Extracellular Messages for Pancreatic B-Cells

  • Toshihiko Yada
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 426)


Insulin secretion from pancreatic B-cells is subject to fine regulation by a variety of extracellular messages, which include nutrients of dietary origin, physiological messengers of neural and hormonal origins, and pharmacological agents. In this article, I will briefly review the major, classical messages of each type, and then focus on new studies on the substances that have recently been discovered or developed. Particular attention will be paid on their origin, action mechanisms in pancreatic B-cells, and potential physiological or pharmacological significance in the regulation of insulin release.


Insulin Release Vasoactive Intestinal Peptide Vasoactive Intestinal Polypeptide Pituitary Adenylate Cyclase Activate Polypeptide Gastric Inhibitory Polypeptide 
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. 1.
    Ashcroft, F.M., Rorsman, P. 1989, Electrophysiology of the pancreatic β-cells, Prog. Biophys. Molec. Biol. 54:87–143.CrossRefGoogle Scholar
  2. 2.
    Hellman, B., Gylfe, E., Grapengiesser, E., Lund, P.-E., and Marcström, A. 1992, Cytoplasmic calcium and insulin secretion, In: “Nutrient regulation of insulin secretion,” P.R. Flatt, ed., pp. 213–246, Portland Press Ltd., London.Google Scholar
  3. 3.
    Penner, R., and Neher, E. 1988, The role of calcium in stimulus secretion coupling in excitable and non-excitable cells, J. Exp. Biol. 139:329–345.PubMedGoogle Scholar
  4. 4.
    Ämmälä, C., Eliasson, L., Bokvist, K., Larsson, O., Ashcroft, F.M., and Rorsman, P. 1993b, Exocytosis elicited by action potentials and voltage-clamp calcium currents in individual mouse pancreatic B-cells, J. Physiol. 472:665–688.PubMedGoogle Scholar
  5. 5.
    Prentki, M., and Matschinsky, F.M., 1987, Ca2+, cAMP, and phospholipid-derived messengers in coupling mechanisms of insulin secretion, Physiol. Rev. 67:1185–1248.PubMedGoogle Scholar
  6. 6.
    Wollheim, C.B., and Sharp, G.W.G., 1981, Regulation of insulin release by calcium, Physiol. Rev. 61:914–973.PubMedGoogle Scholar
  7. 7.
    Yada, T. 1994, Action mechanisms of amino acids in pancreatic B-cells, In: “Frontiers of Pancreatic B-cell Research,” P.R. Flatt, ed., Smith Gordon and Co. Ltd., London, pp. 129–135.Google Scholar
  8. 8.
    Verspohl, E.J., Tacke, R., Mutschier, E., and Lambrecht, G., 1990, Muscarinic receptor subtypes in rat pancreatic islets: binding and functional studies, Eur. J.Pharmacol. 178:303–311.PubMedCrossRefGoogle Scholar
  9. 9.
    Henquin, J.-C., Garcia, M.-C., Bozem, M., Hermans, MR, and Nenquin, M, 1988, Muscarinic control of pancreatic B cell function involves sodium dependent depolarization and calcium influx, Endocrinology 122:2134–2142.PubMedCrossRefGoogle Scholar
  10. 10.
    Ahren, B., Taborsky, G.J., and Porte, D., 1986, Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion, Diabetologia 29:827–836.PubMedCrossRefGoogle Scholar
  11. 11.
    Holst, J.J., Fahrenkrug, J., Knuhtsen, S., Jensen, S.L., Poulsen, S.S., and Nielsen, O.V., 1984, Vasoactive intestinal polypeptide (VIP) in the pig pancreas: role of VIPergic fibers in control of fluid and bicarbonate secretion, Regul. Pept. 8:245–249.PubMedCrossRefGoogle Scholar
  12. 12.
    Yada, T., Sakurada, M., Ihida, K., Nakata, M., Murata, F., Arimura, A., and Kikuchi, M., 1994, Pituitary adenylate cyclase activating polypeptide is an extraordinarily potent intra-pancreatic regulator of insulin secretion from islet, β-cells, J. Biol. Chem. 269:1290–1293.PubMedGoogle Scholar
  13. 13.
    Knuhtsen, S., Holst, J.J., Jensen, S.L., and Nielsen, O.V., 1985, Gastrin-releasing peptide: effect on exocrine secretion and release from isolated perfused pig pancreas, Am. J. Physiol. 248:G281–G287.PubMedGoogle Scholar
