Rat Islet Endocrine Cells Contain Metand Leu-Enkephalins in High- and Low-Molecular-Weight Forms

  • Kim Timmers
  • Nancy R. Voyles
  • Clifford King
  • Michael Wells
  • Richard Fairtile
  • Lillian Recant
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


The rate of insulin secretion is known to be influenced by a large number of substances, including glucose and other substrates, ions, other hormones, and neurotransmitters. For example, Lerner and Porte (1971) showed that an epinephrine infusion profoundly inhibited the acute, first-phase insulin secretory response to glucose in normal humans. More recently, following the reports by Margules et al. (1978) and others (Rossier et al., 1979) of increased β-endorphin in pituitary of genetically obese hyperinsulinemic mice, evidence has begun to accumulate that suggests a role for endogenous opioid peptides in the modulation of insulin secretion and possibly in the pathophysiology of the diabetic state. Types of evidence include pharmacological studies of opiate effects on islet function, a smaller number of reports of the presence in pancreas of endogenous opioids, and a few reports suggesting that islets may secrete endogenous opioid peptides.


Insulin Secretion Islet Cell Insulin Release Opioid Peptide Opiate Receptor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Actams, J. C., 1981, Heavy metal intensification of DAB-based HRP reaction product, J. Histochem. Cytochem. 29:775.Google Scholar
  2. Awoke, S., Voyles, N., Bhathena, S. J., Tanenberg, R., and Recant, L., 1984, Alterations of plasma opioid activity in human diabetics, Life Sci. 34:1999–2006.PubMedCrossRefGoogle Scholar
  3. Baird, A., Klepper, R., and Ling, N., 1984, In vivo and in vitro evidence that the C-terminus of preproenkephalin-A circulates as an 8500-dalton molecule, Proc. Soc. Exp. Biol. Med. 175:304–308.PubMedGoogle Scholar
  4. Barkey, R. J., Würzburger, R. J., and Spector, S., 1981, Selective opiate binding sites in the rat pancreas, Pharmacologist 23:380.Google Scholar
  5. Bloch, B., Baird, A., Ling, N., Benoit, R., and Guillemin, R., 1983, Immunohistochemical evidence that brain enkephalins arise from a precursor similar to adrenal preproenkephalin, Brain Res. 263:251–257.PubMedCrossRefGoogle Scholar
  6. Bruni, J. F., Watkins, W. B., and Yen, S. S. C., 1979, β-Endorphin in the human pancreas, J. Clin. Endocrinol. Metab. 49:649–651.PubMedCrossRefGoogle Scholar
  7. Chang, K., and Cuatrecasas, P., 1981, Heterogeneity and properties of opiate receptors, Fed. Proc. 40:2729–2734.PubMedGoogle Scholar
  8. Dandekar, S., and Sabol, S. L., 1982, Cell-free translation and partial characterization of mRNA coding for enkephalin-precursor protein, Proc. Natl. Acad. Sci. U.S.A. 79:1017–1021.PubMedCrossRefGoogle Scholar
  9. Feldman, M., Kiser, R. S., Unger, R. H., and Li, C. H., 1983, Beta-endorphin and the endocrine pancreas, N. Engl. J. Med. 308:349–353.PubMedCrossRefGoogle Scholar
  10. Feurle, G. E., Weber, U., and Helmsteadter, V., 1980, β-Lipotropin-like material in human pancreas and pyloric antral mucosa, Life Sci. 27:467–473.PubMedCrossRefGoogle Scholar
  11. Feurle, G. E., Helmstaedter, W., and Weber, U., 1982, Met-and leu-enkephalin immuno-and bio-reactivity in human stomach and pancreas, Life Sci. 31:2961–2969.PubMedCrossRefGoogle Scholar
