Regulation of Insulin Granule Exocytosis

  • Erik Renström
  • Patrik Rorsman


Insulin is stored in secretory granules within the pancreatic beta cell. The release of insulin requires the fusion of the secretory granule with the plasma membrane and the discharge of the granule contents into the extracellular space. Insulin secretion follows a characteristic biphasic time course consisting of a rapid but transient 1st phase followed by a slowly developing and sustained 2nd phase. Because type 2 diabetes involves defects of insulin secretion, manifested as a loss of 1st phase and a reduction of the 2nd phase, it is important to understand the cellular mechanisms underlying biphasic insulin secretion. Here we describe how glucose, via electrical activity, triggers insulin secretion. With this background, we consider the molecular machinery involved in the exocytosis of insulin, the possibility that Ca2+-influx through different Ca2+ channels underlies phasic insulin secretion, how Ca2+ is sensed by the beta-cell granules, the maintenance of the pool of release-competent granules by intracellular granule trafficking and glucose metabolism, the existence of two parallel pathways of exocytosis in the beta cell, and finally the evidence suggesting that exocytosis is not an all-or-none event and that significant regulation of beta-cell secretion occurs at the levels of the fusion pore (the connection between the granule interior and the extracellular space).


Insulin Secretion Beta Cell Secretory Granule Fusion Pore Insulin Granule 
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.


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  1. 1.
    Dean PM (1973) Ultrastructural morphometry of the pancreatic beta cell. Diabetologia 9:115–119PubMedCrossRefGoogle Scholar
  2. 2.
    Olofsson CS, Gopel SO, Barg S, Galvanovskis J, Ma X, Salehi A, Rorsman P, Eliasson L (2002) Fast insulin secretion reflects exocytosis of docked granules in mouse pancreatic B-cells. Pflugers Arch 444:43–51PubMedCrossRefGoogle Scholar
  3. 3.
    Huang L, Shen H, Atkinson MA, Kennedy RT (1995) Detection of exocytosis at individual pancreatic beta cells by amperometry at a chemically modified microelectrode. Proc Natl Acad Sci USA 92:9608–9612PubMedCrossRefGoogle Scholar
  4. 4.
    Henquin JC, Meissner HP (1984) Significance of ionic fluxes and changes in membrane potential for stimulus-secretion coupling in pancreatic B-cells. Experientia 40:1043–1052PubMedCrossRefGoogle Scholar
  5. 5.
    Ashcroft FM, Rorsman P (1989) Electrophysiology of the pancreatic beta cell. Prog Biophys Mol Biol 54:87–143PubMedCrossRefGoogle Scholar
  6. 6.
    Valdeolmillos M, Santos RM, Contreras D, Soria B, Rosario LM (1989) Glucoseinduced oscillations of intracellular Ca2+ concentration resembling bursting electrical activity in single mouse islets of Langerhans. FEBS Lett 259:19–23PubMedCrossRefGoogle Scholar
  7. 7.
    Gilon P, Shepherd RM, Henquin JC (1993) Oscillations of secretion driven by oscillations of cytoplasmic Ca2+ as evidences in single pancreatic islets. J Biol Chem 268:22265–22268PubMedGoogle Scholar
  8. 8.
    Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49:1751–1760PubMedCrossRefGoogle Scholar
  9. 9.
    Kanno T, Rorsman P, Gopel SO (2002) Glucose-dependent regulation of rhythmic action potential firing in pancreatic beta-cells by K(ATP) channel modulation. J Physiol 545:501–507PubMedCrossRefGoogle Scholar
  10. 10.
    Gopel SO, Kanno T, Barg S, Eliasson L, Galvanovskis J, Renstrom E, Rorsman P (1999) Activation of Ca(2+)-dependent K(+) channels contributes to rhythmic firing of action potentials in mouse pancreatic beta cells. J Gen Physiol 114:759–770PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang M, Houamed K, Kupershmidt S, Roden D, Satin LS (2005) Pharmacological properties and functional role of Kslow current in mouse pancreatic beta-cells: SK channels contribute to Kslow tail current and modulate insulin secretion. J Gen Physiol 126:353–363PubMedCrossRefGoogle Scholar
  12. 12.
    Ammala C, Eliasson L, Bokvist K, Larsson O, Ashcroft FM, Rorsman P (1993) Exocytosis elicited by action potentials and voltage-clamp calcium currents in individual mouse pancreatic B-cells. J Physiol 472:665–688PubMedGoogle Scholar
  13. 13.
    Wollheim CB, Sharp GW (1981) Regulation of insulin release by calcium. Physiol Rev 61:914–973PubMedGoogle Scholar
  14. 14.
