Glucagon-Like Peptide-1: An Insulinotropic Hormone With Potent Growth Factor Actions at the Pancreatic Islets of Langerhans

  • George G. Holz
  • Colin A. Leech
Part of the Endocrine Updates book series (ENDO, volume 11)


Identification of chemical mediators that support pancreatic (3-cell neogenesis, differentiation, growth, and survival offers the prospect for introduction of novel therapeutic strategies in the treatment of diabetes mellitus. One such chemical mediator is glucagon-like peptide-1 (GLP-1), an intestinally-derived blood glucose-lowering hormone that is a potential therapeutic agent for use in treatment of adult-onset diabetes mellitus (type 2 diabetes) (1-4). GLP-1 exerts a direct action at the pancreatic islets of Langerhans to stimulate biosynthesis and secretion of insulin, thereby lowering levels of blood glucose. Additional effects of GLP-1 at the islets include stimulation of DNA synthesis, increased cellular proliferation, and alterations in the pattern of gene expression that are critical to maintenance of a fully differentiated 13-cell phenotype. Such growth factor-like effects of GLP- 1 suggest its possible usefulness as a stimulus for de novo production of islets in diabetic subjects, or for ex vivo expansion of (3-cells in islets isolated for purposes of transplantation. It is also appreciated that GLP- 1 acts within the central nervous system as an appetite suppressant (5,6). This surprising finding suggests an additional beneficial action of GLP-1 for treatment of eating disorders, obesity, and/or adipogenic diabetes mellitus.


Insulin Secretion Pituitary Adenylate Cyclase Activate Polypeptide Growth Factor Action Insulinoma Cell Pancreas Development 
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.
    Habener JF. The incretin notion and its relevance to diabetes. Endocrinol Metabol Clin N Am 1993;22:775–794.Google Scholar
  2. 2.
    Thorens B, Waeber G. Glucagon-like peptide-1 and the control of insulin secretion in the normal state and in NIDDM. Diabetes 1993;42:1219–1225.PubMedGoogle Scholar
  3. 3.
    Holst JJ. Glucagon-like peptide-1: A newly discovered gastrointestinal hormone. Gastroenterology 1994;107:1848–1855.PubMedGoogle Scholar
  4. 4.
    Drucker DJ. Glucagon-like peptides. Diabetes 1998;47:159–169.PubMedGoogle Scholar
  5. 5.
    Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K, Choi Si, Taylor GM, Heath MM, Lambert PD, Wilding JP, Smith DM, Ghatei MA, Herbert J, Bloom SR. A role for glucagonlike peptide-1 in the central regulation of feeding. Nature 1996;379:69–72.PubMedGoogle Scholar
  6. 6.
    Blazquez E, Alvarez E, Navarro M, Roncero I, Rodriguez-Fonseca F, Chowen JA, Zueco JA. Glucagon-like peptide-1(7–36)amide as a novel neuropeptide. Mol Neurobiol 1998;18:157–173.PubMedGoogle Scholar
  7. 7.
    Thorens B. Expression cloning of the pancreatic ß cell receptor for the gluco-incretin hormone glucagon-like peptide-1. Proc Natl Acad Sci USA 1992;89:8641–8645.PubMedGoogle Scholar
  8. 8.
    Fehmann HC, Goke R, Goke B. Cell and molecular biology of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulin releasing polypeptide. Endocrine Rev 1995;16:390–410.Google Scholar
  9. 9.
    Gromada J, Holst JJ, Rorsman P. Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide-1. Pflugers Arch 1998;435:583–594.PubMedGoogle Scholar
  10. 10.
    Holst JJ. Enteroglucagon. Ann Rev Physiol 1997;59:257–271.Google Scholar
  11. 11.
    Kreymann B, Ghatei MA, Williams G, Bloom SR. Glucagon-like peptide-1(7–36): A physiological incretin in man. Lancet 1987;2:1300–1304.PubMedGoogle Scholar
  12. 12.
    Nathan DM, Schreiber E, Fogel H, Mojsov S, Habener JF. Insulinotropic action of glucagon-like peptide-1(7–37) in diabetic and nondiabetic subjects. Diabetes Care 1992;15:270–276.PubMedGoogle Scholar
  13. 13.
    Gutniak M, Orskov C, Holst JJ, Ahren B, Efendic S. Antidiabetogenic effect of glucagon-like peptide-1(7–36)amide in normal subjects and patients with diabetes mellitus. N Engl J Med 1992;326:1316–1322.PubMedGoogle Scholar
  14. 14.
    Wang Y, Perfetti R, Greig NH, Holloway HW, DeOre KA, Montrose-Rafizadeh C, Elahi D, Egan JM. Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest 1997;99:2883–2889.PubMedGoogle Scholar
  15. 15.
    Buteau J, Roduit R, Susini S, Prentki M. Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding in beta (INS-1)-cells. Diabetologia 1999;42:856–864.PubMedGoogle Scholar
  16. 16.
    Wang X, Cahill CM, Pineyro MA, Zhou J, Doyle ME, Egan JM. Glucagon-like peptide-1 regulates the 13-cell transcription factor, PDX-1, in insulinoma cells. Endocrinology 1999;140:4904–4907.PubMedGoogle Scholar
  17. 17.
    Alcantara AI, Morales M, Delgado E, Lopez-Delgado Ml, Clemente F, Luque MA, Malaisse WI, Valverde I, Villanueva-Penacarrillo ML. Exendin-4 agonist and exendin(9–39)amide antagonist of the GLP-1(7–36)amide effects in liver and muscle. Arch Biochem Biophys 1997;341:1–7.PubMedGoogle Scholar
  18. 18.
    Trapote MA, Clemente F, Galera C, Morales M, Alcantara AI, Lopez-Delgado MI, VillanuevaPenacarrillo ML, Valverde I. Inositolphosphoglycans are possible mediators of the glucagon-like peptide-1(7–36)amide action in the liver. J Endocrinol Invest 1996;19:114–118.PubMedGoogle Scholar
  19. 19.
    Yang H, Egan JM, Wang Y, Moyes CD, Roth J, Montrose MH, Montrose-Rafizadeh C. GLP-I action in L6 myotubes is via a receptor different from the pancreatic GLP-1 receptor. Am J Physiol 1998;275:C675–C683.PubMedGoogle Scholar
  20. 20.
    Egan JM, Montrose-Rafizadeh C, Wang Y, Bernier M, Roth J. Glucagon-like peptide-1(7–36)amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-Li adipocytes: One of several potential extrapancreatic sites of GLP-1 action. Endocrinology 1994;135:2070–2075.PubMedGoogle Scholar
  21. 21.
    Perea A, Vinambres C, Clemente F, Villanueva-Panacarrillo ML, Valverde I. GLP-1(7–36)amide: effects on glucose transport and metabolism in rat adipose tissue. Horm Metab Res 1997;29:417–421.PubMedGoogle Scholar
  22. 22.
    Tolessa T, Gutniak M, Holst JJ, Hellstrom PM. Glucagon-like peptide-1 retards gastric emptying and small bowel transit in the rat: effect mediated through central or enteric nervous mechanisms. Dig Dis Sci 1998;43:2284–2290.Google Scholar
  23. 23.
    Imereyuz N, Yegen BC, Bozkurt A, Coskun T, Villanueva-Penacarrillo ML, Ulusoy NB. Glucagonlike peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Physiol 1997;273:G920–6927.Google Scholar
  24. 24.
    Dupre J, Behme MT, Hramiak IM, McFarlane P, Williamson MP, Zabel P, McDonald TJ. Glucagon-like peptide-1 reduces postprandial glycemic excursions in IDDM. Diabetes 1995;44:626–630.PubMedGoogle Scholar
  25. 25.
    Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide-1(7–36)amide in type-1 diabetic patients. Diabetes Care 1996;19:580–586.PubMedGoogle Scholar
  26. 26.
    Jehle PM, Jehle D, Fussganger RD, Adler G. Effects of glucagon-like peptide-I (GLP-1) in RINm5F insulinoma cells. Stimulation of insulin secetion, insulin content, and insulin receptor binding. Exp. Clin. Endocrinol. Diabetes 1995;103:31–36.Google Scholar
  27. 27.