  12. Giugliano, D., Ceriello, A., Di Pinto, P., Saccomanno, F., Gentile, S., and Cappiapuoti, F., 1982, Impaired insulin secretion in human diabetes mellitus: The effect of naloxone-induced opiate receptor blockade, Diabetes 31:367–370.PubMedCrossRefGoogle Scholar
  13. Green, I. C., Perrin, D., Pedley, K. C., Leslie, R. D. G., and Pyke, D. A., 1980, Effect of enkephalins and morphine on insulin secretion from isolated rat islets, Diabetologia 19:158–161.PubMedCrossRefGoogle Scholar
  14. Green, I. C., Ray, K., and Perrin, D., 1983a, Opioid peptide effects on insulin release and c-AMP in islets of Langerhans, Horm. Metab. Res. 15:124–128.PubMedCrossRefGoogle Scholar
  15. Green, I. C., Perrin, D., Penman, E., Yaseen, A., Ray, K., and Howell, S. L., 1983b, Effect of dynorphin on insulin and somatostatin secretion, calcium uptake, and c-AMP levels in isolated rat islets of Langerhans, Diabetes 32:685–690.PubMedCrossRefGoogle Scholar
  16. Grube, D., Voigt, K. H., and Weber, E., 1978, Pancreatic glucagon cells contain endorphin-like immunoreactivity, Histochemistry 59:75–79.PubMedCrossRefGoogle Scholar
  17. Hambrook, J. M., Morgan, B. A., Ranee, M. J., and Smith, C. F., 1976, Mode of deactivation of the enkephalins by rat and human plasma and rat brain homogenates, Nature 262:782–783.PubMedCrossRefGoogle Scholar
  18. Hermansen, K., 1983, Enkephalins and the secretion of pancreatic somatostatin and insulin in the dog: Studies in vitro, Endocrinology 113:1149–1154.PubMedCrossRefGoogle Scholar
  19. Houck, J. C., Chang, C. M., and Kimball, C. D., 1981, Pancreatic beta-endorphin-like polypeptides, Pharmacology 23:14–23.PubMedCrossRefGoogle Scholar
  20. Ipp, E., Dobbs, R., and Unger, R. H., 1978, Morphine and β-endorphin influence the secretion of the endocrine pancreas, Nature 276:190–191.PubMedCrossRefGoogle Scholar
  21. Ipp, E., Schusdziarra, V., Harris, V., and Unger, R. H., 1980, Morphine-induced hyperglycemia: Role of insulin and glucagon, Endocrinology 107:461–463.PubMedCrossRefGoogle Scholar
  22. Ipp, E., Dhorajiwala, J., Pugh, W., Moosa, A. R., and Rubenstein, A. H., 1982, Effects of an enkephalin analog on pancreatic endocrine function and glucose homeostasis in normal and diabetic dogs, Endocrinology 111:2110–2116.PubMedCrossRefGoogle Scholar
  23. James, J. F., Chavkin, C., and Goldstein, A., 1982, Preparation of brain membranes containing a single type of opioid receptor highly selective for dynorphin, Proc. Natl. Acad. Sci. U.S.A. 79:7570–7574.PubMedCrossRefGoogle Scholar
  24. Jeanrenaud, X., Maeder, E., Del Pozo, E., and Felber, J. P., 1981, Enkephalin-induced glucose-insulin dissociation in man, Diabetologia 21:287.Google Scholar
  25. Kanter, R. A., Esinck, J. W., and Fujimoto, W. Y., 1980, Disparate effects of enkephalin and morphine upon insulin and glucagon secretion by islet cell cultures, Diabetes 29:84–86.PubMedCrossRefGoogle Scholar
  26. Kilpatrick, D. L., Taniguchi, T., Jones, B. N., Stern, A. S., Shively, J. E., Hullihan, J., Kimura, S., Stein, S., and Udenfriend, S., 1981, A highly potent 3200-dalton adrenal opioid peptide that contains both a [Met]-and [Leu]enkephalin sequence, Proc. Natl. Acad. Sci. U.S.A. 78:3265–3268.PubMedCrossRefGoogle Scholar
  27. Lacy, P. E., and Kostianovsky, M., 1967, Method for the isolation of intact islets of Langerhans from the rat pancreas, Diabetes 16:35–39.PubMedGoogle Scholar
  28. Larsson, L., 1979, Innervation of the pancreas by substance P, enkephalin, vasoactive intestinal poly-peptide and gastrin/CCK immunoreactive nerves, J. Histochem. Cytochem. 27:1283–1284.PubMedCrossRefGoogle Scholar