    Schulla V, Renstrom E, Feil R, Feil S, Franklin I, Gjinovci A, Jing XJ, Laux D, Lundquist I, Magnuson MA, Obermuller S, Olofsson CS, Salehi A, Wendt A, Klugbauer N, Wollheim CB, Rorsman P, Hofmann F (2003) Impaired insulin secretion and glucose tolerance in beta cell-selective Ca(v)1.2 Ca2+ channel null mice. EMBO J 22:3844–3854PubMedCrossRefGoogle Scholar
  15. 15.
    Vignali S, Leiss V, Karl R, Hofmann F, Welling A (2006) Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A-and B-cells. J Physiol 572:691–706PubMedGoogle Scholar
  16. 16.
    Jing X, Li DQ, Olofsson CS, Salehi A, Surve VV, Caballero J, Ivarsson R, Lundquist I, Pereverzev A, Schneider T, Rorsman P, Renstrom E (2005) CaV2.3 calcium channels control second-phase insulin release. J Clin Invest 115:146–154PubMedGoogle Scholar
  17. 17.
    Hiriart M, Matteson DR (1988) Na channels and two types of Ca channels in rat pancreatic B cells identified with the reverse hemolytic plaque assay. J Gen Physiol 91:617–639PubMedCrossRefGoogle Scholar
  18. 18.
    Pressel DM, Misler S (1990) Sodium channels contribute to action potential generation in canine and human pancreatic islet B cells. J Membr Biol 116:273–280PubMedCrossRefGoogle Scholar
  19. 19.
    MacDonald PE, Wheeler MB (2003) Voltage-dependent K(+) channels in pancreatic beta cells: role, regulation and potential as therapeutic targets. Diabetologia 46: 1046–1062PubMedCrossRefGoogle Scholar
  20. 20.
    Wiser O, Trus M, Hernandez A, Renstrom E, Barg S, Rorsman P, Atlas D (1999) The voltage sensitive Lc-type Ca2+ channel is functionally coupled to the exocytotic machinery. Proc Natl Acad Sci USA 96:248–253PubMedCrossRefGoogle Scholar
  21. 21.
    MacDonald PE, Wang G, Tsuk S, Dodo C, Kang Y, Tang L, Wheeler MB, Cattral MS, Lakey JR, Salapatek AM, Lotan I, Gaisano HY (2002) Synaptosome-associated protein of 25 kilodaltons modulates Kv2.1 voltage-dependent K(+) channels in neuroendocrine islet beta-cells through an interaction with the channel N terminus. Mol Endocrinol 16:2452–2461PubMedCrossRefGoogle Scholar
  22. 22.
    Rorsman P, Bokvist K, Ammala C, Arkhammar P, Berggren PO, Larsson O, Wahlander K (1991) Activation by adrenaline of a low-conductance G proteindependent K+ channel in mouse pancreatic B cells. Nature 349:77–79PubMedCrossRefGoogle Scholar
  23. 23.
    Debuyser A, Drews G, Henquin JC (1991) Adrenaline inhibition of insulin release: role of the repolarization of the B cell membrane. Pflugers Arch 419:131–137PubMedCrossRefGoogle Scholar
  24. 24.
    Drews G, Debuyser A, Nenquin M, Henquin JC (1990) Galanin and epinephrine act on distinct receptors to inhibit insulin release by the same mechanisms including an increase in K+ permeability of the B-cell membrane. Endocrinology 126:1646–1653PubMedGoogle Scholar
  25. 25.
    Cook DL, Perara E (1982) Islet electrical pacemaker response to alpha-adrenergic stimulation. Diabetes 31:985–990PubMedCrossRefGoogle Scholar
  26. 26.
    Renstrom E, Ding WG, Bokvist K, Rorsman P (1996) Neurotransmitter-induced inhibition of exocytosis in insulin-secreting beta cells by activation of calcineurin. Neuron 17:513–522PubMedCrossRefGoogle Scholar
  27. 27.
    Rolland JF, Henquin JC, Gilon P (2002) G protein-independent activation of an inward Na(+) current by muscarinic receptors in mouse pancreatic beta-cells. J Biol Chem 277:38373–38380PubMedCrossRefGoogle Scholar
  28. 28.
    Salehi A, Fan BG, Ekelund M, Nordin G, Lundquist I (2001) TPN-evoked dysfunction of islet lysosomal activity mediates impairment of glucose-stimulated insulin release. Am J Physiol Endocrinol Metab 281:E171–E179PubMedGoogle Scholar
  29. 29.
    Kashyap S, Belfort R, Gastaldelli A, Pratipanawatr T, Berria R, Pratipanawatr W, Bajaj M, Mandarino L, DeFronzo R, Cusi K (2003) A sustained increase in plasma free fatty acids impairs insulin secretion in nondiabetic subjects genetically predisposed to develop type 2 diabetes. Diabetes 52:2461–2474PubMedCrossRefGoogle Scholar
  30. 30.