    Harbeck MC, Louie DC, Howland J, Wolf BA, Rothenberg PL. Expression of insulin receptor mRNA and insulin receptor susbstrate 1 in pancreatic islet 0-cells. Diabetes 1996;45:711–717.PubMedGoogle Scholar
  28. 28.
    Velloso LA, Carneiro EM, Crepaldi SC, Boschero AC, Saad MJA. Glucose-and insulin-induced phosphorylation of the insulin receptor and its primary substrates IRS-1 and IRS-2 in rat pancreatic islets. FEBS Lett 1995;377:353–357.PubMedGoogle Scholar
  29. 29.
    Hugl SR, White MF, Rhodes CJ. Insulin-like growth factor 1 (IGF-1)-stimulated pancreatic 13-cell growth is glucose-dependent. Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-1 in INS-1 cells. J Biol Chem 1998;273:17771–17779.PubMedGoogle Scholar
  30. 30.
    Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR. Tissue-specific knockout of the insulin receptor in pancreatic ß cells creates an insulin secretory defect similar to that in type-2 diabetes. Cell 1999;96:329–339.PubMedGoogle Scholar
  31. 31.
    Xu GG, Gao Z, Borge PD, Wolf BA. Insulin receptor substrate 1-induced inhibition of endoplasmic reticulum Cal’ uptake in ß cells. Autocrine regulation of intracellular Cat` homeostasis and insulin secretion. J Biol Chem 1999;274:18067–18074.PubMedGoogle Scholar
  32. 32.
    Aspinwall CA, Lakey JR, Kennedy RT. Insulin-stimulated insulin secretion in single pancreatic ß cells. J Biol Chem 1999;274:6360–6365.PubMedGoogle Scholar
  33. 33.
    Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner-Weir S, White MF. Disruption of IRS-2 causes type-2 diabetes in mice. Nature 1998;391:900–904.PubMedGoogle Scholar
  34. 34.
    Holz GG, Kuhtreiber WM, Habener JF. Induction of glucose competence in pancreatic ß cells by glucagon-like peptide-1(7–37). Trans Assoc Amer Phys 1992;105:260–267.Google Scholar
  35. 35.
    Holz GG, Habener JF. Signal transduction crosstalk in the endocrine system: Pancreatic ß cells and the glucose competence concept. Trends in Biochem Sci 1992;17:388–393.Google Scholar
  36. 36.
    Holz GG, Kuhtreiber WM, Habener JF. Pancreatic 13-cells are rendered glucose competent by the insulinotropic hormone GLP-1(7–37). Nature 1993;361:362–365.PubMedGoogle Scholar
  37. 37.
    Holz GG, Leech CA. Glucagon-like peptide-I and the glucose competence concept of pancreatic beta-cell function. In: The insulinotropic hormone glucagon-like peptide I. Eds. Fehmann, HC and Goke, B 1997;13:171–193.Google Scholar
  38. 38.
    Dachicourt N, Serradas P, Bailbe D, Kergoat M, Doare L, Portha B. Glucagon-like peptide-1(736)amide confers glucose sensitivity to previously glucose-incompetent I3-cells in diabetic rats: in vivo and in vitro studies. J Endocrinol 1997;155:369–376.PubMedGoogle Scholar
  39. 39.
    Abdel-Halim SM, Guenifi A, Khan A, Larsson O, Berggren PO, Ostenson CG, Efendic S. Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK rats: a defect ameliorated by cAMP. Diabetes 1996;45:934–40.PubMedGoogle Scholar
  40. 40.
    Byrne MM, Gliem K, Wank U, Arnold R, Katschinski M, Polonsky KS, Goke B. Glucagon-like peptide 1 improves the ability of the 13-cell to sense and respond to glucose in subjects with impaired glucose tolerance. Diabetes 1998;47:1259–65.PubMedGoogle Scholar
  41. 41.
    Linn T, Schneider K, Goke B, Federlin K. Glucagon-like-peptide-1(7–36)amide improves glucose sensitivity in beta-cells of NOD mice. Acta Diabetol 1996;33:19–24.PubMedGoogle Scholar
  42. 42.
    Montrose-Rafizadeh C, Wang Y, Janczewski AM, Henderson TE, Egan JM. Overexpression of glucagon-like peptide-1 receptor in an insulin-secreting cell line enhances glucose responsiveness. Mol Cell Endocrinol 1997;130:109–17.PubMedGoogle Scholar
  43. 43.
    Otonkoski T, Hayek A. Constitution of a biphasic insulin response to glucose in human fetal pancreatic beta-cells with glucagon-like peptide 1. J Clin Endocrinol Metab 1995;80:3779–83.PubMedGoogle Scholar
  44. 44.
    Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like peptide-1(7–36)amide but not of synthetic human gastric inhibitory peptide in patients with type-2 diabetes mellitus. J Clin Invest 1993;91:301–307.PubMedGoogle Scholar
  45. 45.
    Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide-1 (7–36 amide) in type 2 (non-insulin dependent) diabetic patients. Diabetologia 1993;36:741–744.PubMedGoogle Scholar
  46. 46.
    Flamez D, Breusegem AV, Scrocchi LA, Quartier E, Pipeleers D, Drucker DJ, Schuit F. Mouse pancreatic ß cells exhibit preserved glucose competence after disruption of the glucagon-like peptide-I receptor gene. Diabetes 1998;47:646–652.PubMedGoogle Scholar
  47. 47.
    Zawalich WS, Zawalich KC, Rasmussen H. Influence of glucagon-like peptide- I on ß-cell responsiveness. Regul Pept 1993;44:277–283.PubMedGoogle Scholar
  48. 48.
    Leclercq-Meyer V, Malaisse WJ. Potentiation of GLP-1 insulinotropic action by a nonglucidic nutrient in the pancreas of diabetic GK rats. Biochem Mol Med 1996;59:87–90.PubMedGoogle Scholar
  49. 49.
    Newgard CB, McGarry JD. Metabolic coupling factors in pancreatic 13-cell signal transduction. Ann Rev Biochem 1995;64:689–719.PubMedGoogle Scholar
  50. 50.
    Matschinsky FM, Glaser B, Magnuson MA. Pancreatic 11-cell glucokinase. Closing the gap between theoretical concepts and experimental realities. Diabetes 1998;47:307–315.PubMedGoogle Scholar
  51. 51.
    Fridolf T, Ahren B. GLP-1(7–36)amide stimulates insulin secretion in rat islets: studies on the mode of action. Diabetes Res 1991;16:185–191.PubMedGoogle Scholar
  52. 52.
    Dukes ID, McIntyre MS, Mertz RJ, Philipson LH, Roe MW, Spencer B, Worley JF. Dependence on NADH produced during glycolysis for f3-cell glucose signaling. J Biol Chem 1994;269:10979–10982.PubMedGoogle Scholar
  53. 53.
    Mertz RJ, Worley JF, Spencer B, Johnson JH, Dukes ID. Activation of stimulus-secretion coupling in pancreatic ß cells by specific products of glucose metabolism. Evidence for privileged signaling by glycolysis. J Biol Chem 1996;271:4838–4845.PubMedGoogle Scholar
  54. 54.
    Eto K, Tsubamoto Y, Terauchi Y, Sugiyama T, Kishimoto T, Takahashi N, Yamauchi N, Kubota N, Murayama S, Aizawa T, Akanuma Y, Kasai H, Yazaki Y, Kadowaki T. Role of NADH shuttle system in glucose-induced activation of mitochondrial metabolism and insulin secretion. Science 1999;283:981–985.PubMedGoogle Scholar
  55. 55.
    Eto K, Suga S, Wakui M, Tsubamoto Y, Terauchi Y, Taka J, Aizawa S, Noda M, Kimura S, Kasai H, Kadowaki T. NADH shuttle system regulates KATP channel-dependent pathway and steps distal to cytosolic Ca’* concentration elevation in glucose-induced insulin secretion. J Biol Chem 1999;274:15386–25392.Google Scholar
  56. 56.
