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Intercellular Communication in the Islet of Langerhans in Health and Disease

Xue W. Ng, Yong H. Chung, David W. Piston

10.1002/cphy.c200026

Source: Volume 11, Issue 3, July 2021

Published online: June 2021

Full Article on Wiley Online Library



Abstract

Blood glucose homeostasis requires proper function of pancreatic islets, which secrete insulin, glucagon, and somatostatin from the β‐, α‐, and δ‐cells, respectively. Each islet cell type is equipped with intrinsic mechanisms for glucose sensing and secretory actions, but these intrinsic mechanisms alone cannot explain the observed secretory profiles from intact islets. Regulation of secretion involves interconnected mechanisms among and between islet cell types. Islet cells lose their normal functional signatures and secretory behaviors upon dispersal as compared to intact islets and in vivo. In dispersed islet cells, the glucose response of insulin secretion is attenuated from that seen from whole islets, coordinated oscillations in membrane potential and intracellular Ca2+ activity, as well as the two‐phase insulin secretion profile, are missing, and glucagon secretion displays higher basal secretion profile and a reverse glucose‐dependent response from that of intact islets. These observations highlight the critical roles of intercellular communication within the pancreatic islet, and how these communication pathways are crucial for proper hormonal and nonhormonal secretion and glucose homeostasis. Further, misregulated secretions of islet secretory products that arise from defective intercellular islet communication are implicated in diabetes. Intercellular communication within the islet environment comprises multiple mechanisms, including electrical synapses from gap junctional coupling, paracrine interactions among neighboring cells, and direct cell‐to‐cell contacts in the form of juxtacrine signaling. In this article, we describe the various mechanisms that contribute to proper islet function for each islet cell type and how intercellular islet communications are coordinated among the same and different islet cell types. © 2021 American Physiological Society. Compr Physiol 11:2191‐2225, 2021.

Figure 1. Figure 1. Comparison of insulin and glucagon secretory responses to glucose in intact islets and isolated cells. Green, red, and blue cells represent β‐, α‐, and δ‐cells, respectively.
Figure 2. Figure 2. Overview of the intercellular communication pathways within the islet. β‐Cells and δ‐cells sense glucose directly through glucose transporters and are coupled via gap junctions. α‐Cells undergo a series of paracrine regulation by insulin receptors (IR), 5‐HT1F receptors, and SSTR2 which are activated by β‐ and δ‐cell secretory products. α‐Cells are also regulated by EphA‐ephrinA juxtacrine signaling through direct cell‐to‐cell contacts with β‐cells. Secretion of insulin, glucagon, and somatostatin by β‐, α‐, and δ‐cells, respectively, is coupled to intracellular Ca2+, ATP/ADP, and cAMP concentrations.
Figure 3. Figure 3. Image of an intact human islet immunostained with insulin (green), glucagon (red), and somatostatin (yellow) for the identification of β‐, α‐, and δ‐cells, respectively.
Figure 4. Figure 4. Formation of functional homotypic Cx36 gap junctions between β‐cells and nonfunctional heterotypic Cx36‐Cx46 gap junctions between β‐ and α‐cells on the plasma membrane.
Figure 5. Figure 5. Overview of paracrine interactions between islet cells.
Figure 6. Figure 6. Intracellular and intercellular pathway mechanisms that regulate insulin secretion in the β‐cell.
Figure 7. Figure 7. Dependence of intracellular Ca2+ dynamics on gap junction coupling in heterozygous Cx36 knockout Cx36+/− (approximately 50% gap junction conductance; A and B) and homozygous Cx36 knockout Cx36−/− (approximately 0% gap junction conductance; C and D) intact mouse islets. A phase map of synchronized (colored cells) and unsynchronized or lack (gray cells) of Ca2+ oscillations and representative Ca2+ intensity traces in four cells of an islet are shown for each islet type. Gradual loss of synchronicity in intracellular Ca2+ oscillations is observed as gap junction conductance is reduced with increasing knockout of Cx36. Reused, with permission, from Benninger RK, et al., 2008 26 © 2008, Elsevier.
Figure 8. Figure 8. Intracellular and intercellular pathway mechanisms that regulate glucagon secretion in the α‐cell.
Figure 9. Figure 9. Intracellular and intercellular pathway mechanisms that regulate somatostatin secretion in the δ‐cell.


Figure 1. Comparison of insulin and glucagon secretory responses to glucose in intact islets and isolated cells. Green, red, and blue cells represent β‐, α‐, and δ‐cells, respectively.


Figure 2. Overview of the intercellular communication pathways within the islet. β‐Cells and δ‐cells sense glucose directly through glucose transporters and are coupled via gap junctions. α‐Cells undergo a series of paracrine regulation by insulin receptors (IR), 5‐HT1F receptors, and SSTR2 which are activated by β‐ and δ‐cell secretory products. α‐Cells are also regulated by EphA‐ephrinA juxtacrine signaling through direct cell‐to‐cell contacts with β‐cells. Secretion of insulin, glucagon, and somatostatin by β‐, α‐, and δ‐cells, respectively, is coupled to intracellular Ca2+, ATP/ADP, and cAMP concentrations.


Figure 3. Image of an intact human islet immunostained with insulin (green), glucagon (red), and somatostatin (yellow) for the identification of β‐, α‐, and δ‐cells, respectively.


Figure 4. Formation of functional homotypic Cx36 gap junctions between β‐cells and nonfunctional heterotypic Cx36‐Cx46 gap junctions between β‐ and α‐cells on the plasma membrane.


Figure 5. Overview of paracrine interactions between islet cells.


Figure 6. Intracellular and intercellular pathway mechanisms that regulate insulin secretion in the β‐cell.


Figure 7. Dependence of intracellular Ca2+ dynamics on gap junction coupling in heterozygous Cx36 knockout Cx36+/− (approximately 50% gap junction conductance; A and B) and homozygous Cx36 knockout Cx36−/− (approximately 0% gap junction conductance; C and D) intact mouse islets. A phase map of synchronized (colored cells) and unsynchronized or lack (gray cells) of Ca2+ oscillations and representative Ca2+ intensity traces in four cells of an islet are shown for each islet type. Gradual loss of synchronicity in intracellular Ca2+ oscillations is observed as gap junction conductance is reduced with increasing knockout of Cx36. Reused, with permission, from Benninger RK, et al., 2008 26 © 2008, Elsevier.


Figure 8. Intracellular and intercellular pathway mechanisms that regulate glucagon secretion in the α‐cell.