    Gerst JE (2003) SNARE regulators: matchmakers and matchbreakers. Biochim Biophys Acta 1641:99–110PubMedCrossRefGoogle Scholar
  31. 31.
    Hatsuzawa K, Lang T, Fasshauer D, Bruns D, Jahn R (2003) The R-SNARE motif of tomosyn forms SNARE core complexes with syntaxin 1 and SNAP-25 and downregulates exocytosis. J Biol Chem 278:31159–31166PubMedCrossRefGoogle Scholar
  32. 32.
    Cheviet S, Bezzi P, Ivarsson R, Renstrom E, Viertl D, Kasas S, Catsicas S, Regazzi R (2006) Tomosyn-1 is involved in a post-docking event required for pancreatic betacell exocytosis. J Cell Sci 119:2912–2920PubMedCrossRefGoogle Scholar
  33. 33.
    Yizhar O, Matti U, Melamed R, Hagalili Y, Bruns D, Rettig J, Ashery U (2004) Tomosyn inhibits priming of large dense-core vesicles in a calcium-dependent manner. Proc Natl Acad Sci USA 101:2578–2583PubMedCrossRefGoogle Scholar
  34. 34.
    Tsuboi T, da Silva Xavier G, Leclerc I, Rutter GA (2003) 5′-AMP-activated protein kinase controls insulin-containing secretory vesicle dynamics. J Biol Chem 278: 52042–52051PubMedCrossRefGoogle Scholar
  35. 35.
    Atwater I, Goncalves A, Herchuelz A, Lebrun P, Malaisse WJ, Rojas E, Scott A (1984) Cooling dissociates glucose-induced insulin release from electrical activity and cation fluxes in rodent pancreatic islets. J Physiol 348:615–627PubMedGoogle Scholar
  36. 36.
    Sudhof TC (2001) Synaptotagmins why so many?. J Biol Chem 277:7629–7632PubMedCrossRefGoogle Scholar
  37. 37.
    Iezzi M, Wollheim CB (2005) Adenovirus-mediated silencing of synaptotagmin 9 inhibits Ca2+-dependent insulin secretion in islets. FEBS Lett 579: 5241–5246PubMedCrossRefGoogle Scholar
  38. 38.
    Fujimoto K, Shibasaki T, Yokoi N, Kashima Y, Matsumoto M, Sasaki T, Tajima N, Iwanaga T, Seino S (2002) Piccolo, a Ca2+ sensor in pancreatic beta-cells. Involvement of cAMP-GEFII.Rim2.Piccolo complex in cAMP-dependent exocytosis. J Biol Chem 277:50497–50502PubMedCrossRefGoogle Scholar
  39. 39.
    Eliasson L, Ma X, Renstrom E, Barg S, Berggren PO, Galvanovskis J, Gromada J, Jing X, Lundquist I, Salehi A, Sewing S, Rorsman P (2003) SUR1 regulates PKA-independent cAMP-induced granule priming in mouse pancreatic B-cells. J Gen Physiol 121:181–197PubMedCrossRefGoogle Scholar
  40. 40.
    Bratanova-Tochkova TK, Cheng H, Daniel S, Gunawardana S, Liu YJ, Mulvaney-Musa J, Schermerhorn T, Straub SG, Yajima H, Sharp GW (2002) Triggering and augmentation mechanisms, granule pools, and biphasic insulin secretion. Diabetes 51: S83–S90PubMedCrossRefGoogle Scholar
  41. 41.
    Straub SG, Sharp GW (2004) Hypothesis: one rate-limiting step controls the magnitude of both phases of glucose-stimulated insulin secretion. Am J Physiol Cell Physiol 287: C565–C571PubMedCrossRefGoogle Scholar
  42. 42.
    Gopel S, Zhang Q, Eliasson L, Ma XS, Galvanovskis J, Kanno T, Salehi A, Rorsman P (2004) Capacitance measurements of exocytosis in mouse pancreatic alpha-, beta-and delta-cells within intact islets of Langerhans. J Physiol 556:711–726PubMedCrossRefGoogle Scholar
  43. 43.
    Kwan EP, Xie L, Sheu L, Nolan CJ, Prentki M, Betz A, Brose N, Gaisano HY (2006) Munc13-1 deficiency reduces insulin secretion and causes abnormal glucose tolerance. Diabetes 55:1421–1429PubMedCrossRefGoogle Scholar
  44. 44.