    Susini S, Roche E, Prentki M, Schlegel W. Glucose and glucoincretin peptides synergize to induce c-fos, c-jun, junB, zif-268, and nur-77 gene expression in pancreatic 13(INS-1) cells. FASEB J 1998;12:1173–1182.PubMedGoogle Scholar
  57. 57.
    Edvell A, Lindstrom P. Initiation of increased pancreatic islet growth in young normoglycemic mice (Umea +1?). Endocrinology 1999;140:778–783.PubMedGoogle Scholar
  58. 58.
    Rothenberg PL, Willison D, Simon J, Wolf BA. Glucose-induces insulin receptor tyrosine phosphorylation in insulin-secreting 13-cells. Diabetes 1995;44:802–809.PubMedGoogle Scholar
  59. 59.
    Hirayama I, Tamemoto H, Yokata H, Kubo SK, Wang J, Kuwano H, Nagamachi Y, Takeuchi T, Izumi T. Insulin receptor-related receptor is expressed in pancreatic 13-cells and stimulates tyrosine phosphorylation of insulin receptor substrate-1 and -2. Diabetes 1999;48:1237–1244.PubMedGoogle Scholar
  60. 60.
    Frodin M, Sekine N, Roche E, Filloux C, Prentki M, Wollheim CB, Van, Obberghen, E. Glucose, other secretagogues, and nerve growth factor stimulate mitogen-activated protein kinase in the insulin-secreting 13-cell line, INS-1. J Biol Chem 1995;270:7882–7889.PubMedGoogle Scholar
  61. 61.
    Montrose-Rafizadeh C, Avdonin P, Garant Mi, Rodgers BD, Kole S, Yang H, Levine MA, Schwindinger W, Bernier M. Pancreatic glucagon-like peptide-1 receptor couples to multiple G proteins and activates mitogen-activated protein kinase pathways in Chinese hamster ovary cells. Endocrinology 1999;140:1132–1140.PubMedGoogle Scholar
  62. 62.
    Kawasaki H, Springett GM, Mochizuki N, Toki S, Nakaya M, Matsuda M, Housman DE, Graybiel AM. A family of cAMP-binding proteins that directly activate Rapl. Science 1998;282:2275–2279.PubMedGoogle Scholar
  63. 63.
    Ohtsuka T, Shimizu K, Yamamori B, Kuroda S, Takei Y. Activation of brain B-Raf protein kinase by Rap1B small GTP-binding protein. J Biol Chem 1996;271:1258–1261.PubMedGoogle Scholar
  64. 64.
    Labadia ME, Bokoch GM, Huang CK. The RaplA protein enhances protein kinase C activity in vitro. Biochem Biophys Res Comm. 1993;195:1321–1328.PubMedGoogle Scholar
  65. 65.
    Leiser M, Efrat S, Fleischer N. Evidence that Rapl carboxymethylation is involved in regulated insulin secretion. Endocrinology 1995;136:2521–2530.PubMedGoogle Scholar
  66. 66.
    Kowluru A, Seavey SE, Li G, Sorenson RL, Weinhaus AJ, Nesher R, Rabaglia ME, Vadakekalam J, Metz SA. Glucose-and GTP-dependent stimulation of the carboxyl methylation of CDC42 in rodent and human pancreatic islets and pure (3-cells. Evidence for an essential role of GTP-binding proteins in nutrient-induced insulin secretion. J Clin Invest 1996;98:540–555.PubMedGoogle Scholar
  67. 67.
    Gherzi R, Briata P, Fehmann HC, Goke B. Ras antagonizes cAMP stimulated glucagon gene transcription in pancreatic islet cell lines. FEBS Lett 1994;353:277–280.PubMedGoogle Scholar
  68. 68.
    Widmann C, Burki E, Dolci W, Thorens B. Signal transduction by the cloned Glucagon-like peptide-1 receptor: Comparison with signalling by the endogenous receptors of ß cell lines. Mol Pharmacol 1994;45:1029–1035.PubMedGoogle Scholar
  69. 69.
    Thorens B, Widmann C. Molecular and functional characterization of the pancreatic ß cell glucagon-like peptide-1 receptor. Diabetes 1994 1995;Excerpta Medica Int Congress Series 1100:184–186.Google Scholar
  70. 70.
    Thorens B, Porret A, Buhler L, Deng SP, Morel P, Widmann C. Cloning and functional expression of the human islet GLP-1 receptor. Demonstration that exendin-4 is an agonist and exendin-(9–39) an antagonist of the receptor. Diabetes 1993;42:1678–1682.PubMedGoogle Scholar
  71. 71.
    Goke R. Fehmann HC, Linn T, Schmidt H, Krause M, Eng J, Goke B. Exendin-4 is a high potency agonist and truncated exendin-(9–39)amide an antagonist at the glucagon-like peptide-1 receptor of insulin-secreting 13-cells. J Biol Chem 1993;268:19650–19655.PubMedGoogle Scholar
  72. 72.
    Greig NH, Holloway HW, DeOre KA, Jani D, Wang Y, Zhou J, Garant MJ, Egan JM. Once daily injection of exendin-4 to diabetic mice achieves long-term beneficial effects on blood glucose concentrations. Diabetologia 1999;42:45–50.PubMedGoogle Scholar
  73. 73.
    Young AA, Gedulin BR, Bhaysar S, Bodkin N, Jodka C, Hansen B, Denaro M. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob,db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 1999;48:1026–1034.PubMedGoogle Scholar
  74. 74.
    Holz GG, Habener JF. Black widow spider a-latrotoxin: a presynaptic neurotoxin that shares structural homology with the glucagon-like peptide-1 family of insulin secretagogic hormones. Comp Biochem Physiol B 1998;121:177–184.PubMedGoogle Scholar
  75. 75.
    Heller RS, Kieffer TJ, Habener JF. Point mutations in the first and third intracellular loops of the glucagon-like peptide- I receptor alter intracellular signaling. Biochem Biophys Res Comm 1996;223:624–632.PubMedGoogle Scholar
  76. 76.
    Takhar S, Gyomorey S, Su RC, Mathi SK, Li X, Wheeler MB. The third cytoplasmic domain of the GLP-1(7–36)amide receptor is required for coupling to the adenylyl cyclase system. Endocrinology 1996;137:2175–2178.PubMedGoogle Scholar
  77. 77.
    Mathi SK, Chan Y, Li X, Wheeler MB. Scanning of the glucagon-like peptide-1 receptor localizes G protein-activating determinants primarily to the N-terminus of the third intracellular loop. Mol Endocrinol 1997;11:424–432.PubMedGoogle Scholar
  78. 78.
    Salapatek AM, MacDonald PE, Gaisano HY, Wheeler MB. Mutations to the third cytoplasmic domain of the glucagon-like peptide-1 (GLP-1) receptor can functionally uncouple GLP-1stimulated insulin secretion in HIT-T15 cells. Mol Endocrinol 1999;13:1305–1317.PubMedGoogle Scholar
  79. 79.
    Abdel-Halim SM, Guenifi A, He B, Yang B, Mustafa M, Hojeberg B, Hillert J, Bakhiet M, Efendic S. Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes. Diabetes 1998;47:498–504.PubMedGoogle Scholar
  80. 80.
    Leech CA, Castonguay MA, Habener JF. Expression of adenylyl cyclase subtypes in pancreatic 1 cells. Biochem. Biophys. Res. Comm. 1999;254:703–706.Google Scholar
  81. 81.
    Yang B, He B, Abdel-Halim SM, Tibell A, Brendel MD, Bretzel RG, Efendic S, Hillert J. Molecular cloning of a full length cDNA for human type 3 adenylyl cyclase and its expression in human islets. Biochem Biophys Res Comm 1999;254:548–551.PubMedGoogle Scholar
  82. 82.
    Gromada J, Dissing S, Bokvist K, Renstrom E, Frokjaer-Jensen J, Wulff BS, Rorsman P. Glucagonlike peptide-1 increases cytoplasmic calcium in insulin-secreting 13TC-3-cells by enhancement of intracellular calcium mobilization. Diabetes 1995;44:767–774.PubMedGoogle Scholar
  83. 83.