Figure 9. Intracellular and intercellular pathway mechanisms that regulate somatostatin secretion in the δ‐cell.
References
 1.Abdel‐Halim SM, Guenifi A, Efendić S. Both somatostatin and insulin responses to glucose are impaired in the perfused pancreas of the spontaneously noninsulin‐dependent diabetic GK (Goto‐Kakizaki) rats. Acta Physiol Scand 148: 219‐226, 1993.
 2.Adeghate E, Ponery AS, Pallot D, Parvez SH, Singh J. Distribution of serotonin and its effect on glucagon secretion from normal and diabetic pancreatic tissue fragment in rat. Neuroendocrinol Lett 20: 315‐322, 1999.
 3.Adham N, Kao HT, Schechter LE, Bard J, Olsen M, Urquhart D, Durkin M, Hartig PR, Weinshank RL, Branchek TA. Cloning of another human serotonin receptor (5‐HT(1F)): A fifth 5‐HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci USA 90: 408‐412, 1993.
 4.Adriaenssens AE, Svendsen B, Lam BYH, Yeo GSH, Holst JJ, Reimann F, Gribble FM. Transcriptomic profiling of pancreatic alpha, beta and delta cell populations identifies delta cells as a principal target for ghrelin in mouse islets. Diabetologia 59: 2156‐2165, 2016.
 5.Ahren B. Autonomic regulation of islet hormone secretion–implications for health and disease. Diabetologia 43: 393‐410, 2000.
 6.Ainscow EK, Rutter GA. Glucose‐stimulated oscillations in free cytosolic ATP concentration imaged in single islet beta‐cells: Evidence for a Ca2+‐dependent mechanism. Diabetes 51 (Suppl 1): S162‐S170, 2002.
 7.Almaca J, Molina J, Menegaz D, Pronin AN, Tamayo A, Slepak V, Berggren PO, Caicedo A. Human beta cells produce and release serotonin to inhibit glucagon secretion from alpha cells. Cell Rep 17: 3281‐3291, 2016.
 8.Almaça J, Weitz J, Rodriguez‐Diaz R, Pereira E, Caicedo A. The pericyte of the pancreatic islet regulates capillary diameter and local blood flow. Cell Metab 27: 630‐644.e4, 2018.
 9.Arrojo EDR, Jacob S, Garcia‐Prieto CF, Zheng X, Fukuda M, Nhu HTT, Stelmashenko O, Pecanha FLM, Rodriguez‐Diaz R, Bushong E, Deerinck T, Phan S, Ali Y, Leibiger I, Chua M, Boudier T, Song SH, Graf M, Augustine GJ, Ellisman MH, Berggren PO. Structural basis for delta cell paracrine regulation in pancreatic islets. Nat Commun 10: 3700, 2019.
 10.Ashcroft FM, Rorsman P. Electrophysiology of the pancreatic beta‐cell. Prog Biophys Mol Biol 54: 87‐143, 1989.
 11.Aspinwall CA, Lakey JR, Kennedy RT. Insulin‐stimulated insulin secretion in single pancreatic beta cells. J Biol Chem 274: 6360‐6365, 1999.
 12.Atwater I, Rosario L, Rojas E. Properties of the Ca‐activated K+ channel in pancreatic beta‐cells. Cell Calcium 4: 451‐461, 1983.
 13.Aughsteen AA. The ultrastructure of primary cilia in the endocrine and excretory duct cells of the pancreas of mice and rats. Eur J Morphol 39: 277‐283, 2001.
 14.Baggio LL, Drucker DJ. Biology of incretins: GLP‐1 and GIP. Gastroenterology 132: 2131‐2157, 2007.
 15.Bailey SJ, Ravier MA, Rutter GA. Glucose‐dependent regulation of gamma‐aminobutyric acid (GABA A) receptor expression in mouse pancreatic islet alpha‐cells. Diabetes 56: 320‐327, 2007.
 16.Bansal P, Wang Q. Insulin as a physiological modulator of glucagon secretion. Am J Physiol Endocrinol Metab 295: E751‐E761, 2008.
 17.Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 12: 141‐146, 1992.
 18.Barg S, Galvanovskis J, Gpel SO, Rorsman P, Eliasson L. Tight coupling between electrical activity and exocytosis in mouse glucagon‐secreting alpha‐cells. Diabetes 49: 1500‐1510, 2000.
 19.Batterham RL, Le Roux CW, Cohen MA, Park AJ, Ellis SM, Patterson M, Frost GS, Ghatei MA, Bloom SR. Pancreatic polypeptide reduces appetite and food intake in humans. J Clin Endocrinol Metab 88: 3989‐3992, 2003.
 20.Bennet H, Balhuizen A, Medina A, Nitert MD, Laakso EO, Essén S, Spégel P, Storm P, Krus U, Wierup N, Fex M. Altered serotonin (5‐HT) 1D and 2A receptor expression may contribute to defective insulin and glucagon secretion in human type 2 diabetes. Peptides 71: 113‐120, 2015.
 21.Bennet H, Mollet IG, Balhuizen A, Medina A, Nagorny C, Bagge A, Fadista J, Ottosson‐Laakso E, Vikman P, Dekker‐Nitert M, Eliasson L, Wierup N, Artner I, Fex M. Serotonin (5‐HT) receptor 2b activation augments glucose‐stimulated insulin secretion in human and mouse islets of Langerhans. Diabetologia 59: 744‐754, 2016.
 22.Bennett BD, Jetton TL, Ying G, Magnuson MA, Piston DW. Quantitative subcellular imaging of glucose metabolism within intact pancreatic islets. J Biol Chem 271: 3647‐3651, 1996.
 23.Benninger RK, Head WS, Zhang M, Satin LS, Piston DW. Gap junctions and other mechanisms of cell‐cell communication regulate basal insulin secretion in the pancreatic islet. J Physiol 589: 5453‐5466, 2011.
 24.Benninger RK, Hutchens T, Head WS, McCaughey MJ, Zhang M, Le Marchand SJ, Satin LS, Piston DW. Intrinsic islet heterogeneity and gap junction coupling determine spatiotemporal Ca(2)(+) wave dynamics. Biophys J 107: 2723‐2733, 2014.
 25.Benninger RK, Piston DW. Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics. Trends Endocrinol Metab 25: 399‐406, 2014.
 26.Benninger RK, Zhang M, Head WS, Satin LS, Piston DW. Gap junction coupling and calcium waves in the pancreatic islet. Biophys J 95: 5048‐5061, 2008.
 27.Benninger RKP, Dorrell C, Hodson DJ, Rutter GA. The impact of pancreatic beta cell heterogeneity on type 1 diabetes pathogenesis. Curr Diab Rep 18: 112, 2018.
 28.Benninger RKP, Hodson DJ. New understanding of beta‐cell heterogeneity and in situ islet function. Diabetes 67: 537‐547, 2018.
 29.Benoit R, Esch F, Bennett HP, Ling N, Ravazzola M, Orci L, Mufson EJ. Processing of prosomatostatin. Metabolism 39: 22‐25, 1990.
 30.Berbari NF, Lewis JS, Bishop GA, Askwith CC, Mykytyn K. Bardet‐Biedl syndrome proteins are required for the localization of G protein‐coupled receptors to primary cilia. Proc Natl Acad Sci USA 105: 4242‐4246, 2008.
 31.Bergsten P. Slow and fast oscillations of cytoplasmic Ca2+ in pancreatic islets correspond to pulsatile insulin release. Am J Phys 268: E282‐E287, 1995.
 32.Bergsten P. Role of oscillations in membrane potential, cytoplasmic Ca2+, and metabolism for plasma insulin oscillations. Diabetes 51 (Suppl 1): S171‐S176, 2002.
 33.Berthault C, Staels W, Scharfmann R. Purification of pancreatic endocrine subsets reveals increased iron metabolism in beta‐cells. Mol Metab 42: 101060, 2020.
 34.Bertram R, Satin L, Zhang M, Smolen P, Sherman A. Calcium and glycolysis mediate multiple bursting modes in pancreatic islets. Biophys J 87: 3074‐3087, 2004.
 35.Bertram R, Satin LS, Sherman AS. Closing in on the mechanisms of pulsatile insulin secretion. Diabetes 67: 351‐359, 2018.
 36.Bertrand G, Gross R, Puech R, Loubatires‐Mariani MM, Bockaert J. Glutamate stimulates glucagon secretion via an excitatory amino acid receptor of the AMPA subtype in rat pancreas. Eur J Pharmacol 237: 45‐50, 1993.
 37.Berts A, Ball A, Dryselius S, Gylfe E, Hellman B. Glucose stimulation of somatostatin‐producing islet cells involves oscillatory Ca2+ signaling. Endocrinology 137: 693‐697, 1996.
 38.Blodgett DM, Nowosielska A, Afik S, Pechhold S, Cura AJ, Kennedy NJ, Kim S, Kucukural A, Davis RJ, Kent SC, Greiner DL, Garber MG, Harlan DM, diIorio P. Novel observations from next‐generation RNA sequencing of highly purified human adult and fetal islet cell subsets. Diabetes 64: 3172‐3181, 2015.
 39.Boel E, Schwartz TW, Norris KE, Fiil NP. A cDNA encoding a small common precursor for human pancreatic polypeptide and pancreatic icosapeptide. EMBO J 3: 909‐912, 1984.
 40.Bokvist K, Olsen HL, Hoy M, Gotfredsen CF, Holmes WF, Buschard K, Rorsman P, Gromada J. Characterisation of sulphonylurea and ATP‐regulated K+ channels in rat pancreatic A‐cells. Pflugers Arch: Eur J Physiol 438: 428‐436, 1999.
 41.Bonner‐Weir S. Morphological evidence for pancreatic polarity of beta‐cell within islets of Langerhans. Diabetes 37: 616‐621, 1988.
 42.Bonner‐Weir S, Orci L. New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31: 883‐889, 1982.
 43.Borden P, Houtz J, Leach SD, Kuruvilla R. Sympathetic innervation during development is necessary for pancreatic islet architecture and functional maturation. Cell Rep 4: 287‐301, 2013.
 44.Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, Muller YD, Giovannoni L, Parnaud G, Berney T. Unique arrangement of alpha‐ and beta‐cells in human islets of Langerhans. Diabetes 59: 1202‐1210, 2010.
 45.Bosco D, Haefliger JA, Meda P. Connexins: Key mediators of endocrine function. Physiol Rev 91: 1393‐1445, 2011.
 46.Bouche C, Lopez X, Fleischman A, Cypess AM, O'Shea S, Stefanovski D, Bergman RN, Rogatsky E, Stein DT, Kahn CR, Kulkarni RN, Goldfine AB. Insulin enhances glucose‐stimulated insulin secretion in healthy humans. Proc Natl Acad Sci USA 107: 4770‐4775, 2010.
 47.Boyd AW, Bartlett PF, Lackmann M. Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov 13: 39‐62, 2014.
 48.Braun M, Ramracheya R, Bengtsson M, Clark A, Walker JN, Johnson PR, Rorsman P. Gamma‐aminobutyric acid (GABA) is an autocrine excitatory transmitter in human pancreatic beta‐cells. Diabetes 59: 1694‐1701, 2010.
 49.Braun M, Wendt A, Karanauskaite J, Galvanovskis J, Clark A, MacDonald PE, Rorsman P. Corelease and differential exit via the fusion pore of GABA, serotonin, and ATP from LDCV in rat pancreatic beta cells. J Gen Physiol 129: 221‐231, 2007.
 50.Brereton MF, Vergari E, Zhang Q, Clark A. Alpha‐, delta‐ and PP‐cells: Are they the architectural cornerstones of islet structure and co‐ordination? J Histochem Cytochem 63: 575‐591, 2015.
 51.Briant L, Salehi A, Vergari E, Zhang Q, Rorsman P. Glucagon secretion from pancreatic alpha‐cells. Ups J Med Sci 121: 113‐119, 2016.