    Kang L, He Z, Xu P, Fan J, Betz A, Brise N, Xu T (2006) Munc13-1 is required for the sustained release of insulin from pancreatic beta cells. Cell Metab 3:463–468PubMedCrossRefGoogle Scholar
  45. 45.
    van Obberghen E, Somers G, Devis G, Vaughan GD, Malaisse-Lagae F, Orci L, Malaisse WJ (1973) Dynamics of insulin release and microtubular-microfilamentous system. I. Effect of cytochalasin B. J Clin Invest 52:1041–1051PubMedCrossRefGoogle Scholar
  46. 46.
    Orci L, Gabbay KH, Malaisse WJ (1972) Pancreatic beta-cell web: its possible role in insulin secretion. Science 175:1128–1130PubMedCrossRefGoogle Scholar
  47. 47.
    Kanazawa Y, Kawazu S, Ikeuchi M, Kosaka K (1980) The relationship of intracytoplasmic movement of beta granules to insulin release in monolayer-cultured pancreatic beta-cells. Diabetes 29:953–959PubMedCrossRefGoogle Scholar
  48. 48.
    Ivarsson R, Obermuller S, Rutter GA, Galvanovskis J, Renstrom E (2004) Temperature-sensitive random insulin granule diffusion is a prerequisite for recruiting granules for release. Traffic 5:750–762PubMedCrossRefGoogle Scholar
  49. 49.
    Vitale ML, Seward EP, Trifaro JM (1995) Chromaffin cell cortical actin network dynamics control the size of the release-ready vesicle pool and the initial rate of exocytosis. Neuron 14:353–363PubMedCrossRefGoogle Scholar
  50. 50.
    Trifaro JM, Lejen T, Rose SD, Pene TD, Barkar ND, Seward EP (2002) Pathways that control cortical F-actin dynamics during secretion. Neurochem Res 27: 1371–1385PubMedCrossRefGoogle Scholar
  51. 51.
    Varadi A, Ainscow EK, Allan VJ, Rutter GA (2002) Involvement of conventional kinesin in glucose-stimulated secretory granule movements and exocytosis in clonal pancreatic beta cells. J Cell Sci 115:4177–4189PubMedCrossRefGoogle Scholar
  52. 52.
    Varadi A, Tsuboi T, Johnson-Cadwell LI, Allan VJ, Rutter GA (2003) Kinesin I and cytoplasmic dynein orchestrate glucose-stimulated insulin-containing vesicle movements in clonal MIN6 beta cells. Biochem Biophys Res Commun 311:272–282PubMedCrossRefGoogle Scholar
  53. 53.
    Varadi A, Tsuboi T, Rutter GA (2005) Myosin Va transports dense core secretory vesicles in pancreatic MIN6 beta-cells. Mol Biol Cell 16:2670–2680PubMedCrossRefGoogle Scholar
  54. 54.
    Ivarsson R, Jing X, Waselle L, Regazzi R, Renstrom E (2005) Myosin 5a controls insulin granule recruitment during late-phase secretion. Traffic 6:1027–1035PubMedCrossRefGoogle Scholar
  55. 55.
    Pouli AE, Emmanouilidou E, Zhao C, Wasmeier C, Hutton JC, Rutter GA (1998) Secretory-granule dynamics visualized in vivo with a phogrin-green fluorescent protein chimaera. Biochem J 333 (Pt 1):193–199PubMedGoogle Scholar
  56. 56.
    Niki I, Niwa T, Yu W, Budzko D, Miki T, Senda T (2003) Ca2+ influx does not trigger glucose-induced traffic of the insulin granules and alteration of their distribution. Exp Biol Med (Maywood) 228:1218–1226Google Scholar
  57. 57.
    Niki I, Hisatomi M (1997) Analysis of the secretory granule movement in the pancreatic beta cell: regulation by intracellular messengers. Jpn J Physiol 47Suppl 1: S25–S26PubMedGoogle Scholar
  58. 58.
    Escolar JC, Hoo-Paris R, Castex C, Sutter BC (1987) Effect of low temperatures on glucose-induced insulin secretion and ionic fluxes in rat pancreatic islets. J Endocrinol 115:225–231PubMedGoogle Scholar
  59. 59.
    Catterall WA (1998) Structure and function of neuronal Ca2+ channels and their role in neurotransmitter release. Cell Calcium 24:307–323PubMedCrossRefGoogle Scholar
  60. 60.
    Dolphin AC (1999) L-type calcium channel modulation. Adv Second Messenger Phosphoprotein Res 33:153–177PubMedGoogle Scholar
  61. 61.
    Catterall WA (2000) Structure and regulation of voltage-gated Ca2+ channels. Annu Rev Cell Dev Biol 16:521–555PubMedCrossRefGoogle Scholar
  62. 62.
    Reid CA, Bekkers JM, Clements JD (2003) Presynaptic Ca2+ channels: a functional patchwork. Trends Neurosci 26:683–687PubMedCrossRefGoogle Scholar
  63. 63.