    Gromada J, Rorsman P, Dissing S, Wulff BS. Stimulation of cloned human glucagon-like peptide-1 receptor expressed in HEK 293 cells induces cAMP-dependent activation of calcium-induced calcium release. FEBS Lett 1995;373:182–186.PubMedGoogle Scholar
  84. 84.
    Holz GG, Leech CA, Heller RS, Castonguay MA, Habener JF. cAMP-dependent mobilization of intracellular Ca’ stores by activation of ryanodine receptors in pancreatic 13-cells. A Ca’ signaling system activated by the insulinotropic hormone glucagon-like peptide-1(7–37). J Biol Chem 1999;274:14147–14156.PubMedGoogle Scholar
  85. 85.
    Gromada J, Rorsman P. Molecular mechanism underlying glucagon-like peptide-1 induced calcium mobilization from internal stores in insulin-secreting f3TC3 cells. Acta Physiol Scand 1996;157:349–351.PubMedGoogle Scholar
  86. 86.
    Yaekura K, Yada T. [Ca2+]i-reducing action of cAMP in rat pancreatic β-cells: involvement of thapsigargin-sensitive stores. Am J Physiol 1998;274:C513–0521.PubMedGoogle Scholar
  87. 87.
    Lester LB, Langeberg LK, Scott JD. Anchoring of protein kinase A facilitates hormone-mediated insulin secretion. Proc Natl Acad Sci USA 1997;94:14942–14947.PubMedGoogle Scholar
  88. 88.
    Gray PC, Tibbs VC, Catterall WA, Murphy BJ. Identification of a 15-kDa cAMP-dependent protein kinase-anchoring protein associated with skeletal muscle L-type Calcium channels. J Biol Chem 1997;272:6297–6302.PubMedGoogle Scholar
  89. 89.
    Holz GG, Hussain MA, Skoglund GS. Rat insulin gene promoter activity stimulated by picomolar concentrations of GLP-1. Abst American Diabetes Assoc Meeting, San Diego. 1999;Google Scholar
  90. 90.
    Wheeler MB, Lu M, Dillon JS, Leng XH, Chen C, Boyd AE. Functional expression of the rat glucagon-like peptide-1 receptor, evidence for coupling to both adenylyl cyclase and phospholipase C. Endocrinology 1993;133:57–62.PubMedGoogle Scholar
  91. 91.
    Gromada J, Anker C, Bokvist K, Knudsen LB, Wahl P. Glucagon-like peptide-1 receptor expression in Xenopus oocytes stimulates inositol trisphosphate-dependent intracellular Ca“ mobilization. FEBS Lett 1998;425:277–280.PubMedGoogle Scholar
  92. 92.
    Lu M, Wheeler MB, Leng XH, Boyd AE. The role of free cytosolic calcium level in ß cell signal transduction by gastric inhibitory polypeptide and glucagon-like peptide-1(7–37). Endocrinol 1993;132:94–100.Google Scholar
  93. 93.
    Rasmussen H, Isales CM, Calle R, Throckmorton D, Anderson M, Gassalla-Herraiz J, McCarthy R. Diacylglycerol production, Ca’ influx, and protein kinase C activation in sustained cellular responses. Endocrine Rev 1995;16:649–681.Google Scholar
  94. 94.
    Gromada J, Frokjaer-Jensen J, Dissing S. Glucose stimulates voltage-and calcium-dependent inositol trisphosphate production and intracellular calcium mobilization in insulin-secreting ßTC3 cells. Biochem J 1996;314:339–345.PubMedGoogle Scholar
  95. 95.
    Holz GG, Leech CA, Habener JF. Activation of a cAMP-regulated Ca’-signalling pathway in pancreatic ß cells by the insulinotropic hormone glucagon-like peptide-1. J Biol Chem 1995;270:17749–17757.PubMedGoogle Scholar
  96. 96.
    Suga S, Kanno T, Nakano K, Takeo T, Dobashi Y, Wakui M. GLP-1(7–36)amide augments Bat* current through L-type Ca“ channel of rat pancreatic 13-cell in a cAMP-dependent manner. Diabetes 1997;46:1755–1760.PubMedGoogle Scholar
  97. 97.
    Suga S, Kanno T, Dobashi Y, Wakui M. GLP-1(7–36)amide activates L-type Ca’ channels of pancreatic 13-cells through cAMP signaling. Jap J Physiol 1997;47:513-S14.Google Scholar
  98. 98.
    Gromada J, Bokvist K, Ding WG, Holst JJ, Nielsen JH, Rorsman P. Glucagon-like peptide-1(736)amide stimulates exocytosis in human pancreatic beta-cells by both proximal and distal regulatory steps in stimulus-secretion coupling. Diabetes 1998;47:57–65.PubMedGoogle Scholar
  99. 99.
    Leech CA, Habener JF. Insulinotropic glucagon-like peptide-1-mediated activation of non-selective cation currents in insulinoma cells is mimicked by maitotoxin. J Biol Chem 1997;272:17987–17993.PubMedGoogle Scholar
  100. 100.
    Cook DL, Satin LS, Hopkins WF. Pancreatic ß cells are bursting, but how? Trends in Neurosci 1991;14:411–414.Google Scholar
  101. 101.
    Cook DL. Isolated islets of Langerhans have slow oscillations of electrical activity. Metabolism 1983;32:681–685.PubMedGoogle Scholar
  102. 102.
    Cook DL, Satin LS, Ashford MLJ, Hales CN. ATP-sensitive K. channels in pancreatic 0-cells. Spare channel hypothesis. Diabetes 1988;37:495–498.PubMedGoogle Scholar
  103. 103.
    Eddlestone GT, Oldham SB, Lipson LG, Premdas FH, Biegelman PM. Electrical activity, cAMP concentration, and insulin release in mouse islets of Langerhans. Am J Physiol 1985;248:C145–C153.PubMedGoogle Scholar
  104. 104.
    Inagaki N, Gonoi T, Seino S. Subunit stoichiometry of the pancreatic 13-cell ATP-sensitive K+ channel. FEBS Lett 1997;409:232–236.PubMedGoogle Scholar
  105. 105.
    Clement JP, Kunjilwar K, Gonzalez G, Schwanstecher M, Panten U, Aguilar-Bryan L, Bryan J. Association and stoichiometry of KATD channel subunits. Neuron 1997;18:827–838.PubMedGoogle Scholar
  106. 106.
    Shyng SL, Nichols CG. Octameric stoichiometry of the KATP channel complex. J Gen Physiol 1997;110:655–664.PubMedGoogle Scholar
  107. 107.
    Alekseev AE, Kennedy ME, Navarro B, Terzic A. Burst kinetics of co-expressed Kir6.2/SUR1 clones: Comparison of recombinant with native ATP-sensitive K+ channel behaviour. J Membrane Biol 1997;159:161–168.Google Scholar
  108. 108.
    Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic 3-cell. Prog Biophys Molec Biol 1989;54:87–143.Google Scholar
  109. 109.
    Barnett DW, Pressel DM, Chern HT, Scharp DW, Misler S. cAMP-enhancing agents permit stimulus-secretion coupling in canine pancreatic islet ß cells. J Membrane Biol 1994;138:113–120.Google Scholar
  110. 110.
    He LP, Mears D, Atwater I, Kitasato H. Glucagon induces suppression of ATP-sensitive K+ channel activity through a Cat+/calmodulin-dependent pathway in mouse pancreatic 3-cells. J Membrane Biol 1998;166:237–244.Google Scholar
  111. 111.
    Ribalet B, Ciani S, Eddlestone GT. ATP mediates both activation and inhibition of K(ATP) channel via cyclic-AMP dependent protein kinase in insulin secreting cell lines. J Gen Physiol 1989;94:693–717.PubMedGoogle Scholar
  112. 112.
    He LP, Kitasato H. Glucagon induces Cat+ dependent increase of reduced pyridine nucleotides in mouse pancreatic _-cells. Biochim Biophys Acta 1996;1310:325–333.PubMedGoogle Scholar
  113. 113.
    Ribalet B, Ciani S. Characterization of the G-protein coupling of a glucagon receptor to the K-ATP channel in insulin secreting cells. J Membrane Biol 1994;142:395–408.Google Scholar
  114. 114.
