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. 1984 May 1;219(3):819–827. doi: 10.1042/bj2190819

The inhibition of glucose-stimulated insulin secretion by primary amines. A role for transglutaminase in the secretory mechanism.

P J Bungay, J M Potter, M Griffin
PMCID: PMC1153549  PMID: 6146312

Abstract

Rat pancreatic islets contain a Ca2+-activated and thiol-dependent transglutaminase (EC 2.3.2.13) comparable in activity with that found in rat liver, lung and spleen. The Ca2+-dependence of this enzyme is such that half-maximal velocity was obtained in the region of 40 microM. Preincubation of rat islets with primary-amine substrates of transglutaminase (monodansylcadaverine, methylamine, ethylamine, propylamine and cystamine) led to an inhibition of glucose-stimulated insulin release by these amines. Kinetic analysis of the competitive substrates methylamine, monodansylcadaverine, propylamine and ethylamine for their ability to inhibit islet transglutaminase activity indicated a potency that matched their ability to inhibit glucose-stimulated insulin release. When these amines were tested for their effects on glucose-stimulated protein synthesis and glucose utilization, the most potent inhibitor of insulin release, monodansylcadaverine, had no effect on either process at 100 microM. The amines cystamine, ethylamine, methylamine and propylamine had variable effects on these metabolic processes. For ethylamine, methylamine and propylamine, concentrations were found which inhibited glucose-stimulated insulin release in a manner which was found to be independent of their effects on either glucose oxidation or protein synthesis. Primary amines may therefore inhibit insulin release through their incorporation by islet transglutaminase into normal cross-linking sites. A role for protein cross-linking in the secretory mechanism is suggested.