 52.Briant LJ, Zhang Q, Vergari E, Kellard JA, Rodriguez B, Ashcroft FM, Rorsman P. Functional identification of islet cell types by electrophysiological fingerprinting. J R Soc Interface 14: 20160999, 2017.
 53.Briant LJB, Reinbothe TM, Spiliotis I, Miranda C, Rodriguez B, Rorsman P. Delta‐cells and beta‐cells are electrically coupled and regulate alpha‐cell activity via somatostatin. J Physiol 596: 197‐215, 2018.
 54.Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, Powers AC. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 53: 1087‐1097, 2005.
 55.Brissova M, Haliyur R, Saunders D, Shrestha S, Dai C, Blodgett DM, Bottino R, Campbell‐Thompson M, Aramandla R, Poffenberger G, Lindner J, Pan FC, von Herrath MG, Greiner DL, Shultz LD, Sanyoura M, Philipson LH, Atkinson M, Harlan DM, Levy SE, Prasad N, Stein R, Powers AC. Alpha cell function and gene expression are compromised in type 1 diabetes. Cell Rep 22: 2667‐2676, 2018.
 56.Brunicardi FC, Kleinman R, Moldovan S, Nguyen TH, Watt PC, Walsh J, Gingerich R. Immunoneutralization of somatostatin, insulin, and glucagon causes alterations in islet cell secretion in the isolated perfused human pancreas. Pancreas 23: 302‐308, 2001.
 57.Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA 103: 2334‐2339, 2006.
 58.Cabrera O, Jacques‐Silva MC, Speier S, Yang SN, Kohler M, Fachado A, Vieira E, Zierath JR, Kibbey R, Berman DM, Kenyon NS, Ricordi C, Caicedo A, Berggren PO. Glutamate is a positive autocrine signal for glucagon release. Cell Metab 7: 545‐554, 2008.
 59.Caicedo A. Paracrine and autocrine interactions in the human islet: More than meets the eye. Semin Cell Dev Biol 24: 11‐21, 2013.
 60.Calabrese A, Zhang M, Serre‐Beinier V, Caton D, Mas C, Satin LS, Meda P. Connexin 36 controls synchronization of Ca2+ oscillations and insulin secretion in MIN6 cells. Diabetes 52: 417‐424, 2003.
 61.Cardenas‐Rodriguez M, Badano JL. Ciliary biology: Understanding the cellular and genetic basis of human ciliopathies. Am J Med Genet C Semin Med Genet 151C: 263‐280, 2009.
 62.Caton D, Calabrese A, Mas C, Serre‐Beinier V, Wonkam A, Meda P. Beta‐cell crosstalk: A further dimension in the stimulus‐secretion coupling of glucose‐induced insulin release. Diabetes Metab 28: 3S45‐3S53; discussion 43S108‐43S112, 2002.
 63.Cejvan K, Coy DH, Efendic S. Intra‐islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Diabetes 52: 1176‐1181, 2003.
 64.Chay TR, Keizer J. Minimal model for membrane oscillations in the pancreatic beta‐cell. Biophys J 42: 181‐190, 1983.
 65.Chen J, Ostenson C‐G. Glucagon release is regulated by tyrosine phosphatase and PI3‐kinase activity. Biochem Biophys Res Commun 325: 555‐560, 2004.
 66.Cherubini E, Gaiarsa JL, Ben‐Ari Y. GABA: An excitatory transmitter in early postnatal life. Trends Neurosci 14: 515‐519, 1991.
 67.Chimienti F, Devergnas S, Favier A, Seve M. Identification and cloning of a beta‐cell‐specific zinc transporter, ZnT‐8, localized into insulin secretory granules. Diabetes 53: 2330‐2337, 2004.
 68.Cho JH, Chen L, Kim MH, Chow RH, Hille B, Koh D‐S. Characteristics and functions of alpha‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate receptors expressed in mouse pancreatic alpha‐cells. Endocrinology 151: 1541‐1550, 2010.
 69.Christensen M, Bagger JI, Vilsboll T, Knop FK. The alpha‐cell as target for type 2 diabetes therapy. Rev Diabet Stud 8: 369‐381, 2011.
 70.Christensen ST, Clement CA, Satir P, Pedersen LB. Primary cilia and coordination of receptor tyrosine kinase (RTK) signalling. J Pathol 226: 172‐184, 2012.
 71.Christensen ST, Morthorst SK, Mogensen JB, Pedersen LB. Primary cilia and coordination of receptor tyrosine kinase (RTK) and transforming growth factor beta (TGF‐beta) signaling. Cold Spring Harb Perspect Biol 9: a028167, 2017.
 72.Cirulli V, Baetens D, Rutishauser U, Halban PA, Orci L, Rouiller DG. Expression of neural cell adhesion molecule (N‐CAM) in rat islets and its role in islet cell type segregation. J Cell Sci 107 (Pt 6): 1429‐1436, 1994.
 73.Cognard E, Dargaville CG, Hay DL, Shepherd PR. Identification of a pathway by which glucose regulates β‐catenin signalling via the cAMP/protein kinase A pathway in β‐cell models. Biochem J 449: 803‐811, 2013.
 74.Collares‐Buzato CB, Carvalho CPF, Furtado AG, Boschero AC. Upregulation of the expression of tight and adherens junction‐associated proteins during maturation of neonatal pancreatic islets in vitro. J Mol Histol 35: 811‐822, 2004.
 75.Dadi PK, Luo B, Vierra NC, Jacobson DA. TASK‐1 potassium channels limit pancreatic alpha‐cell calcium influx and glucagon secretion. Mol Endocrinol 29: 777‐787, 2015.
 76.Dahl G, Berger W, Meissner HP. Intracellular membrane junctions during the exocytosis of insulin. J Physiol Paris 72: 703‐709, 1976.
 77.Dahl U, Sjodin A, Semb H. Cadherins regulate aggregation of pancreatic beta‐cells in vivo. Development 122: 2895‐2902, 1996.
 78.De Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F, Bengtsson M, Braha O, Braun M, Ramracheya R, Amisten S, Habib AM, Moritoh Y, Zhang E, Reimann F, Rosengren AH, Shibasaki T, Gribble F, Renstrom E, Seino S, Eliasson L, Rorsman P. GLP‐1 inhibits and adrenaline stimulates glucagon release by differential modulation of N‐ and L‐type Ca2+ channel‐dependent exocytosis. Cell Metab 11: 543‐553, 2010.
 79.de Souza AH, Tang J, Yadev AK, Saghafi ST, Kibbe CR, Linnemann AK, Merrins MJ, Davis DB. Intra‐islet GLP‐1, but not CCK, is necessary for beta‐cell function in mouse and human islets. Sci Rep 10: 2823, 2020.
 80.De Vries G, Sherman A. Channel sharing in pancreatic beta‐cells revisited: Enhancement of emergent bursting by noise. J Theor Biol 207: 513‐530, 2000.
 81.Deeney JT, Kohler M, Kubik K, Brown G, Schultz V, Tornheim K, Corkey BE, Berggren PO. Glucose‐induced metabolic oscillations parallel those of Ca(2+) and insulin release in clonal insulin‐secreting cells. A multiwell approach to oscillatory cell behavior. J Biol Chem 276: 36946‐36950, 2001.
 82.Deisseroth K. Optogenetics: 10 years of microbial opsins in neuroscience. Nat Neurosci 18: 1213‐1225, 2015.
 83.Del Guercio MJ, di Natale B, Gargantini L, Garlaschi C, Chiumello G. Effect of somatostatin on blood sugar, plasma growth hormone, and glucagon levels in diabetic children. Diabetes 25: 550‐553, 1976.
 84.Denwood G, Tarasov A, Salehi A, Vergari E, Ramracheya R, Takahashi H, Nikolaev VO, Seino S, Gribble F, Reimann F, Rorsman P, Zhang Q. Glucose stimulates somatostatin secretion in pancreatic delta‐cells by cAMP‐dependent intracellular Ca2+ release. J Gen Physiol 151: 1094‐1115, 2019.
 85.Detimary P, Dejonghe S, Ling Z, Pipeleers D, Schuit F, Henquin JC. The changes in adenine nucleotides measured in glucose‐stimulated rodent islets occur in beta cells but not in alpha cells and are also observed in human islets. J Biol Chem 273: 33905‐33908, 1998.
 86.Diao J, Asghar Z, Chan CB, Wheeler MB. Glucose‐regulated glucagon secretion requires insulin receptor expression in pancreatic alpha‐cells. J Biol Chem 280: 33487‐33496, 2005.
 87.Dickerson MT, Dadi PK, Altman MK, Verlage KR, Thorson AS, Jordan XKL, Vierra NC, Amarnath G, Jacobson DA. Glucose‐mediated inhibition of calcium‐activated potassium channels limits alpha‐cell calcium influx and glucagon secretion. Am J Physiol Endocrinol Metab 316: E646‐E659, 2019.
 88.DiGruccio MR, Mawla AM, Donaldson CJ, Noguchi GM, Vaughan J, Cowing‐Zitron C, van der Meulen T, Huising MO. Comprehensive alpha, beta and delta cell transcriptomes reveal that ghrelin selectively activates delta cells and promotes somatostatin release from pancreatic islets. Mol Metab 5: 449‐458, 2016.
 89.diIorio P, Rittenhouse AR, Bortell R, Jurczyk A. Role of cilia in normal pancreas function and in diseased states. Birth Defects Res C Embryo Today 102: 126‐138, 2014.
 90.Dinneen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia 38: 337‐343, 1995.
 91.Dodson G, Steiner D. The role of assembly in insulin's biosynthesis. Curr Opin Struct Biol 8: 189‐194, 1998.
 92.Doliba NM, Qin W, Vatamaniuk MZ, Li C, Zelent D, Najafi H, Buettger CW, Collins HW, Carr RD, Magnuson MA, Matschinsky FM. Restitution of defective glucose‐stimulated insulin release of sulfonylurea type 1 receptor knockout mice by acetylcholine. Am J Physiol Endocrinol Metab 286: E834‐E843, 2004.
 93.Donath MY, Størling J, Maedler K, Mandrup‐Poulsen T. Inflammatory mediators and islet beta‐cell failure: A link between type 1 and type 2 diabetes. J Mol Med (Berl) 81: 455‐470, 2003.
 94.Dorrell C, Schug J, Lin CF, Canaday PS, Fox AJ, Smirnova O, Bonnah R, Streeter PR, Stoeckert CJ Jr, Kaestner KH, Grompe M. Transcriptomes of the major human pancreatic cell types. Diabetologia 54: 2832‐2844, 2011.
 95.Drobinskaya I, Neumaier F, Pereverzev A, Hescheler J, Schneider T. Diethyldithiocarbamate‐mediated zinc ion chelation reveals role of Cav2.3 channels in glucagon secretion. Biochim Biophys Acta 1853: 953‐964, 2015.
 96.Dufrane D, Gianello P. Pig islet for xenotransplantation in human: Structural and physiological compatibility for human clinical application. Transplant Rev (Orlando) 26: 183‐188, 2012.
 97.Dumonteil E, Magnan C, Ritz‐Laser B, Meda P, Dussoix P, Gilbert M, Ktorza A, Philippe J. Insulin, but not glucose lowering corrects the hyperglucagonemia and increased proglucagon messenger ribonucleic acid levels observed in insulinopenic diabetes. Endocrinology 139: 4540‐4546, 1998.
 98.Dumonteil E, Ritz‐Laser B, Magnan C, Grigorescu I, Ktorza A, Philippe J. Chronic exposure to high glucose concentrations increases proglucagon messenger ribonucleic acid levels and glucagon release from InR1G9 cells. Endocrinology 140: 4644‐4650, 1999.