    Sui JL, Petit-Jacques J, Logothetis DE. Activation of the atrial KACh channel by the _ subunits of G proteins or intracellular Na+ ions depends on the presence of phosphatidylinositol phosphates. Proc Natl Acad Sci USA 1998;95:1307–1312.PubMedGoogle Scholar
  115. 115.
    Huang CL, Feng S, Hilgemann DW. Direct activation of inward rectifier potassium channels by PIP2 and its stabilization by G1’y. Nature 1998;391:803–806.PubMedGoogle Scholar
  116. 116.
    Shyng SL, Nichols CG. Membrane phospholipid control of nucleotide sensitivity of KATPchannels. Science 1998;282:1138–1141.PubMedGoogle Scholar
  117. 117.
    Baukrowitz T, Schulte U, Oliver D, Herlitze S, Krauter T, Tucker SJ, Ruppersberg JP, Fakler B. PIP2 and PIP as determinants for ATP inhibition of KATP channels. Science 1998;282:1141–1144.PubMedGoogle Scholar
  118. 118.
    Laychock SG. Identification and metabolism of polyphosphoinositides in isolated islets of Langerhans. Biochem J 1983;216:101–106.PubMedGoogle Scholar
  119. 119.
    Seino S, Chen L, Seino M, Blondel O, Takeda J, Johnson JH, G.I. B. Cloning of the a, subunit of a voltage-dependent calcium channel expressed in pancreatic ß-cells. Proc Natl Acad Sci USA 1992;89:584–588.PubMedGoogle Scholar
  120. 120.
    Seino S. CACN4, the major alpha 1 subunit isoform of voltage-dependent calcium channels in pancreatic 0-cells: a minireview of current progress. Diabetes & Clin Practice 1995;28:s99-s103.Google Scholar
  121. 121.
    Satin LS, Tavalin SJ, Kinard TA, Teague J. Contribution of L- and non-L-type calcium channels to voltage-gated calcium current and glucose-dependent insulin secretion in HIT-T15 cells. Endocrinology 1995;136:4589–4601.PubMedGoogle Scholar
  122. 122.
    Bokvist K, Eliasson L, Ammala C, Renstrom E, Rorsman P. Co-localization of L-type Cat+ channels and insulin-containing secretory granules and its significance for the initiation of exocytosis in mouse pancreatic 0-cells. EMBO J 1995;14:50–57.PubMedGoogle Scholar
  123. 123.
    Kindmark H, Kohler M, Larsson O, Khan A, Berggren PO. Dissociation between exocytosis and Cat+-channel activity in mouse pancreatic 3-cells stimulated with calmidazolium (compound R24571). FEBS Lett 1995;315–320.Google Scholar
  124. 124.
    Wiser O, Trus M, Hernandez A, Renstrom E, Barg S, Rorsman P, Atlas D. The voltage sensitive Lc-type Cat+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci USA 1999;96:248–253.PubMedGoogle Scholar
  125. 125.
    Yang SN, Larsson O, Branstrom R, Bertorello AM, Leibiger B, Leibiger IB, Moede T, Kohler M, Meister B, P.O. B. Syntaxin 1 interacts with the LE, subtype of voltage-gated Ca’-+ channel in pancreatic 13 cells. Proc Natl Acad Sci USA 1999;96:10164–10169.PubMedGoogle Scholar
  126. 126.
    Smith PA, Rorsman P, Ashcroft FM. Modulation of dihydropyridine-sensitive Ca’ channels by glucose metabolism in mouse pancreatic 13-cells. Nature 1989;342:550–553.PubMedGoogle Scholar
  127. 127.
    Arkhammer P, Juntti-Berggren L, Larrson O, Welch M, Nanberg E, Sjoholm A, Kohler M, Berggren PO. Protein kinase C modulates the insulin secretory process by maintaining a proper function of the 13-cell voltage-activated Ca“-channels. J Biol Chem 1994;269:2743–2749.Google Scholar
  128. 128.
    Haby C, Larsson O, Islam MS, Aunis D, Berggren PO, Zwiller J. Inhibition of serine/threonine protein phosphatases promotes opening of voltage-activated L-type Ca“ channels in insulin-secreting cells Biochem J 1994;298:341–346.Google Scholar
  129. 129.
    Larsson O, Barker CJ, Sjoholm A, Carlqvist H, Michell RH, Bertorello A, Nillson T, Honkanon RE, Mayr GW, Zwiller J, Berggren PO. Inhibition of phosphatases and increased Ca’ channel activity by inositol hexakisphosphate. Science 1997;278:471–474.PubMedGoogle Scholar
  130. 130.
    Leech CA, Holz GG, Habener JF. Signal Transduction of PACAP and GLP-1 in pancreatic 0-cells. Ann NY Acad Sci 1996;805:81–93.PubMedGoogle Scholar
  131. 131.
    Ammala C, Ashcroft FM, Rorsman P. Calcium-independent potentiation of insulin release by cyclic AMP in single 0-cells. Nature 1993;363:356–358.PubMedGoogle Scholar
  132. 132.
    Britsch S, Krippeit-Drews P, Lang F, Gregor M, Drews G. Glucagon-like peptide-1 modulates Ca“ current but not K’ATP current in intact mouse pancreatic ß cells. Biochem Biophys Res Comm 1995;207:33–39.PubMedGoogle Scholar
  133. 133.
    Gromada J, Ding WG, Barg S, Renstrom E, Rorsman P. Multisite regulation of insulin secretion by cAMP-increasing agonists: evidence that glucagon-like peptide-1 and glucagon act via distinct receptors. Pflugers Arch 1997;434:515–524.PubMedGoogle Scholar
  134. 134.
    Yada T, Sakurada M, Nakata M, Ihida K, Yaekura K, Shioda S, Kikuchi M. Current status of PACAP as a regulator of insulin secretion in pancreatic islets. Ann NY Acad Sci 1996;805:329–342.PubMedGoogle Scholar
  135. 135.
    af Klinteberg K, Karlsson S, Ahren B. Signaling mechanisms underlying the insulinotropic effect of pituitary adenylate cyclase-activating polypeptide in HIT-T15 cells. Endocrinology 1996;137:2791–2798.Google Scholar
  136. 136.
    af Klinteberg K, Karlsson S, Moller K, Sundler F, Ahren B. Pituitary adenylate cyclase activating polypeptide (PACAP) and insulin secretion: Effects and mechanisms. Ann NY Acad Sci 1996;805:543–548.Google Scholar
  137. 137.
    Filipsson K, Ahren B. Protein kinase A inhibition and PACAP-induced insulin secretion in HIT-T15 cells. Ann NY Acad Sci 1998;865:441–444.PubMedGoogle Scholar
  138. 138.
    Filipsson K, Sundler F, Ahren B. PACAP is an islet neuropeptide which contributes to glucose-stimulated insulin secretion. Biochem Biophys Res Comm 1999;256:664–667.PubMedGoogle Scholar
  139. 139.
    Moreno Davila H. Molecular and functional diversity of voltage-gated calcium channels. Ann NY Acad Sci 1999;868:102–117.PubMedGoogle Scholar
  140. 140.
    Magnelli V, Grassi C, Parlatore E, Sher E, Carbone E. Down-regulation of non-L, non-N-type (Q-like) CaZ’ channels by Lambert-Eaton myasthenic syndrome (LEMS) antibodies in rat insulinoma RINm5F cells. FEBS Lett 1996;387:47–52.PubMedGoogle Scholar
  141. 141.
    Ligon B, Boyd AE, Dunlap K. Class A calcium channel variants in pancreatic islets and their role in insulin secretion. J Biol Chem 1998;273:13905–13911.PubMedGoogle Scholar
  142. 142.
    Yaney GC, Wheeler MB, Wei X, Perez-Reyes E, Birmbaumer L, Boyd AE, Moss LG. Cloning of a novel a,-subunit of the voltage-dependent calcium channel from the 13-cell. Mol Endo 1992;6:2143–2152.Google Scholar
  143. 143.
    Safayhi H, Haase H, Kramer U, Bihlmayer A, Roenfeldt M, Ammon HPT, Froschmayr M, Cassidy TN, Morano I, Ahlijanaian MK, Striessnig J. L-type calcium channels in insulin-secreting cells: biochemical characterization and phosphorylation in RINm5F cells. Mol Endo 1997;11:619–629.Google Scholar
  144. 144.