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Selected References

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

  1. Birckbichler P. J., Dowben R. M., Matacic S., Loewy A. G. Isopeptide bonds in membrane proteins from eukaryotic cells. Biochim Biophys Acta. 1973 Jan 2;291(1):149–155. doi: 10.1016/0005-2736(73)90070-9. [DOI] [PubMed] [Google Scholar]
  2. Bjerrum O. J., Hawkins M., Swanson P., Griffin M., Lorand L. An immunochemical approach for the analysis of membrane protein alterations in Ca2+-loaded human erythrocytes. J Supramol Struct Cell Biochem. 1981;16(3):289–301. doi: 10.1002/jsscb.1981.380160309. [DOI] [PubMed] [Google Scholar]
  3. Cheng S. Y., Maxfield F. R., Robbins J., Willingham M. C., Pastan I. H. Receptor-mediated uptake of 3,3',5-triiodo-L-thyronine by cultured fibroblasts. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3425–3429. doi: 10.1073/pnas.77.6.3425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Chung S. I. Comparative studies on tissue transglutaminase and factor XIII. Ann N Y Acad Sci. 1972 Dec 8;202:240–255. doi: 10.1111/j.1749-6632.1972.tb16338.x. [DOI] [PubMed] [Google Scholar]
  5. Davies P. J., Davies D. R., Levitzki A., Maxfield F. R., Milhaud P., Willingham M. C., Pastan I. H. Transglutaminase is essential in receptor-mediated endocytosis of alpha 2-macroglobulin and polypeptide hormones. Nature. 1980 Jan 10;283(5743):162–167. doi: 10.1038/283162a0. [DOI] [PubMed] [Google Scholar]
  6. Farquhar M. G. Membrane recycling in secretory cells: implications for traffic of products and specialized membranes within the Golgi complex. Methods Cell Biol. 1981;23:399–427. doi: 10.1016/s0091-679x(08)61511-3. [DOI] [PubMed] [Google Scholar]
  7. Folk J. E., Finlayson J. S. The epsilon-(gamma-glutamyl)lysine crosslink and the catalytic role of transglutaminases. Adv Protein Chem. 1977;31:1–133. doi: 10.1016/s0065-3233(08)60217-x. [DOI] [PubMed] [Google Scholar]
  8. Fésüs L., Falus A., Erdei A., Laki K. Human beta 2-microglobulin is a substrate of tissue transglutaminase: polymerization in solution and on the cell surface. J Cell Biol. 1981 Jun;89(3):706–710. doi: 10.1083/jcb.89.3.706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Heding L. G. Determination of total serum insulin (IRI) in insulin-treated diabetic patients. Diabetologia. 1972 Aug;8(4):260–266. doi: 10.1007/BF01225569. [DOI] [PubMed] [Google Scholar]
  10. Kaplan J., Keogh E. A. Analysis of the effect of amines on inhibition of receptor-mediated and fluid-phase pinocytosis in rabbit alveolar macrophages. Cell. 1981 Jun;24(3):925–932. doi: 10.1016/0092-8674(81)90118-5. [DOI] [PubMed] [Google Scholar]
  11. King A. C., Hernaez-Davis L., Cuatrecasas P. Lysomotropic amines cause intracellular accumulation of receptors for epidermal growth factor. Proc Natl Acad Sci U S A. 1980 Jun;77(6):3283–3287. doi: 10.1073/pnas.77.6.3283. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  13. Lacy P. E., Kostianovsky M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes. 1967 Jan;16(1):35–39. doi: 10.2337/diab.16.1.35. [DOI] [PubMed] [Google Scholar]
  14. Lorand L., Campbell-Wilkes L. K., Cooperstein L. A filter paper assay for transamidating enzymes using radioactive amine substrates. Anal Biochem. 1972 Dec;50(2):623–631. doi: 10.1016/0003-2697(72)90074-7. [DOI] [PubMed] [Google Scholar]
  15. Lorand L., Parameswaran K. N., Stenberg P., Tong Y. S., Velasco P. T., Jönsson N. A., Mikiver L., Moses P. Specificity of guinea pig liver transglutaminase for amine substrates. Biochemistry. 1979 May 1;18(9):1756–1765. doi: 10.1021/bi00576a019. [DOI] [PubMed] [Google Scholar]
  16. MYCEK M. J., CLARKE D. D., NEIDLE A., WAELSCH H. Amine incorporation into insulin as catalyzed by transglutaminase. Arch Biochem Biophys. 1959 Oct;84:528–540. doi: 10.1016/0003-9861(59)90613-7. [DOI] [PubMed] [Google Scholar]
  17. Malaisse W. J., Sener A., Mahy M. The stimulus-secretion coupling of glucose-induced insulin release. Sorbitol metabolism in isolated islets. Eur J Biochem. 1974 Sep 1;47(2):365–370. doi: 10.1111/j.1432-1033.1974.tb03701.x. [DOI] [PubMed] [Google Scholar]
  18. Morris G. E., Korner A. The effect of glucose on insulin biosynthesis by isolated islets of Langerhans of the rat. Biochim Biophys Acta. 1970 Jun;208(3):404–413. doi: 10.1016/0304-4165(70)90213-8. [DOI] [PubMed] [Google Scholar]
  19. Orci L., Perrelet A., Gorden P. Less-understood aspects of the morphology of insulin secretion and binding. Recent Prog Horm Res. 1978;34:95–121. doi: 10.1016/b978-0-12-571134-0.50007-7. [DOI] [PubMed] [Google Scholar]
  20. Palade G. E. Problems in intracellular membrane traffic. Ciba Found Symp. 1982;(92):1–14. doi: 10.1002/9780470720745.ch1. [DOI] [PubMed] [Google Scholar]
  21. Pastan I. H., Willingham M. C. Journey to the center of the cell: role of the receptosome. Science. 1981 Oct 30;214(4520):504–509. doi: 10.1126/science.6170111. [DOI] [PubMed] [Google Scholar]
  22. Pearse B. M., Bretscher M. S. Membrane recycling by coated vesicles. Annu Rev Biochem. 1981;50:85–101. doi: 10.1146/annurev.bi.50.070181.000505. [DOI] [PubMed] [Google Scholar]
  23. Schatzmann H. J. Dependence on calcium concentration and stoichiometry of the calcium pump in human red cells. J Physiol. 1973 Dec;235(2):551–569. doi: 10.1113/jphysiol.1973.sp010403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Siefring G. E., Jr, Apostol A. B., Velasco P. T., Lorand L. Enzymatic basis for the Ca2+-induced cross-linking of membrane proteins in intact human erythrocytes. Biochemistry. 1978 Jun 27;17(13):2598–2604. doi: 10.1021/bi00606a022. [DOI] [PubMed] [Google Scholar]
  25. Smith J. S., Pace C. S. Modification of glucose-induced insulin release by alteration of pH. Diabetes. 1983 Jan;32(1):61–66. doi: 10.2337/diab.32.1.61. [DOI] [PubMed] [Google Scholar]
  26. Van Leuven F., Cassiman J. J., Van Den Berghe H. Primary amines inhibit recycling of alpha 2M receptors in fibroblasts. Cell. 1980 May;20(1):37–43. doi: 10.1016/0092-8674(80)90232-9. [DOI] [PubMed] [Google Scholar]
  27. Wollheim C. B., Kikuchi M., Renold A. E., Sharp G. W. The roles of intracellular and extracellular Ca++ in glucose-stimulated biphasic insulin release by rat islets. J Clin Invest. 1978 Aug;62(2):451–458. doi: 10.1172/JCI109146. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Wollheim C. B., Sharp G. W. Regulation of insulin release by calcium. Physiol Rev. 1981 Oct;61(4):914–973. doi: 10.1152/physrev.1981.61.4.914. [DOI] [PubMed] [Google Scholar]

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