 99.Dwulet JM, Ludin NWF, Piscopio RA, Schleicher WE, Moua O, Westacott MJ, Benninger RKP. How heterogeneity in glucokinase and gap‐junction coupling determines the islet [Ca(2+)] response. Biophys J 117: 2188‐2203, 2019.
 100.Dyachok O, Idevall‐Hagren O, Sagetorp J, Tian G, Wuttke A, Arrieumerlou C, Akusjarvi G, Gylfe E, Tengholm A. Glucose‐induced cyclic AMP oscillations regulate pulsatile insulin secretion. Cell Metab 8: 26‐37, 2008.
 101.Dybala MP, Kuznetsov A, Motobu M, Hendren‐Santiago BK, Philipson LH, Chervonsky AV, Hara M. Integrated pancreatic blood flow: Bidirectional microcirculation between endocrine and exocrine pancreas. Diabetes 69: 1439‐1450, 2020.
 102.Eddlestone GT, Goncalves A, Bangham JA, Rojas E. Electrical coupling between cells in islets of Langerhans from mouse. J Membr Biol 77: 1‐14, 1984.
 103.Efendic S, Enzmann F, Nylen A, Uvns‐Wallensten K, Luft R. Effect of glucose/sulfonylurea interaction on release of insulin, glucagon, and somatostatin from isolated perfused rat pancreas. Proc Natl Acad Sci USA 76: 5901‐5904, 1979.
 104.Eiberger J, Degen J, Romualdi A, Deutsch U, Willecke K, Sohl G. Connexin genes in the mouse and human genome. Cell Commun Adhes 8: 163‐165, 2001.
 105.Ekholm R, Ericson LE, Lundquist I. Monoamines in the pancreatic islets of the mouse ‐ subcellular localization of 5‐hydroxytryptamine by electron microscopic autoradiography. Diabetologia 7: 339‐348, 1971.
 106.Elliott AD, Ustione A, Piston DW. Somatostatin and insulin mediate glucose‐inhibited glucagon secretion in the pancreatic alpha‐cell by lowering cAMP. Am J Physiol Endocrinol Metab 308: E130‐E143, 2015.
 107.Esni F, Täljedal I‐B, Perl A‐K, Cremer H, Christofori G, Semb H. Neural cell adhesion molecule (N‐CAM) is required for cell type segregation and normal ultrastructure in pancreatic islets. J Cell Biol 144: 325‐337, 1999.
 108.Falcão VTFL, Maschio DA, de Fontes CC, Oliveira RB, Santos‐Silva JC, Almeida ACS, Vanzela EC, Cartaxo MT, Carvalho CPF, Collares‐Buzato CB. Reduced insulin secretion function is associated with pancreatic islet redistribution of cell adhesion molecules (CAMs) in diabetic mice after prolonged high‐fat diet. Histochem Cell Biol 146: 13‐31, 2016.
 109.Farnsworth NL, Hemmati A, Pozzoli M, Benninger RK. Fluorescence recovery after photobleaching reveals regulation and distribution of connexin36 gap junction coupling within mouse islets of Langerhans. J Physiol 592: 4431‐4446, 2014.
 110.Fisher SJ, Lekas MC, McCall RH, Shi ZQ, Giacca A, Vranic M. Determinants of glucose turnover in the pathophysiology of diabetes: An in vivo analysis in diabetic dogs. Diabetes Metab 22: 111‐121, 1996.
 111.Fiske MP, Anstotz M, Welty LJ, Maccaferri G. The intrinsic cell type‐specific excitatory connectivity of the developing mouse subiculum is sufficient to generate synchronous epileptiform activity. J Physiol 598: 1965‐1985, 2020.
 112.Franklin I, Gromada J, Gjinovci A, Theander S, Wollheim CB. Beta‐cell secretory products activate alpha‐cell ATP‐dependent potassium channels to inhibit glucagon release. Diabetes 54: 1808‐1815, 2005.
 113.Gan WJ, Zavortink M, Ludick C, Templin R, Webb R, Webb R, Ma W, Poronnik P, Parton RG, Gaisano HY, Shewan AM, Thorn P. Cell polarity defines three distinct domains in pancreatic beta‐cells. J Cell Sci 130: 143‐151, 2017.
 114.Gandasi NR, Yin P, Omar‐Hmeadi M, Ottosson Laakso E, Vikman P, Barg S. Glucose‐dependent granule docking limits insulin secretion and is decreased in human type 2 diabetes. Cell Metab 27: 470‐478.e4, 2018.
 115.Ganesan S, Calle R, Zawalich K, Greenawalt K, Zawalich W, Shulman GI, Rasmussen H. Immunocytochemical localization of alpha‐protein kinase C in rat pancreatic beta‐cells during glucose‐induced insulin secretion. J Cell Biol 119: 313‐324, 1992.
 116.Gaskins HR, Balden ME, Selassie L, Beverly JL. Glucose modulates gamma‐aminobutyric acid release from the pancreatic beta‐TC6 cell line. J Biol Chem 270: 30286‐30289, 1995.
 117.Gautam D, Han SJ, Hamdan FF, Jeon J, Li B, Li JH, Cui Y, Mears D, Lu H, Deng C, Heard T, Wess J. A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metab 3: 449‐461, 2006.
 118.Gerber PPG, Trimble ER, Wollheim CB, Renold AE. Effect of insulin on glucose‐ and arginine‐stimulated somatostatin secretion from the isolated perfused rat pancreas. Endocrinology 109: 279‐283, 1981.
 119.Gerdes JM, Christou‐Savina S, Xiong Y, Moede T, Moruzzi N, Karlsson‐Edlund P, Leibiger B, Leibiger IB, Ostenson CG, Beales PL, Berggren PO. Ciliary dysfunction impairs beta‐cell insulin secretion and promotes development of type 2 diabetes in rodents. Nat Commun 5: 5308, 2014.
 120.Gerich JE. Role of somatostatin and its analogues in the pathogenesis and treatment of diabetes mellitus. Metabolism 39: 52‐54, 1990.
 121.Gerich JE, Charles MA, Grodsky GM. Regulation of pancreatic insulin and glucagon secretion. Annu Rev Physiol 38: 353‐388, 1976.
 122.Gerich JE, Lovinger R, Grodsky GM. Inhibition by somatostatin of glucagon and insulin release from the perfused rat pancreas in response to arginine, isoproterenol and theophylline: Evidence for a preferential effect on glucagon secretion. Endocrinology 96: 749‐754, 1975.
 123.Gerich JE, Schultz TA, Lewis SB, Karam JH. Clinical evaluation of somatostatin as a potential ajunct to insulin in the management of diabetes mellitus. Diabetologia 13: 537‐544, 1977.
 124.Ghazvini Zadeh EH, Huang Z, Xia J, Li D, Davidson HW, Li WH. ZIGIR, a granule‐specific Zn(2+) indicator, reveals human islet alpha cell heterogeneity. Cell Rep 32: 107904, 2020.
 125.Gilliam LK, Palmer JP, Taborsky GJ Jr. Tyramine‐mediated activation of sympathetic nerves inhibits insulin secretion in humans. J Clin Endocrinol Metab 92: 4035‐4038, 2007.
 126.Gilon P, Bertrand G, Loubatires‐Mariani MM, Remacle C, Henquin JC. The influence of gamma‐aminobutyric acid on hormone release by the mouse and rat endocrine pancreas. Endocrinology 129: 2521‐2529, 1991.
 127.Giorgio C, Incerti M, Pala D, Russo S, Chiodelli P, Rusnati M, Cantoni AM, Di Lecce R, Barocelli E, Bertoni S, Ravassard P, Manenti F, Piemonti L, Ferlenghi F, Lodola A, Tognolini M. Inhibition of Eph/ephrin interaction with the small molecule UniPR500 improves glucose tolerance in healthy and insulin‐resistant mice. Pharmacol Res 141: 319‐330, 2019.
 128.Godoy‐Matos AF. The role of glucagon on type 2 diabetes at a glance. Diabetol Metab Syndr 6: 91, 2014.
 129.Goldberg GS, Moreno AP, Lampe PD. Gap junctions between cells expressing connexin 43 or 32 show inverse permselectivity to adenosine and ATP. J Biol Chem 277: 36725‐36730, 2002.
 130.Golster H, Linden M, Bertuglia S, Colantuoni A, Nilsson G, Sjoberg F. Red blood cell velocity and volumetric flow assessment by enhanced high‐resolution laser Doppler imaging in separate vessels of the hamster cheek pouch microcirculation. Microvasc Res 58: 62‐73, 1999.
 131.Gopel SO, Kanno T, Barg S, Weng XG, Gromada J, Rorsman P. Regulation of glucagon release in mouse‐cells by KATP channels and inactivation of TTX‐sensitive Na+ channels. J Physiol 528: 509‐520, 2000.
 132.Grapengiesser E, Gylfe E, Dansk H, Hellman B. Nitric oxide induces synchronous Ca2+ transients in pancreatic beta cells lacking contact. Pancreas 23: 387‐392, 2001.
 133.Greenbaum CJ, Prigeon RL, D'Alessio DA. Impaired beta‐cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes 51: 951‐957, 2002.
 134.Gregg T, Sdao SM, Dhillon RS, Rensvold JW, Lewandowski SL, Pagliarini DJ, Denu JM, Merrins MJ. Obesity‐dependent CDK1 signaling stimulates mitochondrial respiration at complex I in pancreatic beta‐cells. J Biol Chem 294: 4656‐4666, 2019.
 135.Gromada J, Bokvist K, Ding WG, Barg S, Buschard K, Renstrom E, Rorsman P. Adrenaline stimulates glucagon secretion in pancreatic A‐cells by increasing the Ca2+ current and the number of granules close to the L‐type Ca2+ channels. J Gen Physiol 110: 217‐228, 1997.
 136.Gromada J, Chabosseau P, Rutter GA. The alpha‐cell in diabetes mellitus. Nat Rev Endocrinol 14: 694‐704, 2018.
 137.Gromada J, Franklin I, Wollheim CB. Alpha‐cells of the endocrine pancreas: 35 years of research but the enigma remains. Endocr Rev 28: 84‐116, 2007.
 138.Gromada J, Hy M, Buschard K, Salehi A, Rorsman P. Somatostatin inhibits exocytosis in rat pancreatic alpha‐cells by Gi2‐dependent activation of calcineurin and depriming of secretory granules. J Physiol 535: 519‐532, 2001.
 139.Gromada J, Hy M, Olsen HL, Gotfredsen CF, Buschard K, Rorsman P, Bokvist K. Gi2 proteins couple somatostatin receptors to low‐conductance K+ channels in rat pancreatic alpha‐cells. Pflugers Arch Eur J Physiol 442: 19‐26, 2001.
 140.Gromada J, Ma X, Hoy M, Bokvist K, Salehi A, Berggren PO, Rorsman P. ATP‐sensitive K+ channel‐dependent regulation of glucagon release and electrical activity by glucose in wild‐type and SUR1−/− mouse alpha‐cells. Diabetes 53 (Suppl 3): S181‐S189, 2004.
 141.Gunawardana SC, Rocheleau JV, Head WS, Piston DW. Mechanisms of time‐dependent potentiation of insulin release: Involvement of nitric oxide synthase. Diabetes 55: 1029‐1033, 2006.
 142.Guzman CB, Zhang XM, Liu R, Regev A, Shankar S, Garhyan P, Pillai SG, Kazda C, Chalasani N, Hardy TA. Treatment with LY2409021, a glucagon receptor antagonist, increases liver fat in patients with type 2 diabetes. Diabetes Obes Metab 19: 1521‐1528, 2017.
 143.Gylfe E. Glucose control of glucagon secretion‐‘there's a brand‐new gimmick every year’. Ups J Med Sci 121: 120‐132, 2016.