  29. Lerner, R. L. and Porte, D., 1971, Epinephrine: Selective inhibiton of the acute insulin response to glucose, J. Clin. Invest. 50:2453–2457.PubMedCrossRefGoogle Scholar
  30. Lowry, O. H., Rosebrough, N. J., Farr, A. L., and Randall, R. J., 1951, Protein measurement with the Folin phenol reagent, J. Biol. Chem. 193:265–275.PubMedGoogle Scholar
  31. Margules, D. L., Moisset, B., Lewis, M. J., Shibuya, H., and Pert, C. B., 1978, β-Endorphin is associated with overeating in genetically obese mice (obi ob) and rats (if alfa), Science 202:988–991.PubMedCrossRefGoogle Scholar
  32. Matsumura, M., Yamanoi, A., Sato, K., Tsuda, M., Chikamori, K., Mori, H., and Saito, S., 1984, Alterations in the levels of β-endorphin-like immunoreactivity in plasma and tissues of obese rats with hypothalamic lesions, Horm. Metab. Res. 16:105–106.PubMedCrossRefGoogle Scholar
  33. Miller, R. E., 1981, Pancreatic neuroendocrinology: Peripheral neural mechanisms in the regulation of the islets of Langerhans, Endocr. Rev. 2:471–494.PubMedCrossRefGoogle Scholar
  34. Mizuno, K., Minamino, N., Kangawa, K., and Matsuo, H., 1980, A new family of endogenous “big” met-enkephalins from bovine adrenal medulla: Purification and structure of docosa-(BAM-22P) and eicosapeptide (BAM-20P) with very potent opiate activity, Biochem. Biophys. Res. Commun. 97:1283–1290.PubMedCrossRefGoogle Scholar
  35. Morley, J. E., Baranetsky, N. G., Wingert, T. D., Carlson, H. E., Hershman, J. M., Melmed, S., Levin, S. R., Jamison, K. R., Weitzman, R., Chang, R. J., and Varner, A. A., 1980, Endocrine effects of naloxone induced opiate receptor blockade, J. Clin. Endocrinol. Metab. 50:251–257.PubMedCrossRefGoogle Scholar
  36. Pfeiffer, A., and Herz, A., 1984, Endocrine actions of opioids, Horm. Metab. Res. 16:386–397.PubMedCrossRefGoogle Scholar
  37. Pierluissi, R., Pierluissi, J., and Ashcroft, S. J. H., 1981, Effects of an enkephalin analogue (DAMME) on insulin release from cultured rat islets of Langerhans. Diabetologia 20:642–646.PubMedCrossRefGoogle Scholar
  38. Recant, L., Voyles, N., Luciano, M., and Pert, C. B., 1980, Naltrexone reduces weight gain, alters “β-endorphin,” and reduces insulin output from pancreatic islets of genetically obese mice, Peptides 1:309–313.PubMedCrossRefGoogle Scholar
  39. Recant, L., Voyles, N., Wade, A., Awoke, S., and Bhathena, S., 1983, Studies on the role of opiate peptides in two forms of genetic obesity: obi ob mouse and falfa rat, Horm. Metab. Res. 15:589–593.PubMedCrossRefGoogle Scholar
  40. Reid, R. L., and Yen, S. S. C., 1981, β-Endorphin stimulates the secretion of insulin and glucagon in humans, J. Clin. Endocrinol. Metab. 52:592–594.PubMedCrossRefGoogle Scholar
  41. Reid, R. L., Sandler, J. A., and Yen, S.S., 1984, Beta-endorphin stimulates the secretion of insulin and glucagon in diabetes mellitus, Metabolism 33:197–199.PubMedCrossRefGoogle Scholar
  42. Robinson, R. P., Williams, P. E., Gooch, B. R., and Abumrad, N. N., 1982, The effect of morphine and naloxone on plasma glucagon and glucose production in the diabetic dog. Diabetes (Suppl. 2)31:161A.Google Scholar
  43. Rossier, J., Rogers, J., Shibasaki, T., Guillemin, R., and Bloom, F. E., 1979, Opioid peptides and a-melanocyte-stimulating hormone in genetically obese (oblob) mice during development, Proc. Natl. Acad. Sci. U.S.A. 76:2077–2080.PubMedCrossRefGoogle Scholar