    Perez-Reyes E (2003) Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev 83:117–161PubMedGoogle Scholar
  64. 64.
    Heady TN, Gomora JC, Macdonald TL, Perez-Reyes E (2001) Molecular pharmacology of T-type Ca2+ channels. Jpn J Pharmacol 85:339–350PubMedCrossRefGoogle Scholar
  65. 65.
    Triggle DJ (1998) The physiological and pharmacological significance of cardiovascular T-type, voltage-gated calcium channels. Am J Hypertens 11:80S–87SPubMedCrossRefGoogle Scholar
  66. 66.
    Vajna R, Klockner U, Pereverzev A, Weiergraber M, Chen X, Miljanich G, Klugbauer N, Hescheler J, Perez-Reyes E, Schneider T (2001) Functional coupling between “R-type” Ca2+ channels and insulin secretion in the insulinoma cell line INS-1. Eur J Biochem 268:1066–1075PubMedCrossRefGoogle Scholar
  67. 67.
    Rorsman P, Trube G (1986) Calcium and delayed potassium currents in mouse pancreatic beta cells under voltage-clamp conditions. J Physiol 374:531–550PubMedGoogle Scholar
  68. 68.
    Namkung Y, Skrypnyk N, Jeong MJ, Lee T, Lee MS, Kim HL, Chin H, Suh PG, Kim SS, Shin HS (2001) Requirement for the L-type Ca(2+) channel alpha(1D) subunit in postnatal pancreatic beta cell generation. J Clin Invest 108:1015–1022PubMedGoogle Scholar
  69. 69.
    Barg S, Ma X, Eliasson L, Galvanovskis J, Gopel SO, Obermuller S, Platzer J, Renstrom E, Trus M, Atlas D, Striessnig J, Rorsman P (2001) Fast exocytosis with few Ca(2+) channels in insulin-secreting mouse pancreatic B cells. Biophys J 81:3308–3323PubMedCrossRefGoogle Scholar
  70. 70.
    Lee JY, Ristow M, Lin X, White MF, Magnuson MA, Hennighausen L (2006) RIP-Cre revisited, evidence for impairments of pancreatic beta-cell function. J Biol Chem 281:2649–2653PubMedCrossRefGoogle Scholar
  71. 71.
    Vignali S, Leiss V, Karl R, Hofmann F, Weling A. Characterization of voltage-dependent sodium and calcium channels in mouse pancreatic A-and B-cells. J Physiol. 2006 May 1; 572 (Pt 3):691–706PubMedGoogle Scholar
  72. 72.
    Jing X, Li DQ, Olofsson CS, Salehi A, Surve VV, Caballero J, Ivarsson R, Lundquist I, Pereverzev A, Schneider T, Rorsman P, Renstrom E. CaV2.3 calcium channels control second-phase inculin release. J Clin Invest. 2005 Jan;115(1):146–154PubMedGoogle Scholar
  73. 73.
    Gromada J, Hoy M, Renstrom E, Bokvist K, Eliasson L, Gopel S, Rorsman P (1999) CaM kinase II-dependent mobilization of secretory granules underlies acetylcholine-induced stimulation of exocytosis in mouse pancreatic B-cells. J Physiol 518 (Pt 3):745–759PubMedCrossRefGoogle Scholar
  74. 74.
    Eliasson L, Renstrom E, Ding WG, Proks P, Rorsman P (1997) Rapid ATP-dependent priming of secretory granules precedes Ca(2+)-induced exocytosis in mouse pancreatic B-cells. J Physiol 503 (Pt 2):399–412PubMedCrossRefGoogle Scholar
  75. 75.
    Barg S, Eliasson L, Renstrom E, Rorsman P (2002) A subset of 50 secretory granules in close contact with L-type Ca2+ channels accounts for first-phase insulin secretion in mouse beta-cells. Diabetes 51Suppl 1:S74–S82PubMedCrossRefGoogle Scholar
  76. 76.
    Ivarsson R, Quintens R, Dejonghe S, Tsukamoto K, in’t Veld P, Renstrom E, Schuit FC (2005) Redox control of exocytosis: regulatory role of NADPH, thioredoxin, and glutaredoxin. Diabetes 54:2132–2142PubMedCrossRefGoogle Scholar
  77. 77.
    Maechler P, Wollheim CB (1999) Mitochondrial glutamate acts as a messenger in glucose-induced insulin exocytosis. Nature 402:685–689PubMedCrossRefGoogle Scholar
  78. 78.
    MacDonald MJ, Fahien LA (2000) Glutamate is not a messenger in insulin secretion. J Biol Chem 275:34025–34027PubMedCrossRefGoogle Scholar
  79. 79.