 144.Gylfe E, Grapengiesser E, Dansk H, Hellman B. The neurotransmitter ATP triggers Ca2+ responses promoting coordination of pancreatic islet oscillations. Pancreas 41: 258‐263, 2012.
 145.Gyulkhandanyan AV, Lu H, Lee SC, Bhattacharjee A, Wijesekara N, Fox JEM, MacDonald PE, Chimienti F, Dai FF, Wheeler MB. Investigation of transport mechanisms and regulation of intracellular Zn2+ in pancreatic alpha‐cells. J Biol Chem 283: 10184‐10197, 2008.
 146.Halban PA, Powers SL, George KL, Bonner‐Weir S. Spontaneous reassociation of dispersed adult rat pancreatic islet cells into aggregates with three‐dimensional architecture typical of native islets. Diabetes 36: 783‐790, 1987.
 147.Hani EH, Stoffers DA, Chèvre JC, Durand E, Stanojevic V, Dina C, Habener JF, Froguel P. Defective mutations in the insulin promoter factor‐1 (IPF‐1) gene in late‐onset type 2 diabetes mellitus. J Clin Invest 104: R41‐R48, 1999.
 148.Harris AL. Emerging issues of connexin channels: Biophysics fills the gap. Q Rev Biophys 34: 325‐472, 2001.
 149.Hauge‐Evans AC, Anderson RL, Persaud SJ, Jones PM. Delta cell secretory responses to insulin secretagogues are not mediated indirectly by insulin. Diabetologia 55: 1995‐2004, 2012.
 150.Hauge‐Evans AC, King AJ, Carmignac D, Richardson CC, Robinson IC, Low MJ, Christie MR, Persaud SJ, Jones PM. Somatostatin secreted by islet delta‐cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58: 403‐411, 2009.
 151.Havel PJ, Ahren B. Activation of autonomic nerves and the adrenal medulla contributes to increased glucagon secretion during moderate insulin‐induced hypoglycemia in women. Diabetes 46: 801‐807, 1997.
 152.Hayashi M, Yamada H, Uehara S, Morimoto R, Muroyama A, Yatsushiro S, Takeda J, Yamamoto A, Moriyama Y. Secretory granule‐mediated co‐secretion of l‐glutamate and glucagon triggers glutamatergic signal transmission in islets of Langerhans. J Biol Chem 278: 1966‐1974, 2003.
 153.Hdersdal S, Lund A, Knop FK, Vilsbll T. The role of glucagon in the pathophysiology and treatment of type 2 diabetes. Mayo Clin Proc 93: 217‐239, 2018.
 154.Head WS, Orseth ML, Nunemaker CS, Satin LS, Piston DW, Benninger RK. Connexin‐36 gap junctions regulate in vivo first‐ and second‐phase insulin secretion dynamics and glucose tolerance in the conscious mouse. Diabetes 61: 1700‐1707, 2012.
 155.Heimberg H, De Vos A, Moens K, Quartier E, Bouwens L, Pipeleers D, Van Schaftingen E, Madsen O, Schuit F. The glucose sensor protein glucokinase is expressed in glucagon‐producing alpha‐cells. Proc Natl Acad Sci USA 93: 7036‐7041, 1996.
 156.Heimberg H, De Vos A, Pipeleers D, Thorens B, Schuit F. Differences in glucose transporter gene expression between rat pancreatic alpha‐ and beta‐cells are correlated to differences in glucose transport but not in glucose utilization. J Biol Chem 270: 8971‐8975, 1995.
 157.Hellman B. Pulsatility of insulin release–a clinically important phenomenon. Ups J Med Sci 114: 193‐205, 2009.
 158.Hellman B, Salehi A, Gylfe E, Dansk H, Grapengiesser E. Glucose generates coincident insulin and somatostatin pulses and antisynchronous glucagon pulses from human pancreatic islets. Endocrinology 150: 5334‐5340, 2009.
 159.Henquin JC. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49: 1751‐1760, 2000.
 160.Henquin JC. The challenge of correctly reporting hormones content and secretion in isolated human islets. Mol Metab 30: 230‐239, 2019.
 161.Hermansen K. Tolbutamide, glucose, calcium, and somatostatin secretion. Acta Endocrinol 99: 86‐93, 1982.
 162.Hiriart M, Ramirez‐Medeles MC. Functional subpopulations of individual pancreatic B‐cells in culture. Endocrinology 128: 3193‐3198, 1991.
 163.Hodson DJ, Mitchell RK, Bellomo EA, Sun G, Vinet L, Meda P, Li D, Li WH, Bugliani M, Marchetti P, Bosco D, Piemonti L, Johnson P, Hughes SJ, Rutter GA. Lipotoxicity disrupts incretin‐regulated human beta cell connectivity. J Clin Invest 123: 4182‐4194, 2013.
 164.Honey RN, Fallon MB, Weir GC. Effects of exogenous insulin, glucagon, and somatostatin on islet hormone secretion in the perfused chicken pancreas. Metabolism 29: 1242‐1246, 1980.
 165.Hope KM, Tran POT, Zhou H, Oseid E, Leroy E, Robertson RP. Regulation of alpha‐cell function by the beta‐cell in isolated human and rat islets deprived of glucose: The “switch‐off” hypothesis. Diabetes 53: 1488‐1495, 2004.
 166.Hraha TH, Bernard AB, Nguyen LM, Anseth KS, Benninger RK. Dimensionality and size scaling of coordinated Ca(2+) dynamics in MIN6 beta‐cell clusters. Biophys J 106: 299‐309, 2014.
 167.Hsueh B, Burns VM, Pauerstein P, Holzem K, Ye L, Engberg K, Wang AC, Gu X, Chakravarthy H, Arda HE, Charville G, Vogel H, Efimov IR, Kim S, Deisseroth K. Pathways to clinical CLARITY: Volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease. Sci Rep 7: 5899, 2017.
 168.Hughes JW, Cho JH, Conway HE, DiGruccio MR, Ng XW, Roseman HF, Abreu D, Urano F, Piston DW. Primary cilia control glucose homeostasis via islet paracrine interactions. Proc Natl Acad Sci USA 117 (16): 8912‐8923, 2020.
 169.Hughes JW, Ustione A, Lavagnino Z, Piston DW. Regulation of islet glucagon secretion: Beyond calcium. Diabetes Obes Metab 20 (Suppl 2): 127‐136, 2018.
 170.Hunyady B, Hipkin RW, Schonbrunn A, Mezey E. Immunohistochemical localization of somatostatin receptor SST2A in the rat pancreas. Endocrinology 138: 2632‐2635, 1997.
 171.Hussain K, Aynsley‐Green A. Management of hyperinsulinism in infancy and childhood. Ann Med 32: 544‐551, 2000.
 172.Hutchens T, Piston DW. EphA4 receptor forward signaling inhibits glucagon secretion from alpha‐cells. Diabetes 64: 3839‐3851, 2015.
 173.Hutton JC, Penn EJ, Peshavaria M. Low‐molecular‐weight constituents of isolated insulin‐secretory granules. Bivalent cations, adenine nucleotides and inorganic phosphate. Biochem J 210: 297‐305, 1983.
 174.Ishihara H, Maechler P, Gjinovci A, Herrera PL, Wollheim CB. Islet beta‐cell secretion determines glucagon release from neighbouring alpha‐cells. Nat Cell Biol 5: 330‐335, 2003.
 175.Iwanaga T, Miki T, Takahashi‐Iwanaga H. Restricted expression of somatostatin receptor 3 to primary cilia in the pancreatic islets and adenohypophysis of mice. Biomed Res 32: 73‐81, 2011.
 176.Jacques‐Silva MC, Correa‐Medina M, Cabrera O, Rodriguez‐Diaz R, Makeeva N, Fachado A, Diez J, Berman DM, Kenyon NS, Ricordi C, Pileggi A, Molano RD, Berggren PO, Caicedo A. ATP‐gated P2X3 receptors constitute a positive autocrine signal for insulin release in the human pancreatic beta cell. Proc Natl Acad Sci USA 107: 6465‐6470, 2010.
 177.Jain R, Jain D, Liu Q, Bartosinska B, Wang J, Schumann D, Kauschke SG, Eickelmann P, Piemonti L, Gray NS, Lammert E. Pharmacological inhibition of Eph receptors enhances glucose‐stimulated insulin secretion from mouse and human pancreatic islets. Diabetologia 56: 1350‐1355, 2013.
 178.Jansson L. Glucose stimulation of pancreatic islet blood flow by redistribution of the blood flow within the whole pancreatic gland. Pancreas 3: 409‐412, 1988.
 179.Jansson L, Barbu A, Bodin B, Drott CJ, Espes D, Gao X, Grapensparr L, Kallskog O, Lau J, Liljeback H, Palm F, Quach M, Sandberg M, Stromberg V, Ullsten S, Carlsson PO. Pancreatic islet blood flow and its measurement. Ups J Med Sci 121: 81‐95, 2016.
 180.Jansson L, Carlsson PO. Pancreatic blood flow with special emphasis on blood perfusion of the islets of Langerhans. Compr Physiol 9: 799‐837, 2019.
 181.Jenstad M, Chaudhry FA. The amino acid transporters of the glutamate/GABA‐glutamine cycle and their impact on insulin and glucagon secretion. Front Endocrinol 4: 199, 2013.
 182.Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Phys Endocrinol Metab 284: E671‐E678, 2003.
 183.Jo J, Hara M, Ahlgren U, Sorenson R, Periwal V. Mathematical models of pancreatic islet size distributions. Islets 4: 10‐19, 2012.
 184.Johansson H, Gylfe E, Hellman B. Cyclic AMP raises cytoplasmic calcium in pancreatic alpha‐cells by mobilizing calcium incorporated in response to glucose. Cell Calcium 10: 205‐211, 1989.
 185.Johnston NR, Mitchell RK, Haythorne E, Pessoa MP, Semplici F, Ferrer J, Piemonti L, Marchetti P, Bugliani M, Bosco D, Berishvili E, Duncanson P, Watkinson M, Broichhagen J, Trauner D, Rutter GA, Hodson DJ. Beta cell hubs dictate pancreatic islet responses to glucose. Cell Metab 24: 389‐401, 2016.
 186.Kailey B, van de Bunt M, Cheley S, Johnson PR, MacDonald PE, Gloyn AL, Rorsman P, Braun M. SSTR2 is the functionally dominant somatostatin receptor in human pancreatic beta‐ and alpha‐cells. Am J Physiol Endocrinol Metab 303: E1107‐E1116, 2012.
 187.Kandouz M. Dying to communicate: Apoptotic functions of Eph/Ephrin proteins. Apoptosis 23: 265‐289, 2018.
 188.Kaneko K, Shirotani T, Araki E, Matsumoto K, Taguchi T, Motoshima H, Yoshizato K, Kishikawa H, Shichiri M. Insulin inhibits glucagon secretion by the activation of PI3‐kinase in In‐R1‐G9 cells. Diabetes Res Clin Pract 44: 83‐92, 1999.
 189.Karimian N, Qin T, Liang T, Osundiji M, Huang Y, Teich T, Riddell MC, Cattral MS, Coy DH, Vranic M, Gaisano HY. Somatostatin receptor type 2 antagonism improves glucagon counterregulation in biobreeding diabetic rats. Diabetes 62: 2968‐2977, 2013.
 190.Katzman SM, Messerli MA, Barry DT, Grossman A, Harel T, Wikstrom JD, Corkey BE, Smith PJ, Shirihai OS. Mitochondrial metabolism reveals a functional architecture in intact islets of Langerhans from normal and diabetic Psammomys obesus. Am J Physiol Endocrinol Metab 287: E1090‐E1099, 2004.
 191.Kawamori D, Kurpad AJ, Hu J, Liew CW, Shih JL, Ford EL, Herrera PL, Polonsky KS, McGuinness OP, Kulkarni RN. Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metab 9: 350‐361, 2009.