    Wang L, Bhattacharjee A, Zuo Z, Hu F, Honkanen RE, Berggren PO, Li M. A low voltage-activated Ca“ current mediates cytokine-induced pancreatic 0-cell death. Endocrinology 1999;140:1200–1204.PubMedGoogle Scholar
  145. 145.
    Bhattacharjee A, Whitehurst RM, Zhang M, Wang L, Li M. T-type calcium channels facilitate insulin secretion by enhancing general excitability in the insulin-secreting beta cell line, INS-1. Endocrinology 1997;138:3735–3740.PubMedGoogle Scholar
  146. 146.
    Blondel O, Takeda J, Janssen H, Seino S, Bell GI. Sequence and functional characterization of a third inositol trisphosphate receptor subtype, IP3R-3, expressed in pancreatic islets, kidney, gastrointestinal tract, and other tissues. J Biol Chem 1994;268:11356–11363.Google Scholar
  147. 147.
    Lee B, Bradford PG, Laychock SG. Characterization of inositol 1,4,5-trisphosphate receptor isoform mRNA expression and regulation in rat pancreatic islets. J Mol Endocrinol 1998;21:31–39.PubMedGoogle Scholar
  148. 148.
    Islam MS, Leibiger I, Leibiger B, Rossi D, Sorrentino V, Ekstrom TJ, Westerblad H, Andrade FH, Berggren PO. In situ activation of the type 2 ryanodine receptor in pancreatic beta cells requires CAMP-dependent phosphorylation. Proc Natl Acad Sci USA 1998;95:6145–6150.PubMedGoogle Scholar
  149. 149.
    Takasawa S, Nata K, Yonekura H, Okamoto H. Cyclic ADP-ribose in insulin secretion from pancreatic 0-cells. Science 1993;259:370–373.PubMedGoogle Scholar
  150. 150.
    Noguchi N, Takasawa S, Nata K, Tohgo A, Kato I, Ikehata F, Yonekura H, Okamoto H. CyclicADP-ribose binds to FK506-binding protein 12.6 to release Ca“ from islet microsomes. J Biol Chem 1997;272:3133–3136.PubMedGoogle Scholar
  151. 151.
    Takasawa S, Akiyama T, Nata K, Kuroki M, Tohgo A, Noguchi N, Kobayashi S, Kato I, Katada T, Okamoto H. Cyclic ADP-ribose and inositol 1,4,5-trisphosphate as alternative second messengers for intracellular Ca“ mobilization in normal and diabetic ß-cells. J Biol Chem 1998;273:2497–2500.PubMedGoogle Scholar
  152. 152.
    Takasawa S, Ishida A, Nata K, Nakagawa K, Noguchi N, Tohgo A, Kato I, Yonekura H, Fujisawa H, Okamoto H. Requirement of calmodulin-dependent protein kinase II in cyclic ADP-ribosemediated intracellular Ca“ mobilization. J Biol Chem 1995;270:30257–30259.PubMedGoogle Scholar
  153. 153.
    Roe MW, Philipson LH, Frangakis CJ, Kuzetsov A, Mertz RJ, Lancaster ME, Spencer B, Worley JF, Dukes ID. Defective glucose-dependent endoplasmic reticulum Ca’ sequestration in diabetic mouse islets of Langerhans. J Biol Chem 1994;269:18279–18282.PubMedGoogle Scholar
  154. 154.
    Roe MW, Mertz RJ, Lancaster ME, Worley JF, Dukes ID. Thapsigargin inhibits the glucose-induced decrease of intracellular Ca’ in mouse islets of Langerhans. Am J Physiol 1994;266:E852–E862.PubMedGoogle Scholar
  155. 155.
    Gilon P, Arredouani A, Gailly P, Gromada J, Henquin JC. Uptake and release of Cat+ by the endoplasmic reticulum contribute to the oscillations of the cytosolic Ca’ concentration triggered by Caz+ influx in the electrically excitable pancreatic 13-cell. J Biol Chem 1999;274:20197–20205.PubMedGoogle Scholar
  156. 156.
    Maechler P, Kennedy ED, Sebo E, Valeva A, Pozzan T, Wollheim CB. Secretagogues modulate the calcium concentration in the endoplasmic reticulum of insulin-secreting cells. Studies in aequorinexpressing intact and permeabilized INS-1 cells. J Biol Chem 1999;274:12583–12592.PubMedGoogle Scholar
  157. 157.
    Varadi A, Molnar E, Ashcroft SJ. Characterization of endoplasmic reticulum and plasma membrane Ca“-ATPases in pancreatic p-cells and in islets of Langerhans. Biochim Biophys Acta 1995;1236:119–127.PubMedGoogle Scholar
  158. 158.
    Varadi A, Molnar E, Ostenson CG, Ashcroft Si. Isoforms of endoplasmic reticulum Ca“-ATPase are differentially expressed in normal and diabetic islets of Langerhans. Biochem J 1996;319:521–527.PubMedGoogle Scholar
  159. 159.
    Varadi A, Lebel L, Hashim Y, Mehta Z, Ashcroft SJH, Turner R. Sequence variants of the saco(endo)plasmic reticulum Cat+ transport ATPase 3 gene (SERCA3) in caucasian type II diabetic patients (UK prospective diabetes study 48). Diabetologia 1999;42:1240–1243.PubMedGoogle Scholar
  160. 160.
    Schofl C, Rossig L, Mader T, Von Zur Muhlen A, Brabant G. Cyclic adenosine 3’,5’monophosphate potentiates Ca“ signaling and insulin secretion by phospholipase C-linked hormones in HIT cells. Endocrinology 1996;137:3026–3032.PubMedGoogle Scholar
  161. 161.
    Liu YJ, Grapengiesser E, Gylfe E, Hellman B. Crosstalk between cAMP and inositol trisphosphatesignalling pathways in pancreatic 0-cells. Arch Biochem Biophys 1996;334:295–302.PubMedGoogle Scholar
  162. 162.
    Mak DOD, McBride S, Foskett JK. ATP regulation of type-1 inositol 1,4,5-trisphosphate receptor channel gating by allosteric tuning of Ca’ activation. J Biol Chem 1999;274:22231–22237.PubMedGoogle Scholar
  163. 163.
    Islam MS, Rorsman P, Berggren PO. Cat+-induced Ca’ release in insulin-secreting cells. FEBS Lett 1992;296:287–291.PubMedGoogle Scholar
  164. 164.
    Gamberucci A, Fulceri R, Pralong W, Banhegyi G, Marcolongo P, Watkins SL, Benedetti A. Caffeine releases a glucose-primed endoplasmic reticulum Ca’ pool in the insulin secreting cell line INS-1. FEBS Lett 1999;446:309–312.PubMedGoogle Scholar
  165. 165.
    Bode HP, Moorman B, Dabew R, Goke B. Glucagon-like peptide-1 elevates cytosolic calcium in pancreatic 13-cells independently of protein kinase A. Endocrinology 1999;140:3919–3927.PubMedGoogle Scholar
  166. 166.
    Kato I, Takasawa S, Akabane A, Tanaka O, Abe H, Takamura T, Suzuki Y, Nata K, Yonekura H, Yoshimoto T, Okamoto H. Regulatory role of CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in insulin secretion by glucose in pancreatic 13-cells. Enhanced insulin secretion in CD38-expressing transgenic mice. J Biol Chem 1995;270:30045–30050.PubMedGoogle Scholar
  167. 167.
    Li Q, Yamada Y, Yasuda K, Ihara Y, Okamoto Y, Kaisaki PJ, Watanabe R, Ikeda H, Tsuda K, Seino Y. A cloned rat CD-38-homologous protein and its expression in pancreatic islets. Biochem Biophys Res Comm 1994;202:629–636.PubMedGoogle Scholar
  168. 168.
    Morita K, Kitayama S, Dohi T. Stimulation of cyclic ADP-ribose synthesis by acetylcholine and its role in catecholamine release in bovine adrenal chromaffin cells. J Biol Chem 1997;272:21002–21009.PubMedGoogle Scholar
  169. 169.