    Henquin JC, Schmeer W, Meissner HP (1983) Forskolin, an activator of adenylate cyclase, increases CA2+-dependent electrical activity induced by glucose in mouse pancreatic B cells. Endocrinology 112:2218–2220PubMedCrossRefGoogle Scholar
  80. 80.
    Gromada J, Ding WG, Barg S, Renstrom E, Rorsman P (1997) Multisite regulation of insulin secretion by cAMP-increasing agonists: evidence that glucagon-like peptide 1 and glucagon act via distinct receptors. Pflugers Arch 434:515–524PubMedCrossRefGoogle Scholar
  81. 81.
    Gilon P, Nenquin M, Henquin JC (1995) Muscarinic stimulation exerts both stimulatory and inhibitory effects on the concentration of cytoplasmic Ca2+ in the electrically excitable pancreatic B-cell. Biochem J 311 (Pt 1):259–267PubMedGoogle Scholar
  82. 82.
    Garcia MC, Hermans MP, Henquin JC (1988) Glucose-, calcium-and concentration-dependence of acetylcholine stimulation of insulin release and ionic fluxes in mouse islets. Biochem J 254:211–218PubMedGoogle Scholar
  83. 83.
    Ammala C, Eliasson L, Bokvist K, Berggren PO, Honkanen RE, Sjoholm A, Rorsman P (1994) Activation of protein kinases and inhibition of protein phosphatases play a central role in the regulation of exocytosis in mouse pancreatic beta cells. Proc Natl Acad Sci USA 91:4343–4347PubMedCrossRefGoogle Scholar
  84. 84.
    Nilsson T, Arkhammar P, Rorsman P, Berggren PO (1989) Suppression of insulin release by galanin and somatostatin is mediated by a G-protein. An effect involving repolarization and reduction in cytoplasmic free Ca2+ concentration. J Biol Chem 264:973–980PubMedGoogle Scholar
  85. 85.
    Gromada J, Hoy M, Buschard K, Salehi A, Rorsman P (2001) Somatostatin inhibits exocytosis in rat pancreatic alpha-cells by G(i2)-dependent activation of calcineurin and depriming of secretory granules. J Physiol 535:519–532PubMedCrossRefGoogle Scholar
  86. 86.
    Nagy G, Reim K, Matti U, Brose N, Binz T, Rettig J, Neher E, Sorensen JB (2004) Regulation of releasable vesicle pool sizes by protein kinase A-dependent phosphorylation of SNAP-25. Neuron 41:417–429PubMedCrossRefGoogle Scholar
  87. 87.
    Kasai H (1999) Comparative biology of Ca2+-dependent exocytosis: implications of kinetic diversity for secretory function. Trends Neurosci 22:88–93PubMedCrossRefGoogle Scholar
  88. 88.
    Reetz A, Solimena M, Matteoli M, Folli F, Takei K, De Camilli P (1991) GABA and pancreatic beta-cells: colocalization of glutamic acid decarboxylase (GAD) and GABA with synaptic-like microvesicles suggests their role in GABA storage and secretion. EMBO J 10:1275–1284PubMedGoogle Scholar
  89. 89.
    Wendt A, Birnir B, Buschard K, Gromada J, Salehi A, Sewing S, Rorsman P, Braun M (2004) Glucose inhibition of glucagon secretion from rat alpha-cells is mediated by GABA released from neighboring beta-cells. Diabetes 53:1038–1045PubMedCrossRefGoogle Scholar
  90. 90.
    Braun M, Wendt A, Buschard K, Salehi A, Sewing S, Gromada J, Rorsman P (2004) GABAB receptor activation inhibits exocytosis in rat pancreatic beta-cells by G-protein-dependent activation of calcineurin. J Physiol 559:397–409PubMedCrossRefGoogle Scholar
  91. 91.
    Salehi A, Qader SS, Grapengiesser E, Hellman B (2005) Inhibition of purinoceptors amplifies glucose-stimulated insulin release with removal of its pulsatility. Diabetes 54:2126–2131PubMedCrossRefGoogle Scholar
  92. 92.
    Braun M, Wendt A, Birnir B, Broman J, Eliasson L, Galvanovskis J, Gromada J, Mulder H, Rorsman P (2004) Regulated exocytosis of GABA-containing synaptic-like microvesicles in pancreatic beta-cells. J Gen Physiol 123:191–204PubMedCrossRefGoogle Scholar
  93. 93.
    Gammelsaeter R, Froyland M, Aragon C, Danbolt NC, Fortin D, Storm-Mathisen J, Davanger S, Gundersen V (2004) Glycine, GABA and their transporters in pancreatic islets of Langerhans: evidence for a paracrine transmitter interplay. J Cell Sci 117: 3749–3758PubMedCrossRefGoogle Scholar
  94. 94.