 192.Kazda CM, Frias J, Foga I, Cui X, Guzman CB, Garhyan P, Heilmann C, Yang JA, Hardy TA. Treatment with the glucagon receptor antagonist LY2409021 increases ambulatory blood pressure in patients with type 2 diabetes. Diabetes Obes Metab 19 (8): 1071‐1077, 2017.
 193.Keizer J, Smolen P. Bursting electrical activity in pancreatic beta cells caused by Ca(2+)‐ and voltage‐inactivated Ca2+ channels. Proc Natl Acad Sci USA 88: 3897‐3901, 1991.
 194.Kendall DM, Teuscher AU, Robertson RP. Defective glucagon secretion during sustained hypoglycemia following successful islet allo‐ and autotransplantation in humans. Diabetes 46: 23‐27, 1997.
 195.Kennedy RT, Kauri LM, Dahlgren GM, Jung SK. Metabolic oscillations in beta‐cells. Diabetes 51 (Suppl 1): S152‐S161, 2002.
 196.Kim K, Oh CM, Ohara‐Imaizumi M, Park S, Namkung J, Yadav VK, Tamarina NA, Roe MW, Philipson LH, Karsenty G, Nagamatsu S, German MS, Kim H. Functional role of serotonin in insulin secretion in a diet‐induced insulin‐resistant state. Endocrinology 156: 444‐452, 2015.
 197.Kisanuki K, Kishikawa H, Araki E, Shirotani T, Uehara M, Isami S, Ura S, Jinnouchi H, Miyamura N, Shichiri M. Expression of insulin receptor on clonal pancreatic alpha cells and its possible role for insulin‐stimulated negative regulation of glucagon secretion. Diabetologia 38: 422‐429, 1995.
 198.Kitamura T, Kitamura Y, Kuroda S, Hino Y, Ando M, Kotani K, Konishi H, Matsuzaki H, Kikkawa U, Ogawa W, Kasuga M. Insulin‐induced phosphorylation and activation of cyclic nucleotide phosphodiesterase 3B by the serine‐threonine kinase Akt. Mol Cell Biol 19: 6286‐6296, 1999.
 199.Kleinfeld D, Mitra PP, Helmchen F, Denk W. Fluctuations and stimulus‐induced changes in blood flow observed in individual capillaries in layers 2 through 4 of rat neocortex. Proc Natl Acad Sci USA 95: 15741‐15746, 1998.
 200.Kluth O, Stadion M, Gottmann P, Aga H, Jahnert M, Scherneck S, Vogel H, Krus U, Seelig A, Ling C, Gerdes J, Schurmann A. Decreased expression of cilia genes in pancreatic islets as a risk factor for type 2 diabetes in mice and humans. Cell Rep 26: 3027‐3036.e3, 2019.
 201.Koemeter‐Cox AI, Sherwood TW, Green JA, Steiner RA, Berbari NF, Yoder BK, Kauffman AS, Monsma PC, Brown A, Askwith CC, Mykytyn K. Primary cilia enhance kisspeptin receptor signaling on gonadotropin‐releasing hormone neurons. Proc Natl Acad Sci USA 111: 10335‐10340, 2014.
 202.Koerker DJ, Ruch W, Chideckel E, Palmer J, Goodner CJ, Ensinck J, Gale CC. Somatostatin: Hypothalamic inhibitor of the endocrine pancreas. Science 184: 482‐484, 1974.
 203.Kojima N, Takeuchi S, Sakai Y. Engineering of pseudoislets: Effect on insulin secretion activity by cell number, cell population, and microchannel networks. Transplant Proc 46: 1161‐1165, 2014.
 204.Konstantinova I, Nikolova G, Ohara‐Imaizumi M, Meda P, Kucera T, Zarbalis K, Wurst W, Nagamatsu S, Lammert E. EphA‐Ephrin‐A‐mediated beta cell communication regulates insulin secretion from pancreatic islets. Cell 129: 359‐370, 2007.
 205.Koop I, Ruppert‐Seipp G, Koop H, Schafmayer A, Arnold R. Cholecystokinin release by gastric distension—an atropine‐sensitive mechanism. Digestion 46: 220‐227, 1990.
 206.Koster JC, Marshall BA, Ensor N, Corbett JA, Nichols CG. Targeted overactivity of beta cell K(ATP) channels induces profound neonatal diabetes. Cell 100: 645‐654, 2000.
 207.Koval M, Isakson BE, Gourdie RG. Connexins, pannexins and innexins: Protein cousins with overlapping functions. FEBS Lett 588: 1185, 2014.
 208.Koval M, Molina SA, Burt JM. Mix and match: Investigating heteromeric and heterotypic gap junction channels in model systems and native tissues. FEBS Lett 588: 1193‐1204, 2014.
 209.Ku GM, Kim H, Vaughn IW, Hangauer MJ, Myung Oh C, German MS, McManus MT. Research resource: RNA‐Seq reveals unique features of the pancreatic beta‐cell transcriptome. Mol Endocrinol 26: 1783‐1792, 2012.
 210.Kumar U, Sasi R, Suresh S, Patel A, Thangaraju M, Metrakos P, Patel SC, Patel YC. Subtype‐selective expression of the five somatostatin receptors (hSSTR1‐5) in human pancreatic islet cells: A quantitative double‐label immunohistochemical analysis. Diabetes 48: 77‐85, 1999.
 211.Lanner JT, Georgiou DK, Joshi AD, Hamilton SL. Ryanodine receptors: Structure, expression, molecular details, and function in calcium release. Cold Spring Harb Perspect Biol 2: a003996, 2010.
 212.Lavagnino Z, Dwight J, Ustione A, Nguyen TU, Tkaczyk TS, Piston DW. Snapshot hyperspectral light‐sheet imaging of signal transduction in live pancreatic islets. Biophys J 111: 409‐417, 2016.
 213.Le Marchand SJ, Piston DW. Glucose suppression of glucagon secretion: Metabolic and calcium responses from alpha‐cells in intact mouse pancreatic islets. J Biol Chem 285: 14389‐14398, 2010.
 214.Le Marchand SJ, Piston DW. Glucose decouples intracellular Ca2+ activity from glucagon secretion in mouse pancreatic islet alpha‐cells. PLoS One 7: e47084, 2012.
 215.Leclerc I, Sun G, Morris C, Fernandez‐Millan E, Nyirenda M, Rutter GA. AMP‐activated protein kinase regulates glucagon secretion from mouse pancreatic alpha cells. Diabetologia 54: 125‐134, 2011.
 216.Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH. Glucagon receptor knockout prevents insulin‐deficient type 1 diabetes in mice. Diabetes 60: 391‐397, 2011.
 217.Lernmark A. The preparation of, and studies on, free cell suspensions from mouse pancreatic islets. Diabetologia 10: 431‐438, 1974.
 218.Leung YM, Ahmed I, Sheu L, Gao X, Hara M, Tsushima RG, Diamant NE, Gaisano HY. Insulin regulates islet alpha‐cell function by reducing KATP channel sensitivity to adenosine 5′‐triphosphate inhibition. Endocrinology 147: 2155‐2162, 2006.
 219.Li C, Liu C, Nissim I, Chen J, Chen P, Doliba N, Zhang T, Nissim I, Daikhin Y, Stokes D, Yudkoff M, Bennett MJ, Stanley CA, Matschinsky FM, Naji A. Regulation of glucagon secretion in normal and diabetic human islets by gamma‐hydroxybutyrate and glycine. J Biol Chem 288: 3938‐3951, 2013.
 220.Li H, John AN, Nagatake T, Hamazaki Y, Jiang F‐X. Claudin 4 in pancreatic β cells is involved in regulating the functional state of adult islets. FEBS Open Bio 10: 28‐40, 2020.
 221.Li J, Klughammer J, Farlik M, Penz T, Spittler A, Barbieux C, Berishvili E, Bock C, Kubicek S. Single‐cell transcriptomes reveal characteristic features of human pancreatic islet cell types. EMBO Rep 17: 178‐187, 2016.
 222.Li J, Yu Q, Ahooghalandari P, Gribble FM, Reimann F, Tengholm A, Gylfe E. Submembrane ATP and Ca2+ kinetics in alpha‐cells: Unexpected signaling for glucagon secretion. FASEB J 29: 3379‐3388, 2015.
 223.Lin HV, Wang J, Wang J, Li W, Wang X, Alston JT, Thomas MK, Briere DA, Syed SK, Efanov AM. GPR142 prompts glucagon‐like peptide‐1 release from islets to improve beta cell function. Mol Metab 11: 205‐211, 2018.
 224.Liu YJ, Vieira E, Gylfe E. A store‐operated mechanism determines the activity of the electrically excitable glucagon‐secreting pancreatic alpha‐cell. Cell Calcium 35: 357‐365, 2004.
 225.Lodh S, O'Hare EA, Zaghloul NA. Primary cilia in pancreatic development and disease. Birth Defects Res C Embryo Today 102: 139‐158, 2014.
 226.Lonovics J, Devitt P, Watson LC, Rayford PL, Thompson JC. Pancreatic polypeptide. A review. Arch Surg 116: 1256‐1264, 1981.
 227.Low JT, Zavortink M, Mitchell JM, Gan WJ, Do OH, Schwiening CJ, Gaisano HY, Thorn P. Insulin secretion from beta cells in intact mouse islets is targeted towards the vasculature. Diabetologia 57: 1655‐1663, 2014.
 228.Low MJ. Clinical endocrinology and metabolism. The somatostatin neuroendocrine system: Physiology and clinical relevance in gastrointestinal and pancreatic disorders. Best Pract Res Clin Endocrinol Metab 18: 607‐622, 2004.
 229.Luciani DS, Misler S, Polonsky KS. Ca2+ controls slow NAD(P)H oscillations in glucose‐stimulated mouse pancreatic islets. J Physiol 572: 379‐392, 2006.
 230.Ludvigsen E, Olsson R, Stridsberg M, Janson ET, Sandler S. Expression and distribution of somatostatin receptor subtypes in the pancreatic islets of mice and rats. J Histochem Cytochem 52: 391‐400, 2004.
 231.Ma X, Zhang Y, Gromada J, Sewing S, Berggren PO, Buschard K, Salehi A, Vikman J, Rorsman P, Eliasson L. Glucagon stimulates exocytosis in mouse and rat pancreatic alpha‐cells by binding to glucagon receptors. Mol Endocrinol 19: 198‐212, 2005.
 232.MacDonald PE, De Marinis YZ, Ramracheya R, Salehi A, Ma X, Johnson PRV, Cox R, Eliasson L, Rorsman P. A KATP channel‐dependent pathway within alpha cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol 5: e143, 2007.
 233.Macdonald PE, Obermller S, Vikman J, Galvanovskis J, Rorsman P, Eliasson L. Regulated exocytosis and kiss‐and‐run of synaptic‐like microvesicles in INS‐1 and primary rat beta‐cells. Diabetes 54: 736‐743, 2005.
 234.MacDonald PE, Rorsman P. Oscillations, intercellular coupling, and insulin secretion in pancreatic beta cells. PLoS Biol 4: e49, 2006.
 235.Macfarlane WM, Frayling TM, Ellard S, Evans JC, Allen LI, Bulman MP, Ayres S, Shepherd M, Clark P, Millward A, Demaine A, Wilkin T, Docherty K, Hattersley AT. Missense mutations in the insulin promoter factor‐1 gene predispose to type 2 diabetes. J Clin Invest 104: R33‐R39, 1999.
 236.Macleod JJ, Noble EC, O'Brien K. The influence of the nutritional condition of the animal on the hypoglycaemia produced by insulin. J Physiol 57: 234‐252, 1923.
 237.Maedler K, Spinas GA, Lehmann R, Sergeev P, Weber M, Fontana A, Kaiser N, Donath MY. Glucose induces beta‐cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes 50: 1683‐1690, 2001.
 238.Manning Fox JE, Gyulkhandanyan AV, Satin LS, Wheeler MB. Oscillatory membrane potential response to glucose in islet beta‐cells: A comparison of islet‐cell electrical activity in mouse and rat. Endocrinology 147: 4655‐4663, 2006.
