)-decanoylcarnitine. J Clin Invest. 1973 Apr;52(4):877–884. doi: 10.1172/JCI107252. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. McGarry J. D., Foster D. W. In support of the roles of malonyl-CoA and carnitine acyltransferase I in the regulation of hepatic fatty acid oxidation and ketogenesis. J Biol Chem. 1979 Sep 10;254(17):8163–8168. [PubMed] [Google Scholar]
  16. McGarry J. D., Foster D. W. The metabolism of (minus)-octanoylcarnitine in perfused livers from fed and fasted rats. Evidence for a possible regulatory role of carnitine acyltransferase in the control of ketogenesis. J Biol Chem. 1974 Dec 25;249(24):7984–7990. [PubMed] [Google Scholar]
  17. Pande S. V. A mitochondrial carnitine acylcarnitine translocase system. Proc Natl Acad Sci U S A. 1975 Mar;72(3):883–887. doi: 10.1073/pnas.72.3.883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  19. Ruderman N. B., Toews C. J., Shafrir E. Role of free fatty acids in glucose homeostasis. Arch Intern Med. 1969 Mar;123(3):299–313. [PubMed] [Google Scholar]
  20. 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]
  21. Wolf H. P., Eistetter K., Ludwig G. Phenylalkyloxirane carboxylic acids, a new class of hypoglycaemic substances: hypoglycaemic and hypoketonaemic effects of sodium 2-[5-(4-chlorophenyl)-pentyl]-oxirane-2-carboxylate (B 807-27) in fasted animals. Diabetologia. 1982 Jun;22(6):456–463. doi: 10.1007/BF00282590. [DOI] [PubMed] [Google Scholar]

Articles from Proceedings of the National Academy of Sciences of the United States of America are provided here courtesy of National Academy of Sciences

RESOURCES