    MacDonald PE, Obermuller S, Vikman J, Galvanovskis J, Rorsman P, Eliasson L (2005) Regulated exocytosis and kiss-and-run of synaptic-like microvesicles in INS-1 and primary rat beta-cells. Diabetes 54:736–743PubMedCrossRefGoogle Scholar
  95. 95.
    Braun M, Wendt A, Birnir B, Broman J, Eliasson L, Galvanovskis J, Gromada J, Mulder H, Rorsman P (2004) Regulated exocytosis of GABA-containing synaptic-like microvesicles in pancreatic {beta}-cells. J Gen Physiol 123:191–204PubMedCrossRefGoogle Scholar
  96. 96.
    Fernandez-Peruchena C, Navas S, Montes MA, Alvarez de Toledo G (2005) Fusion pore regulation of transmitter release. Brain Res Brain Res Rev 49:406–415PubMedCrossRefGoogle Scholar
  97. 97.
    Lollike K, Lindau M (1999) Membrane capacitance techniques to monitor granule exocytosis in neutrophils. J Immunol Methods 232:111–120PubMedCrossRefGoogle Scholar
  98. 98.
    MacDonald PE, Braun M, Galvanovskis J, Rorsman P (2006) Release of small transmitters through kiss-and-run fusion pores in rat pancreatic beta cells. Cell Metab 4:28–290CrossRefGoogle Scholar
  99. 99.
    Tsuboi T, McMahon HT, Rutter GA (2004) Mechanisms of dense core vesicle recapture following “kiss and run” (“cavicapture”) exocytosis in insulin-secreting cells. J Biol Chem 279:47115–47124PubMedCrossRefGoogle Scholar
  100. 100.
    Barg S, Olofsson CS, Schriever-Abeln J, Wendt A, Gebre-Medhin S, Renstrom E, Rorsman P (2002) Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells. Neuron 33:287–299PubMedCrossRefGoogle Scholar
  101. 101.
    Obermuller S, Lindqvist A, Karanauskaite J, Galvanovskis J, Rorsman P, Barg S (2005) Selective nucleotide-release from dense-core granules in insulin-secreting cells. J Cell Sci 118:4271–4282PubMedCrossRefGoogle Scholar
  102. 102.
    Holroyd P, Lang T, Wenzel D, De Camilli P, Jahn R (2002) Imaging direct, dynamindependent recapture of fusing secretory granules on plasma membrane lawns from PC12 cells. Proc Natl Acad Sci USA 99:16806–16811PubMedCrossRefGoogle Scholar
  103. 103.
    Taraska JW, Perrais D, Ohara-Imaizumi M, Nagamatsu S, Almers W (2003) Secretory granules are recaptured largely intact after stimulated exocytosis in cultured endocrine cells. Proc Natl Acad Sci USA 100:2070–2075PubMedCrossRefGoogle Scholar
  104. 104.
    Rutter GA, Tsuboi T (2004) Kiss and run exocytosis of dense core secretory vesicles. Neuroreport 15:79–81PubMedCrossRefGoogle Scholar
  105. 105.
    Perrais D, Kleppe IC, Taraska JW, Almers W (2004) Recapture after exocytosis causes differential retention of protein in granules of bovine chromaffin cells. J Physiol 560:413–428PubMedCrossRefGoogle Scholar
  106. 106.
    Tsuboi T, Ravier MA, Parton LE, Rutter GA (2006) Sustained exposure to high glucose concentrations modifies glucose signaling and the mechanics of secretory vesicle fusion in primary rat pancreatic beta-cells. Diabetes 55:1057–1065PubMedCrossRefGoogle Scholar
  107. 107.
    Takahashi N, Kishimoto T, Nemoto T, Kadowaki T, Kasai H (2002) Fusion pore dynamics and insulin granule exocytosis in the pancreatic islet. Science 297: 1349–1352PubMedCrossRefGoogle Scholar
  108. 108.
    Bankston LA, Guidotti G (1996) Characterization of ATP transport into chromaffin granule ghosts. Synergy of ATP and serotonin accumulation in chromaffin granule ghosts. J Biol Chem 271:17132–17138PubMedCrossRefGoogle Scholar
  109. 109.
    Stumvoll M, Gerich J (2001) Clinical features of insulin resistance and beta cell dysfunction and the relationship to type 2 diabetes. Clin Lab Med 21:31–51PubMedGoogle Scholar
  110. 110.
    Hosker JP, Rudenski AS, Burnett MA, Matthews DR, Turner RC (1989) Similar reduction of first-and second-phase B-cell responses at three different glucose levels in type II diabetes and the effect of gliclazide therapy. Metabolism 38: 767–772PubMedCrossRefGoogle Scholar
  111. 111.