 239.Marco J, Hedo JA, Martinell J, Calle C, Villanueva ML. Potentiation of glucagon secretion by serotonin antagonists in man. J Clin Endocrinol Metab 42: 215‐221, 1976.
 240.Marco J, Hedo JA, Villanueva ML. Inhibition of glucagon release by serotonin in mouse pancreatic islets. Diabetologia 13: 585‐588, 1977.
 241.Marston DJ, Anderson KL, Swift MF, Rougie M, Page C, Hahn KM, Volkmann N, Hanein D. High Rac1 activity is functionally translated into cytosolic structures with unique nanoscale cytoskeletal architecture. Proc Natl Acad Sci USA 116: 1267‐1272, 2019.
 242.Marty‐Santos L, Cleaver O. Pdx1 regulates pancreas tubulogenesis and E‐cadherin expression. Development 143: 101‐112, 2016.
 243.Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH. Insulin within islets is a physiologic glucagon release inhibitor. J Clin Invest 74: 2296‐2299, 1984.
 244.Matsuda H. Zebrafish as a model for studying functional pancreatic beta cells development and regeneration. Develop Growth Differ 60: 393‐399, 2018.
 245.Matveyenko AV, Liuwantara D, Gurlo T, Kirakossian D, Dalla Man C, Cobelli C, White MF, Copps KD, Volpi E, Fujita S, Butler PC. Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling. Diabetes 61: 2269‐2279, 2012.
 246.Meda P, Atwater I, Goncalves A, Bangham A, Orci L, Rojas E. The topography of electrical synchrony among beta‐cells in the mouse islet of Langerhans. Q J Exp Physiol 69: 719‐735, 1984.
 247.Meda P, Bosco D, Chanson M, Giordano E, Vallar L, Wollheim C, Orci L. Rapid and reversible secretion changes during uncoupling of rat insulin‐producing cells. J Clin Invest 86: 759‐768, 1990.
 248.Meda P, Pepper MS, Traub O, Willecke K, Gros D, Beyer E, Nicholson B, Paul D, Orci L. Differential expression of gap junction connexins in endocrine and exocrine glands. Endocrinology 133: 2371‐2378, 1993.
 249.Meda P, Perrelet A, Orci L. Increase of gap junctions between pancreatic B‐cells during stimulation of insulin secretion. J Cell Biol 82: 441‐448, 1979.
 250.Menegaz D, Hagan DW, Almaa J, Cianciaruso C, Rodriguez‐Diaz R, Molina J, Dolan RM, Becker MW, Schwalie PC, Nano R, Lebreton F, Kang C, Sah R, Gaisano HY, Berggren P‐O, Baekkeskov S, Caicedo A, Phelps EA. Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell. Nat Metab 1: 1110‐1126, 2019.
 251.Menge BA, Gruber L, Jorgensen SM, Deacon CF, Schmidt WE, Veldhuis JD, Holst JJ, Meier JJ. Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes. Diabetes 60: 2160‐2168, 2011.
 252.Merrins MJ, Poudel C, McKenna JP, Ha J, Sherman A, Bertram R, Satin LS. Phase analysis of metabolic oscillations and membrane potential in pancreatic islet beta‐cells. Biophys J 110: 691‐699, 2016.
 253.Meyer‐Hermann M, Benninger RKP. A mathematical model of beta cells in an islet of Langerhans sensing a glucose gradient. HFSP J 4: 61‐71, 2010.
 254.Meyerhof W. The elucidation of somatostatin receptor functions: A current view. Rev Physiol Biochem Pharmacol 133: 55‐108, 1998.
 255.Michaels RL, Sheridan JD. Islets of Langerhans: Dye coupling among immunocytochemically distinct cell types. Science 214: 801‐803, 1981.
 256.Miki T, Liss B, Minami K, Shiuchi T, Saraya A, Kashima Y, Horiuchi M, Ashcroft F, Minokoshi Y, Roeper J, Seino S. ATP‐sensitive K+ channels in the hypothalamus are essential for the maintenance of glucose homeostasis. Nat Neurosci 4: 507‐512, 2001.
 257.Miki T, Nagashima K, Tashiro F, Kotake K, Yoshitomi H, Tamamoto A, Gonoi T, Iwanaga T, Miyazaki J, Seino S. Defective insulin secretion and enhanced insulin action in KATP channel‐deficient mice. Proc Natl Acad Sci USA 95: 10402‐10406, 1998.
 258.Mirbolooki MR, Taylor GE, Knutzen VK, Scharp DW, Willcourt R, Lakey JR. Pulsatile intravenous insulin therapy: The best practice to reverse diabetes complications? Med Hypotheses 73: 363‐369, 2009.
 259.Molina J, Rodriguez‐Diaz R, Fachado A, Jacques‐Silva MC, Berggren PO, Caicedo A. Control of insulin secretion by cholinergic signaling in the human pancreatic islet. Diabetes 63: 2714‐2726, 2014.
 260.Montesano R, Mouron P, Amherdt M, Orci L. Collagen matrix promotes reorganization of pancreatic endocrine cell monolayers into islet‐like organoids. J Cell Biol 97: 935‐939, 1983.
 261.Moreno AP, Berthoud VM, Perez‐Palacios G, Perez‐Armendariz EM. Biophysical evidence that connexin‐36 forms functional gap junction channels between pancreatic mouse beta‐cells. Am J Phys Endocrinol Metab 288: E948‐E956, 2005.
 262.Muller D, Huang GC, Amiel S, Jones PM, Persaud SJ. Identification of insulin signaling elements in human beta‐cells: Autocrine regulation of insulin gene expression. Diabetes 55: 2835‐2842, 2006.
 263.Mundinger TO, Mei Q, Foulis AK, Fligner CL, Hull RL, Taborsky GJ Jr. Human type 1 diabetes is characterized by an early, marked, sustained, and islet‐selective loss of sympathetic nerves. Diabetes 65: 2322‐2330, 2016.
 264.Mundinger TO, Taborsky GJ Jr. Early sympathetic islet neuropathy in autoimmune diabetes: Lessons learned and opportunities for investigation. Diabetologia 59: 2058‐2067, 2016.
 265.Muroyama A, Uehara S, Yatsushiro S, Echigo N, Morimoto R, Morita M, Hayashi M, Yamamoto A, Koh DS, Moriyama Y. A novel variant of ionotropic glutamate receptor regulates somatostatin secretion from delta‐cells of islets of Langerhans. Diabetes 53: 1743‐1753, 2004.
 266.Nadal A, Quesada I, Soria B. Homologous and heterologous asynchronicity between identified alpha‐, beta‐ and delta‐cells within intact islets of Langerhans in the mouse. J Physiol 517: 85‐93, 1999.
 267.Newgard CB, McGarry JD. Metabolic coupling factors in pancreatic beta‐cell signal transduction. Annu Rev Biochem 64: 689‐719, 1995.
 268.Nishi M, Sanke T, Nagamatsu S, Bell GI, Steiner DF. Islet amyloid polypeptide. A new beta cell secretory product related to islet amyloid deposits. J Biol Chem 265: 4173‐4176, 1990.
 269.Nolsøe RL, Hamid YH, Pociot F, Paulsen S, Andersen KM, Borch‐Johnsen K, Drivsholm T, Hansen T, Pedersen O, Mandrup‐Poulsen T. Association of a microsatellite in FASL to type II diabetes and of the FAS‐670G>A genotype to insulin resistance. Genes Immun 7: 316‐321, 2006.
 270.Nyman LR, Ford E, Powers AC, Piston DW. Glucose‐dependent blood flow dynamics in murine pancreatic islets in vivo. Am J Phys Endocrinol Metab 298: E807‐E814, 2010.
 271.Nyman LR, Wells KS, Head WS, McCaughey M, Ford E, Brissova M, Piston DW, Powers AC. Real‐time, multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets. J Clin Invest 118: 3790‐3797, 2008.
 272.Ohta Y, Kosaka Y, Kishimoto N, Wang J, Smith SB, Honig G, Kim H, Gasa RM, Neubauer N, Liou A, Tecott LH, Deneris ES, German MS. Convergence of the insulin and serotonin programs in the pancreatic beta‐cell. Diabetes 60: 3208‐3216, 2011.
 273.Olofsson CS, Håkansson J, Salehi A, Bengtsson M, Galvanovskis J, Partridge C, SörhedeWinzell M, Xian X, Eliasson L, Lundquist I, Semb H, Rorsman P. Impaired insulin exocytosis in neural cell adhesion molecule−/− mice due to defective reorganization of the submembrane F‐actin network. Endocrinology 150: 3067‐3075, 2009.
 274.Olsen HL, Theander S, Bokvist K, Buschard K, Wollheim CB, Gromada J. Glucose stimulates glucagon release in single rat alpha‐cells by mechanisms that mirror the stimulus‐secretion coupling in beta‐cells. Endocrinology 146: 4861‐4870, 2005.
 275.Omar‐Hmeadi M, Lund P‐E, Gandasi NR, Tengholm A, Barg S. Paracrine control of alpha‐cell glucagon exocytosis is compromised in human type‐2 diabetes. Nat Commun 11: 1896, 2020.
 276.Onuma H, Osawa H, Yamada K, Ogura T, Tanabe F, Granner DK, Makino H. Identification of the insulin‐regulated interaction of phosphodiesterase 3B with 14‐3‐3 beta protein. Diabetes 51: 3362‐3367, 2002.
 277.Orci L. The microanatomy of the islets of Langerhans. Metabolism 25: 1303‐1313, 1976.
 278.Orci L, Malaisse‐Lagae F, Amherdt M, Ravazzola M, Weisswange A, Dobbs R, Perrelet A, Unger R. Cell contacts in human islets of Langerhans. J Clin Endocrinol Metab 41: 841‐844, 1975.
 279.Orci L, Malaisse‐Lagae F, Ravazzola M, Rouiller D, Renold AE, Perrelet A, Unger R. A morphological basis for intercellular communication between alpha‐ and beta‐cells in the endocrine pancreas. J Clin Invest 56: 1066‐1070, 1975.
 280.Parnaud G, Gonelle‐Gispert C, Morel P, Giovannoni L, Muller YD, Meier R, Borot S, Berney T, Bosco D. Cadherin engagement protects human β‐cells from apoptosis. Endocrinology 152: 4601‐4609, 2011.
 281.Patterson GH, Knobel SM, Arkhammar P, Thastrup O, Piston DW. Separation of the glucose‐stimulated cytoplasmic and mitochondrial NAD(P)H responses in pancreatic islet beta cells. Proc Natl Acad Sci USA 97: 5203‐5207, 2000.
 282.Patton GS, Ipp E, Dobbs RE, Orci L, Vale W, Unger RH. Pancreatic immunoreactive somatostatin release. Proc Natl Acad Sci USA 74: 2140‐2143, 1977.
 283.Paulmann N, Grohmann M, Voigt JP, Bert B, Vowinckel J, Bader M, Skelin M, Jevek M, Fink H, Rupnik M, Walther DJ. Intracellular serotonin modulates insulin secretion from pancreatic beta‐cells by protein serotonylation. PLoS Biol 7: e1000229, 2009.
 284.Pearson MJ, Unger RH, Holland WL. Clinical trials, triumphs, and tribulations of glucagon receptor antagonists. Diabetes Care 39: 1075‐1077, 2016.
 285.Pedersen MG, Bertram R, Sherman A. Intra‐ and inter‐islet synchronization of metabolically driven insulin secretion. Biophys J 89: 107‐119, 2005.
 286.Pedersen MG, Sorensen MP. Wave‐block due to a threshold gradient underlies limited coordination in pancreatic islets. J Biol Phys 34: 425‐432, 2008.