    Sturgess NC, Hales CN, Ashford MLJ. Inhibition of a calcium-activated non-selective cation channel, in a rat insulinoma cell line, by adenine derivatives. FEBS Lett 1986;208:397–400.PubMedGoogle Scholar
  170. 170.
    Herson PS, Ashford MLJ. Activation of a novel non-selective cation channel by alloxan and H2O, in the rat insulin-secreting cell line CRI-G1. J Physiol 1997;501:59–66.PubMedGoogle Scholar
  171. 171.
    Sturgess NC, Hales CN, Ashford MLJ. Calcium and ATP regulate the activity of a non-selective cation channel in a rat insulinoma cell line. Pflugers Arch 1987;409:607–615.PubMedGoogle Scholar
  172. 172.
    Fridolf T, Ahren B. GLP-1(7–36)amide-stimulated insulin secretion in rat islets is sodium-dependent. Biochem Biophys Res Commun 1991;179:701–706.PubMedGoogle Scholar
  173. 173.
    Fridolf T, Ahren B. Effects of glucagon-like peptide-1(7–36)amide on the cytoplasmic Ca“- concentration in rat islet cells. Mol Cell Endocrinol 1993;96:85–90.PubMedGoogle Scholar
  174. 174.
    Kato M, Ma HT, Tatemoto K. GLP-1 depolarizes the rat pancreatic 13-cell in a sodium-dependent manner. Regulatory Peptides 1996;62:23–27.PubMedGoogle Scholar
  175. 175.
    Reale V, Hales CN, Ashford MLJ. Nucleotide regulation of a calcium activated cation channel in the rat insulinoma cell line, CRI-G1. J Membrane Biol 1994;141:101–112.Google Scholar
  176. 176.
    Reale V, Hales CN, Ashford MLJ. The effects of pyridine nucleotides on the activity of a calcium-activated non-selective cation channel in the rat insulinoma cell line, CRI-01. J Membrane Biol 1994;142:299–307.Google Scholar
  177. 177.
    Reale V, Hales CN, Ashford MLJ. Regulation of calcium-activated nonselective cation channel activity by cyclic nucleotides in the rat insulinoma cell line, CRI-01. J Membrane Biol 1995;145:267–278.Google Scholar
  178. 178.
    Worley JF, McIntyre MS, Spencer B, Mertz RJ, Roe MW, Dukes ID. Endoplasmic reticulum calcium store regulates membrane potential in mouse islet 13-cells. J Biol Chem 1994;269:14359–14362.PubMedGoogle Scholar
  179. 179.
    Worley JF, McIntyre MS, Spencer B, Dukes ID. Depletion of intracellular Ca“ stores activates a maitotoxin-sensitive nonselective cationic current in 13-cells. J Biol Chem 1994;269:32055–32058.PubMedGoogle Scholar
  180. 180.
    Miura Y, Henquin JC, Gilon P. Emptying of intracellular Ca’ stores stimulates Ca’ entry in mouse pancreatic a-cells by both direct and indirect mechanisms. J Physiol 1997;503:387–398.PubMedGoogle Scholar
  181. 181.
    Liu YJ, Gylfe E. Store-operated Ca“ entry in insulin-releasing pancreatic 13-cells. Cell Calcium 1997;22:277–286.PubMedGoogle Scholar
  182. 182.
    Henquin JC, Garcia MC, Bozem M, Hermans MP, Nenquin M. Muscarinic control of pancreatic (3-cell function involves sodium-dependent depolarization and calcium influx. Endocrinology 1988;122:2134–2142.PubMedGoogle Scholar
  183. 183.
    Roe MW, Worley JF, Qian F, Tamarina N, Mittal AA, Dralyuk F, Blair NT, Mertz RJ, Philipson LH, Dukes ID. Characterization of a Ca’ release-activated nonselective cation current regulating membrane potential and [Ca2+], oscillations in transgenically derived beta cells. J Biol Chem 1998;273:10402–10410.PubMedGoogle Scholar
  184. 184.
    Vaca L, Sinkins WG, Hu Y, Kunze DL, Schilling WP. Activation of recombinant trp by thapsigargin in Sf9 insect cells. Am J Physiol 1994;267:C15O1–C1505.Google Scholar
  185. 185.
    Zhu X, Jiang M, Peyton M, Boulay G, Hurst R, Stefani E, Birnbaumer L. trp, a novel mammalian gene family essential for agonist-activated capacitative Ca’ entry. Cell 1996;85:661–671.PubMedGoogle Scholar
  186. 186.
    Sinkins WG, Vaca L, Hu Y, Kunze DL, Schilling WP. The COOH-terminal domain of Drosophila TRP channels confers thapsigargin sensitivity. J Biol Chem 1996;271:2955–2960.PubMedGoogle Scholar
  187. 187.
    Philipp S, Cavalie A, Freichel M, Wissenbach U, Zimmer S, Trost C, Marquart A, Murakami M, Flockerzi V. A mammalian capacitative calcium entry channel homologous to Drosophila Trp and Trpl. EMBO J 1996;15:6166–6171.PubMedGoogle Scholar
  188. 188.
    Gillo B, Chorna I, Cohen H, Cook B, Manistersky I, Chorev M, Arnon A, Pollock JA, Selinger Z, Minke B. Coexpression of Drosophila TRP and TRP-like proteins in Xenopus oocytes reconstitutes capacitative Ca’ entry. Proc Natl Acad Sci USA. 1996;93:14146–14151.PubMedGoogle Scholar
  189. 189.
    DasGupta S, Qian F, Miller RJ, Philipson LH. Expression of MTrpb-I a mammalian Trp homologue in neuronal and non-neuronal cells. Neurosci Abst 1996;22:1028.Google Scholar
  190. 190.
    Boulay G, Zhu X, Peyton M, Jiang M, Hurst R, Stefani E, Birnbaumer L. Cloning and expression of a novel mammalian homolog of Drosophila Transient Receptor Potential (Trp) involved in calcium entry secondary to activation of receptors coupled by the Gq class of G protein. J Biol Chem 1997;272:29672–29680.PubMedGoogle Scholar
  191. 191.
    Birnbaumer L, Zhu X, Jiang M, Boulay G, Peyton M, Vannier B, Brown D, Platano D, Sadeghi H, Stefani E, Bimbaumer M. On the molecular basis and regulation of cellular capacitative calcium entry: Roles for Trp proteins. Proc Natl Acad Sci USA. 1996;93:15195–15202.PubMedGoogle Scholar
  192. 192.
    Petersen CCH, Berridge MJ, Borgese MF, Bennett DL. Putative capacitative calcium entry channels: expression of Drosophila trp and evidence for the existence of vertebrate homologues. Biochem J 1995;311:41–44.PubMedGoogle Scholar
  193. 193.
    Leech CA, Habener JF. A role for Ca“-dependent non-selective cation channels in regulating the membrane potential of pancreatic 13-cells. Diabetes 1998;47:1066–1073.PubMedGoogle Scholar
  194. 194.
    Bertram R, Smolen P, Sherman A, Mears D, Atwater I, Martin F, Soria B. A role for calcium release-activated current (CRAC) in cholinergic modulation of electrical activity in pancreatic ß cells. Biophys J 1995;68:1–10.Google Scholar
  195. 195.
    Mears D, Sheppard NF, Atwater I, Rojas E, Bertram R, Sherman A. Evidence that calcium release-activated current mediates the biphasic electrical activity of mouse pancreatic 13-cells. J Membrane Biol 1997;155:47–59.Google Scholar
  196. 196.
    Kinard TA, Satin LS. An ATP-sensitive Cl-channel current that is activated by cell swelling, cAMP, and glyburide in insulin-secreting cells. Diabetes 1995;44:1461–1466.PubMedGoogle Scholar
  197. 197.
    Eddleston GT, Beigelman PM. Pancreatic 13-cell electrical activity: the role of anions and the control of pH. Am J Physiol 1983;244:C188–C197.Google Scholar
  198. 198.
    Horn R, Marty A. Muscarinic activation of ionic currents measured by a new whole-cell recording method. J Gen Physiol 1988;92:145–159.PubMedGoogle Scholar
  199. 199.