    Rorsman P, Renstrom E (2003) Insulin granule dynamics in pancreatic beta cells. Diabetologia 46:1029–1045PubMedCrossRefGoogle Scholar
  112. 112.
    Nagamatsu S, Nakamichi Y, Yamamura C, Matsushima S, Watanabe T, Ozawa S, Furukawa H, Ishida H (1999) Decreased expression of t-SNARE, syntaxin 1, and SNAP-25 in pancreatic beta-cells is involved in impaired insulin secretion from diabetic GK rat islets: restoration of decreased t-SNARE proteins improves impaired insulin secretion. Diabetes 48:2367–2373PubMedCrossRefGoogle Scholar
  113. 113.
    Zhang W, Khan A, Ostenson CG, Berggren PO, Efendic S, Meister B (2002) Downregulated expression of exocytotic proteins in pancreatic islets of diabetic GK rats. Biochem Biophys Res Commun 291:1038–1044PubMedCrossRefGoogle Scholar
  114. 114.
    Ohara-Imaizumi M, Nishiwaki C, Nakamichi Y, Kikuta T, Nagai S, Nagamatsu S (2004) Correlation of syntaxin-1 and SNAP-25 clusters with docking and fusion of insulin granules analysed by total internal reflection fluorescence microscopy. Diabetologia 47:2200–2207PubMedCrossRefGoogle Scholar
  115. 115.
    Ohara-Imaizumi M, Nishiwaki C, Kikuta T, Nagai S, Nakamichi Y, Nagamatsu S (2004) TIRF imaging of docking and fusion of single insulin granule motion in primary rat pancreatic beta-cells: different behaviour of granule motion between normal and Goto-Kakizaki diabetic rat beta-cells. Biochem J 381:13–18PubMedCrossRefGoogle Scholar
  116. 116.
    Gauthier BR, Wollheim CB (2006) MicroRNAs: “ribo-regulators” of glucose homeostasis. Nat Med 12:36–38PubMedCrossRefGoogle Scholar
  117. 117.
    Poy MN, Eliasson L, Krutzfeldt J, Kuwajima S, Ma X, Macdonald PE, Pfeffer S, Tuschl T, Rajewsky N, Rorsman P, Stoffel M (2004) A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432:226–230PubMedCrossRefGoogle Scholar
  118. 118.
    Yaney GC, Corkey BE (2003) Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia 46:1297–1312PubMedCrossRefGoogle Scholar
  119. 119.
    Briaud I, Harmon JS, Kelpe CL, Segu VB, Poitout V (2001) Lipotoxicity of the pancreatic beta-cell is associated with glucose-dependent esterification of fatty acids into neutral lipids. Diabetes 50:315–321PubMedCrossRefGoogle Scholar
  120. 120.
    Joseph JW, Koshkin V, Zhang CY, Wang J, Lowell BB, Chan CB, Wheeler MB (2002) Uncoupling protein 2 knockout mice have enhanced insulin secretory capacity after a high-fat diet. Diabetes 51:3211–3219PubMedCrossRefGoogle Scholar
  121. 121.
    Lameloise N, Muzzin P, Prentki M, Assimacopoulos-Jeannet F (2001) Uncoupling protein 2: a possible link between fatty acid excess and impaired glucose-induced insulin secretion? Diabetes 50:803–809PubMedCrossRefGoogle Scholar
  122. 122.
    Olofesson CS, Collins S, Bengtsson M, Eliasson L, Salehi A, Shimomura K, Tarasov A, Holm C, Ashcroft F, Rorsman P. Long-term exposure to glucose and lipids inhibits glucose-induced insulin secretion downstream of granule fusion with plasma membrane. Diabetes. 2007 Jul;56(7):1888–1897CrossRefGoogle Scholar
  123. 123.
    Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K (2006) Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes. Nat Genet 38:320–323PubMedCrossRefGoogle Scholar
  124. 124.
    Henquin JC, Ravier MA, Nenquin M, Jonas JC, Gilon P (2003) Hierarchy of the betacell signals controlling insulin secretion. Eur J Clin Invest 33:742–750PubMedCrossRefGoogle Scholar
  125. 125.
    Jeans AF, Oliver PL, Johnson R, Capogna M, Vikman J, Molnár Z, Babbs A, Partridge CJ, Salehi A, Bengtsson M, Eliasson L, Rorman P, Davies KE (2007) A dominant mutation in Snap25 causes inpaired vesicle trafficking, sensorimotor gating, and ataxia in the blind-drunk mouse. Proc Natl Acad Sci USA. 2007 Feb 13;104(7): 2431–2436PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2008

Authors and Affiliations

  • Erik Renström
    • 1
  • Patrik Rorsman
    • 2
  1. 1.Department of Clinical SciencesLund University Diabetes CentreMalmöSweden
  2. 2.Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK

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