  14. 14.
    Arimura, A., 1992, Pituitary adenylate cyclase activating polypeptide (PACAP): discovery and current status of research, Regul. Pept. 37:287–303.PubMedGoogle Scholar
  15. 15.
    Miyata, A., Arimura, A., Dahl, R.R., Minamino, N., Uehara, A., Jiang, L., Culler, M.D., and Coy, D.H., 1989, Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells, Biochem. Biophys. Res. Commun. 164:567–574.PubMedCrossRefGoogle Scholar
  16. 16.
    Fridolf, T., Sundler, F., and Ahren, B., 1992, Pituitary adenylate cyclase-activating polypeptide (PACAP): occurrence in rodent pancreas and effects on insulin and glucagon secretion in the mouse, Cell Tissue Res. 269:275–279.PubMedCrossRefGoogle Scholar
  17. 17.
    Henquin, J.-C., 1994, Cell biology of insulin secretion, In: “Joslin’s Diabetes Mellitus,” C.R. Kahn and G.C. Weir, eds., pp. 56–80, Lea & Febiger, Malvern.Google Scholar
  18. 18.
    Fehmann, H.-C., Göke, R., and Göke, B., 1992, Glucagon-like peptide-1(7–37)/(7–36)amide is a new incretin, Mol. Cell. Endocrinol. 85:C39–C44.PubMedCrossRefGoogle Scholar
  19. 19.
    Orskov, C., 1992, Glucagon-like peptide-1, a new hormone of the entero-insular axis, Diabetologia 35:701–711.PubMedGoogle Scholar
  20. 20.
    Habener, J.F., 1993, The incretin notion and its relevance to diabetes, Endocrinol. Metabol. Clin. North America 22:775–794.Google Scholar
  21. 21.
    Thorens, B., 1992, Expression cloning of the pancreatic β cell receptor for the gluco-incretin hormone glucagon-like peptide 1, Proc. Natl. Acad. Sci. USA 89:8641–8645.PubMedCrossRefGoogle Scholar
  22. 22.
    Lu, M., Wheeler, M.B., Leng, X.-H., and Boyd, A.E. 1993, The role of the free cytosolic calcium level in β-cell signal transduction by gastric inhibitory polypeptide and glucagon-like peptide I(7–37), Endocrinology 132:94–100.PubMedCrossRefGoogle Scholar
  23. 23.
    Yada, T., Itoh, K., and Nakata, M., 1993, Glucagon-like peptide-1-(7–36)amide and a rise in cyclic adenosine 3′,5′-monophosphate increase cytosolic free Ca2+ in rat pancreatic β-cells by enhancing Ca2+ channel activity, Endocrinology 133:1685–1692.PubMedCrossRefGoogle Scholar
  24. 24.
    Ämmälä, C., Ashcroft, F.M., and Rorsman, P., 1993a, Calcium independent potentiation of insulin release by cyclic AMP in single B-cells, Nature 363:356–358.PubMedCrossRefGoogle Scholar
  25. 25.
    Mei, N., Arlhac, A., and Boyer, A., 1981, Nervous regulation of insulin release by the intestinal vagai glucoreceptors, J. Autonom. Nerv. Syst. 4:351–363.CrossRefGoogle Scholar
  26. 26.
    Nakabayashi, H., Nishizawa, M., Takeda, R., and Niijima, A., 1992, A novel role of truncated glucagon-like peptide-1 in the enteroinsular axis (EIA), Diabetes 41 (suppl. 1): 101A.Google Scholar
  27. 27.
    Vale, W., Rivier, J., Vaughan, J., McClintock, R., Corrigan, A., Woo, W., Karr, D., and Spiess, J. 1986, Purification and characterization of an FSH releasing protein from porcine ovarian follicular fluid, Nature 321:776–779.PubMedCrossRefGoogle Scholar
  28. 28.
    Totsuka, Y., Tabuchi, M., Kojima, I., Shibata, H., and Ogata, E., 1988, A novel action of activin A: stimulation of insulin secretion in rat pancreatic islets, Biochem. Biophys. Res. Commun. 156:335–339.PubMedCrossRefGoogle Scholar
  29. 29.
    Shibata, H., Yasuda, H., Sekine, N., Totsuka, Y, and Kojima, I., 1993, Activin A increases cytoplasmic free calcium concentration in rat pancreatic islet, FEBS Lett. 329:194–198.PubMedCrossRefGoogle Scholar
  30. 30.
    Yasuda, H., Inoue, K., Shibata, H., Takeuchi, T., Eto, Y, Hasegawa, Y, Sekine, N., Totsuka, Y, Mine, T., Ogata, E., and Kojima, I., 1993, Existence of activin A in A-and D-cells of rat pancreatic islet, Endocrinology 133:624–630.PubMedCrossRefGoogle Scholar
  31. 31.