  44. Rossier, J., Liston, D., Patey, G., Chaminade, M., Foutz, A. S., Cupo, A., Giraud, P., Roisin, M. P., Henry, J. P., Verbanck, P., and Vanderhaeghen, J. J., 1983, The enkephalinergic neuron: Implications of a polyenkephalin precursor, Cold Spring Harbor Symp. Quant. Biol. 48:393–404.PubMedCrossRefGoogle Scholar
  45. Sachse, G., and Laube, H., 1980, Leucine-enkephalin plasma levels after an oral or intravenous arginine stimulation in rats, Horm. Metab. Res. 12:416–417.PubMedCrossRefGoogle Scholar
  46. Sachse, G., Svedberg, J., and Laube, H., 1981, Effect of glucose and arginine on L-enkephalin secretion of the isolated perfused rat pancreas, Horm. Metab. Res. 13:360.PubMedCrossRefGoogle Scholar
  47. Sawynok, J., Pinsky, C., and LaBella, F. S., 1979, Minireview on the specificity of naloxone as an opiate antagonist, Life Sci. 25:1621–1632.PubMedCrossRefGoogle Scholar
  48. Shimosegawa, T., Kobayashi, S., Fujita, T., Mochizuki, T., Yanaihara, C., and Yanaihara, N., 1983, Nerve elements containing Met-enkephalin-Arg-Gly-Leu-like immunoreactivity in canine pancreas: A histochemical study, Neurosci. Lett. 42:161–165.PubMedCrossRefGoogle Scholar
  49. Smyth, D. G., and Zakarian, S., 1982, a,N-Acetyl derivatives of β-endorphin in rat pituitary: Chromatographic evidence for processed forms of β-endorphin in pancreas and brain, Life Sci. 31:1887–1890.PubMedCrossRefGoogle Scholar
  50. Stern, A. S., Würzburger, R. J., Barkey, B., and Spector, S., 1982, Opioid polypeptides in guinea pig pancreas, Proc. Natl. Acad. Sci. U.S.A. 79:6703–6706.PubMedCrossRefGoogle Scholar
  51. Sternberger, L. A., 1974, Immunocytochemistry, Prentice-Hall, Englewood Cliffs, N. J.Google Scholar
  52. Stubbs, W. A., Delitala, G., Jones, A., Jeffcoate, W. J., Edwards, C. R., Ratter, S. J., Besser, G. M., Bloom, S. R., and Alberti, K. G., 1978, Hormonal and metabolic responses to an enkephalin analog in normal man, Lancet 2:1225–1227.PubMedCrossRefGoogle Scholar
  53. Tang, J., Yang, H.-Y. T., and Costa, E., 1982, Distribution of Met-enkephalin-Arg6-Phe7 in various tissues of rats and guinea pigs, Neuropharmacology 21:595–600.PubMedCrossRefGoogle Scholar
  54. Timmers, K. I., Voyles, N., King, C., Wells, M., Fairtile, R., and Recant, L., 1986, Opioid peptides in rat islets of Langerhans: Immunoreactive Met-and Leu-enkephalins and BAM 22P, Diabetes 35:52–57.PubMedCrossRefGoogle Scholar
  55. Tung, A. K., and Cockburn, E., 1984, β-Endorphin-like immunoreactivity in extracts of the fetal bovine pancreas, Diabetes 33:235–238.PubMedCrossRefGoogle Scholar
  56. Walker, J. M., Moises, H. C., Coy, D. H., Baldright, F., and Akil, H., 1982, Nonopiate effects of dynorphin and des-Tyr-dynorphin, Science 218:1136–1138.PubMedCrossRefGoogle Scholar
  57. Werther, G. A., Joffe, S., Artal, R., and Sperling, M. A., 1985, Opiate modulation of glucose turnover in dogs, Metabolism 34:136–140.PubMedCrossRefGoogle Scholar
  58. Wolozin, B. L., and Pasternak, G. W., 1981, Classification of multiple morphine and enkephalin binding sites in the central nervous system, Proc. Natl. Acad. Sci. U.S.A. 78:6181–6185.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Kim Timmers
    • 1
  • Nancy R. Voyles
    • 1
  • Clifford King
    • 1
  • Michael Wells
    • 1
  • Richard Fairtile
    • 1
  • Lillian Recant
    • 1
  1. 1.Veterans Administration Medical CenterUSA

Personalised recommendations