    Kozak JA, Logothetis DE. A calcium-dependent chloride current in insulin-secreting 1TC-3 cells. Pflugers Arch 1997;433:679–690.PubMedGoogle Scholar
  200. 200.
    Best L. Glucose and a-ketoisocaproate induce transient inward currents in rat pancreatic beta cells. Diabetologia 1997;40:1–6.PubMedGoogle Scholar
  201. 201.
    Miley HE, Sheader EA, Brown PD, Best L. Glucose-induced swelling in rat pancreatic 43-cells. J Physiol 1997;504:191–198.PubMedGoogle Scholar
  202. 202.
    Best L, Sheader EA, Brown PD. A volume-activated anion conductance in insulin-secreting cells. Pflugers Arch 1996;431:363–370.PubMedGoogle Scholar
  203. 203.
    Miley HE, Brown PD, Best L. Regulation of a volume-sensitive anion channel in rat pancreatic 5- cells by intracellular adenine nucleotides. J Physiol 1999;515:413–417.PubMedGoogle Scholar
  204. 204.
    Barg S, Renstrom E, Berggren PO, Bertorello A, Bokvist K, Eliasson L, Holmes WE, Kohler M, Rorsman P, Thevenod F. The stimulatory action of tolbutamide on CaZ*-dependent exocytosis in pancreatic ß cells is mediated by a 65-kDa mdr-like P-glycoprotein. Proc Natl Acad Sci USA 1999;96:5539–5544.PubMedGoogle Scholar
  205. 205.
    Muller G, Geisen K. Characterization of the molecular mode of action of the sulfonylurea, glimeprimide, at adipocytes. Horm Metab Res 1996;28:469–487.PubMedGoogle Scholar
  206. 206.
    Vanoye CG, Castro AF, Pourcher T, Reuss L, Altenberg GA. Phosphorylation of P-glycoprotein by PICA and PKC modulates swelling-activated C1 currents. Am J Physiol 1999;276:C370–C378.PubMedGoogle Scholar
  207. 207.
    Renstrom E, Eliasson L, Rorsman P. Protein kinase A-dependent and -independent stimulation of exocytosis by cAMP in mouse pancreatic ß-cells. J Physiol 1997;502:105–118.PubMedGoogle Scholar
  208. 208.
    Hisatomi M, Hidaka H, Niki I. CaZ*/calmodulin and cyclic 3’,5’ adenosine monophosphate control movement of secretory granules through protein phosphorylation/dephosphorylation in the pancreatic 5-cell. Endocrinology 1996;137:4644–4649.PubMedGoogle Scholar
  209. 209.
    Lang J. Molecular mechanisms and regulation of insulin exocytosis as a paradigm of endocrine secretion. Eur J Biochem 1998;259:1–16.Google Scholar
  210. 210.
    Takahashi N, Kadowaki T, Yazaki Y, Ellis-Davies GCR, Miyashita Y, Kasai H. Post-priming actions of ATP on CaZ*-dependent exocytosis in pancreatic beta cells. Proc Natl Acad Sci USA 1999;96:760–765.PubMedGoogle Scholar
  211. 211.
    Sato Y, Anello M, Henquin JC. Glucose regulation of insulin secretion independent of the opening or closure of adenosine triphosphate-sensitive K* channels in 5-cells. Endocrinology 1999;140:2252–2257.PubMedGoogle Scholar
  212. 212.
    Aizawa T, Komatsu M, Asanuma N, Sato Y, Sharp GW. Glucose action “beyond ionic events” in the pancreatic ß cell. Trends Pharmacol Sci 1998;19:496–499.PubMedGoogle Scholar
  213. 213.
    Aizawa T, Sato Y, Ishihara F, Taguchi N, Komatsu M, Suzuki N, Hashizume K, Yamada T. ATP-sensitive K* channel-independent glucose action in rat pancreatic ß cell. Am J Physiol 1994;266:C622–C627.PubMedGoogle Scholar
  214. 214.
    Kieffer TJ, Heller RS, Leech CA, Holz GG, Habener JF. Leptin suppression of insulin secretion by the activation of ATP-sensitive K* channels in pancreatic 5-cells. Diabetes 1997;46:1087–1093.PubMedGoogle Scholar
  215. 215.
    Harvey J, McKenna F, Herson PS, Spanswick D, Ashford MU. Leptin activates ATP-sensitive potassium channels in the rat insulin-secreting cell line, CRI-Gl. J Physiol 1997;504:527–535.PubMedGoogle Scholar
  216. 216.
    Seufert JR, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C, Habener JF. Leptin suppression of insulin secretion and gene expression in human pancreatic islets: Implications for the development of adipogenic diabetes mellitus. J Clin Endo Metab 1999;84:670–676.Google Scholar
  217. 217.
    Seufert J, Kieffer TJ, Habener JF. Leptin inhibits insulin gene transcription and reverses hyperinsulinemia in leptin-deficient ob/ob mice. Proc Natl Acad Sci USA 1999;96:674–679.PubMedGoogle Scholar
  218. 218.
    Kieffer TJ, Heller RS, Habener JF. Leptin receptors expressed on pancreatic 5-cells. Biochem Biophys Res Comm 1996;224:522–527.PubMedGoogle Scholar
  219. 219.
    Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman 1M. Positional cloning of the mouse obese gene and its human homologue. Nature 1995;372:425–432.Google Scholar
  220. 220.
    Tartaglia LA, Dembski M, Weng X, Deng N, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI. Identification and expression cloning of a leptin receptor, OB-R. Cell 1995;83:1263–1271.PubMedGoogle Scholar
  221. 221.
    Tartaglia LA. The leptin receptor. J Biol Chem 1997;272:6093–6096.PubMedGoogle Scholar
  222. 222.
    Kellerer M, Koch M, Metzinger E, Mushack 1, Capp E, Haring HU. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 1997;40:1358–1362.PubMedGoogle Scholar
  223. 223.
    Zhou YT, Shimabukuro M, Koyama K, Lee Y, Wang MY, Trieu F, Newgard CB, Unger RH. Induction by leptin of uncoupling protein-2 and enzymes of fatty acid oxidation. Proc Nati Acad Sci USA 1997;94:6386–6390.Google Scholar
  224. 224.
    Emilsson V, Liu YL, Cawthorne MA, Morton NM, Davenport M. Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion. Diabetes 1997;46:313–316.PubMedGoogle Scholar
  225. 225.
    Zhao AZ, Bornfeldt KE, Beavo JA. Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest 1998;102:869–873.PubMedGoogle Scholar
  226. 226.
    Ookuma M, Ookuma K, York DA. Effects of leptin on insulin secretion from isolated rat pancreatic islets. Diabetes 1998;47:219–223.PubMedGoogle Scholar
  227. 227.
    Chen NG, Swick AG, Romsos DR. Leptin constrains acetylcholine-induced insulin secretion from pancreatic islets of ob/ob mice. J Clin Invest 1997;100:1174–1179.PubMedGoogle Scholar
  228. 228.
    Harvey J, Ashford MLJ. Role of tyrosine phosphorylation in leptin activation of ATP-sensitive K* channels in the rat insulinoma cell line CRI-Gl. J Physiol 1998;510:47–61.Google Scholar
  229. 229.
    Morton NM, Emilsson V, deGroot P, Pallet AL, Cawthorne MA. Leptin signalling in pancreatic islets and clonal insulin-secreting cells. J Mol Endocrinol 1999;22:173–184.PubMedGoogle Scholar
  230. 230.
    Wang MY, Koyama K, Shimabukuro M, Mangelsdorf D, Newgard CB, Unger RH. Overexpression of leptin receptors in pancreatic islets of Zucker diabetic fatty rats restores GLUT-2, glucokinase, and glucose-stimulated insulin secretion. Proc Natl Acad Sci USA 1998;95:11921–11926.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2001

Authors and Affiliations

  • George G. Holz
    • 1
  • Colin A. Leech
    • 2
  1. 1.New York University School of MedicineNew YorkUSA
  2. 2.Howard Hughes Medical InstituteMassachusetts General Hospital Harvard Medical SchoolBostonUSA

Personalised recommendations