    Gagliardino, J.J., Borelli, M.I., Estivariz, F., Atwater, I., Boschero, A.C., and Rojas, E., 1997, Islet release of ACTH-like peptides and their modulatory effect on insulin secretion, In “Physiology and Pathophysiology of the Islets of Langerhans,” B. Soria, ed., Plenum Press, New York.Google Scholar
  32. 32.
    Inagaki, N., Yoshida, H., Mizuta, M., Mizuno, N., Fujii, Y, Gonoi, T., Miyazaki, J., and Seino, S., 1994, Cloning and functional characterization of a third pituitary adenylate cyclase-activating polypeptide receptor subtype expressed in insulin secreting cells, Proc. Natl. Acad. Sci. USA 91:2679–2683.PubMedCrossRefGoogle Scholar
  33. 33.
    Yada, T., Sakurada, M., Nakata, M., Yaekura, K., and Kikuchi, M., 1997, PACAP stimulates insulin release via cytosolic Ca2+ increase due to Ca2+ influx through L-type Ca2+ channels in pancreatic, β-cells, In “Physiology and Pathophysiology of the Islets of Langerhans,” B. Soria, ed., Plenum Press, New York.Google Scholar
  34. 34.
    Yamada, Y, Post, S.R., Wang, K., Tager, H.S., Bell, G.I., and Seino, S., 1992, Cloning and functional characterization of a family of human and mouse somatostatin receptors expressed in brain, gastrointestinal tract, and kidney, Proc. Natl. Acad. Sci. USA 89:251–255.PubMedCrossRefGoogle Scholar
  35. 35.
    Schuit, F. C., Derde, M.-P., and Pipeleers, D.G., 1989, Sensitivity of rat pancreatic A and B cells to somatostatin, Diabetologia 32:207–212.PubMedCrossRefGoogle Scholar
  36. 36.
    Wang, Z.-L., Bennet, W.M., Wang, R.-M., Ghatei, M.A., and Bloom, S.R., 1994, Evidence of a paracrine role of neuropeptide-Y in the regulation of insulin release from pancreatic islets of normal and dexamethasone-treated rats, Endocrinology 135:200–206.PubMedCrossRefGoogle Scholar
  37. 37.
    Eriksson, J., Nakazato, M., Miyazato, M., Shiomi, K., Matsukura, S., and Groop, L., 1992, Islet amyloid polypeptide plasma concentrations in individuals at increased risk of developing type 2 (non-insulin-dependent) diabetes mellitus, Diabetologia 35:291–293.PubMedCrossRefGoogle Scholar
  38. 38.
    Henquin, J.-C., 1990, Established, unsuspected and novel pharmacological insulin secretagogues, In: “New antidiabetic drugs,” C.J. Bailey and P.R. Flatt, eds., pp. 93–106, Smith Gordon and Co. Ltd., London.Google Scholar
  39. 39.
    Fujitani, S., and T. Yada., 1994, A novel D-phenylalanine-derivative hypoglycemic agent A-4166 increases cytosolic free Ca2+ in rat pancreatic β-cells by stimulating Ca2+ influx, Endocrinology 134: 1395–1400.PubMedCrossRefGoogle Scholar
  40. 40.
    Chan, S.L.F., Scarpello, K.E., and Morgan, N.G., 1997, Identification and characterization of non-adrenergic binding sites in insulin secreting cells with the imidazoline RX821002, In “Physiology and Pathophysiology of the Islets of Langerhans,” B. Soria, ed., Plenum Press, New York.Google Scholar
  41. 41.
    Lebrun, P., Antoine, M.H., Herchuelz, A., de Tullio, P., Delarge, J., and Pirotte, B., 1997, Pyridothiadiazines as potent inhibitors of glucose-induced insulin release. In “Physiology and Pathophysiology of the Islets of Langerhans,” B. Soria, ed., Plenum Press, New York.Google Scholar
  42. 42.
    Springborg, J., Gromada, J., Madsen, P., and Fuhlendorff, J., 1997, Increase in [Ca2+]i and subsequent insulin release from βTC3-cells with the Ca2+ channel activator FRL 64176, In “Physiology and Pathophysiology of the Islets of Langerhans,” B. Soria, ed., Plenum Press, New York.Google Scholar
  43. 43.
    Silva, A.M., Rosario, L.M., Santos, R.M., 1994, Background Ca2+ influx mediated by a dihydropyridine-and voltage-insensitive channel in pancreatic β-cells, J. Biol. Chem. 269: 17095–17103.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1997

Authors and Affiliations

  • Toshihiko Yada
    • 1
  1. 1.Department of PhysiologyKagoshima University School of MedicineKagoshima 890Japan

Personalised recommendations