 287.Perez‐Armendariz E, Atwater I. Glucose‐evoked changes in [K+] and [Ca2+] in the intercellular spaces of the mouse islet of Langerhans. Adv Exp Med Biol 211: 31‐51, 1986.
 288.Perez‐Armendariz E, Atwater I, Rojas E. Glucose‐induced oscillatory changes in extracellular ionized potassium concentration in mouse islets of Langerhans. Biophys J 48: 741‐749, 1985.
 289.Philippe J. Insulin regulation of the glucagon gene is mediated by an insulin‐responsive DNA element. Proc Natl Acad Sci USA 88: 7224‐7227, 1991.
 290.Phillippe J. Glucagon gene transcription is negatively regulated by insulin in a hamster islet cell line. J Clin Investig 84: 672‐677, 1989.
 291.Pipeleers D. The biosociology of pancreatic B cells. Diabetologia 30: 277‐291, 1987.
 292.Pipeleers D, Kiekens R, Ling Z, Wilikens A, Schuit F. Physiologic relevance of heterogeneity in the pancreatic beta‐cell population. Diabetologia 37 (Suppl 2): S57‐S64, 1994.
 293.Pisania A, Weir GC, O'Neil JJ, Omer A, Tchipashvili V, Lei J, Colton CK, Bonner‐Weir S. Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab Investig 90: 1661‐1675, 2010.
 294.Piston DW, Knobel SM, Postic C, Shelton KD, Magnuson MA. Adenovirus‐mediated knockout of a conditional glucokinase gene in isolated pancreatic islets reveals an essential role for proximal metabolic coupling events in glucose‐stimulated insulin secretion. J Biol Chem 274: 1000‐1004, 1999.
 295.Pitulescu ME, Adams RH. Eph/ephrin molecules–a hub for signaling and endocytosis. Genes Dev 24: 2480‐2492, 2010.
 296.Porksen N, Hollingdal M, Juhl C, Butler P, Veldhuis JD, Schmitz O. Pulsatile insulin secretion: Detection, regulation, and role in diabetes. Diabetes 51 (Suppl 1): S245‐S254, 2002.
 297.Prentki M, Nolan CJ. Islet beta cell failure in type 2 diabetes. J Clin Invest 116: 1802‐1812, 2006.
 298.Proshchina AE, Krivova YS, Barabanov VM, Saveliev SV. Ontogeny of neuro‐insular complexes and islets innervation in the human pancreas. Front Endocrinol (Lausanne) 5: 57, 2014.
 299.Qian WJ, Aspinwall CA, Battiste MA, Kennedy RT. Detection of secretion from single pancreatic beta‐cells using extracellular fluorogenic reactions and confocal fluorescence microscopy. Anal Chem 72: 711‐717, 2000.
 300.Rahn T, Ridderstrle M, Tornqvist H, Manganiello V, Fredrikson G, Belfrage P, Degerman E. Essential role of phosphatidylinositol 3‐kinase in insulin‐induced activation and phosphorylation of the cGMP‐inhibited cAMP phosphodiesterase in rat adipocytes. FEBS Lett 350: 314‐318, 1994.
 301.Rai U, Thrimawithana TR, Valery C, Young SA. Therapeutic uses of somatostatin and its analogues: Current view and potential applications. Pharmacol Ther 152: 98‐110, 2015.
 302.Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD. Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab 13 (Suppl 1): 118‐125, 2011.
 303.Ramracheya R, Chapman C, Chibalina M, Dou H, Miranda C, Gonzlez A, Moritoh Y, Shigeto M, Zhang Q, Braun M, Clark A, Johnson PR, Rorsman P, Briant LJB. GLP‐1 suppresses glucagon secretion in human pancreatic alpha‐cells by inhibition of P/Q‐type Ca2+ channels. Physiol Rep 6: e13852, 2018.
 304.Ramracheya R, Ward C, Shigeto M, Walker JN, Amisten S, Zhang Q, Johnson PR, Rorsman P, Braun M. Membrane potential‐dependent inactivation of voltage‐gated ion channels in alpha‐cells inhibits glucagon secretion from human islets. Diabetes 59: 2198‐2208, 2010.
 305.Raskin P, Unger RH. Hyperglucagonemia and its suppression: Importance in the metabolic control of diabetes. N Engl J Med 299: 433‐436, 1978.
 306.Ravier MA, Guldenagel M, Charollais A, Gjinovci A, Caille D, Sohl G, Wollheim CB, Willecke K, Henquin JC, Meda P. Loss of connexin36 channels alters {beta}‐cell coupling, islet synchronization of glucose‐induced Ca2+ and insulin oscillations, and basal insulin release. Diabetes 54: 1798‐1807, 2005.
 307.Ravier MA, Rutter GA. Glucose or insulin, but not zinc ions, inhibit glucagon secretion from mouse pancreatic {alpha}‐cells. Diabetes 54: 1789‐1797, 2005.
 308.Reetz A, Solimena M, Matteoli M, Folli F, Takei K, De Camilli P. 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: 1275‐1284, 1991.
 309.Reissaus CA, Piston DW. Reestablishment of glucose inhibition of glucagon secretion in small pseudoislets. Diabetes 66: 960‐969, 2017.
 310.Richards‐Williams C, Contreras JL, Berecek KH, Schwiebert EM. Extracellular ATP and zinc are co‐secreted with insulin and activate multiple P2X purinergic receptor channels expressed by islet beta‐cells to potentiate insulin secretion. Purinergic Signal 4: 393‐405, 2008.
 311.Richmond JE, Codignola A, Cooke IM, Sher E. Calcium and barium dependent exocytosis from the rat insulinoma cell line RINm5F assayed using membrane capacitance measurements and serotonin release. Pflugers Arch Eur J Physiol 432: 258‐269, 1996.
 312.Rieck S, White P, Schug J, Fox AJ, Smirnova O, Gao N, Gupta RK, Wang ZV, Scherer PE, Keller MP, Attie AD, Kaestner KH. The transcriptional response of the islet to pregnancy in mice. Mol Endocrinol 23: 1702‐1712, 2009.
 313.Rizzo MA, Magnuson MA, Drain PF, Piston DW. A functional link between glucokinase binding to insulin granules and conformational alterations in response to glucose and insulin. J Biol Chem 277: 34168‐34175, 2002.
 314.Rizzo MA, Piston DW. Regulation of beta cell glucokinase by S‐nitrosylation and association with nitric oxide synthase. J Cell Biol 161: 243‐248, 2003.
 315.Rocheleau JV, Head WS, Nicholson WE, Powers AC, Piston DW. Pancreatic islet beta‐cells transiently metabolize pyruvate. J Biol Chem 277: 30914‐30920, 2002.
 316.Rocheleau JV, Head WS, Piston DW. Quantitative NAD(P)H/flavoprotein autofluorescence imaging reveals metabolic mechanisms of pancreatic islet pyruvate response. J Biol Chem 279: 31780‐31787, 2004.
 317.Rocheleau JV, Piston DW. Chapter 4: Combining microfluidics and quantitative fluorescence microscopy to examine pancreatic islet molecular physiology. Methods Cell Biol 89: 71‐92, 2008.
 318.Rocheleau JV, Remedi MS, Granada B, Head WS, Koster JC, Nichols CG, Piston DW. Critical role of gap junction coupled K(ATP) channel activity for regulated insulin secretion. PLoS Biol 4: e26, 2006.
 319.Rocheleau JV, Walker GM, Head WS, McGuinness OP, Piston DW. Microfluidic glucose stimulation reveals limited coordination of intracellular Ca2+ activity oscillations in pancreatic islets. Proc Natl Acad Sci USA 101: 12899‐12903, 2004.
 320.Rodriguez‐Diaz R, Dando R, Jacques‐Silva MC, Fachado A, Molina J, Abdulreda MH, Ricordi C, Roper SD, Berggren PO, Caicedo A. Alpha cells secrete acetylcholine as a non‐neuronal paracrine signal priming beta cell function in humans. Nat Med 17: 888‐892, 2011.
 321.Rodriguez‐Diaz R, Molano RD, Weitz JR, Abdulreda MH, Berman DM, Leibiger B, Leibiger IB, Kenyon NS, Ricordi C, Pileggi A, Caicedo A, Berggren PO. Paracrine interactions within the pancreatic islet determine the glycemic set point. Cell Metab 27: 549‐558.e4, 2018.
 322.Rodriguez‐Diaz R, Tamayo A, Hara M, Caicedo A. The local paracrine actions of the pancreatic alpha‐cell. Diabetes 69: 550‐558, 2020.
 323.Rondinone CM, Carvalho E, Rahn T, Manganiello VC, Degerman E, Smith UP. Phosphorylation of PDE3B by phosphatidylinositol 3‐kinase associated with the insulin receptor. J Biol Chem 275: 10093‐10098, 2000.
 324.Rorsman P, Ashcroft FM. Pancreatic beta‐cell electrical activity and insulin secretion: Of mice and men. Physiol Rev 98: 117‐214, 2018.
 325.Rorsman P, Berggren P‐O, Bokvist K, Ericson H, Mhler H, Ostenson C‐G, Smith PA. Glucose‐inhibition of glucagon secretion involves activation of GABAA‐receptor chloride channels. Nature 341: 233‐236, 1989.
 326.Rorsman P, Huising MO. The somatostatin‐secreting pancreatic delta‐cell in health and disease. Nat Rev Endocrinol 14: 404‐414, 2018.
 327.Rosario LM, Atwater I, Scott AM. Pulsatile insulin release and electrical activity from single ob/ob mouse islets of Langerhans. Adv Exp Med Biol 211: 413‐425, 1986.
 328.Rouiller DG, Cirulli V, Halban PA. Differences in aggregation properties and levels of the neural cell adhesion molecule (NCAM) between islet cell types. Exp Cell Res 191: 305‐312, 1990.
 329.Rubi B, Ljubicic S, Pournourmohammadi S, Carobbio S, Armanet M, Bartley C, Maechler P. Dopamine D2‐like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion. J Biol Chem 280: 36824‐36832, 2005.
 330.Rutter GA, Hodson DJ. Minireview: Intraislet regulation of insulin secretion in humans. Mol Endocrinol 27: 1984‐1995, 2013.
 331.Ryan EA, Lakey JR, Rajotte RV, Korbutt GS, Kin T, Imes S, Rabinovitch A, Elliott JF, Bigam D, Kneteman NM, Warnock GL, Larsen I, Shapiro AM. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 50: 710‐719, 2001.
 332.Sako Y, Wasada T, Umeda F, Ibayashi H. Effect of glibenclamide on pancreatic hormone release from isolated perifused islets of normal and cysteamine‐treated rats. Metabolism 35: 944‐949, 1986.
 333.Sakurai H, Dobbs R, Unger RH. Somatostatin induced changes in insulin and glucagon secretion in normal and diabetic dogs. J Clin Investig 54: 1395‐1402, 1974.
 334.Salem V, Silva LD, Suba K, Georgiadou E, Neda Mousavy Gharavy S, Akhtar N, Martin‐Alonso A, Gaboriau DCA, Rothery SM, Stylianides T, Carrat G, Pullen TJ, Singh SP, Hodson DJ, Leclerc I, Shapiro AMJ, Marchetti P, Briant LJB, Distaso W, Ninov N, Rutter GA. Leader beta‐cells coordinate Ca(2+) dynamics across pancreatic islets in vivo. Nat Metab 1: 615‐629, 2019.
 335.Salomon D, Meda P. Heterogeneity and contact‐dependent regulation of hormone secretion by individual B cells. Exp Cell Res 162: 507‐520, 1986.
 336.Saltiel AR. Insulin signaling in the control of glucose and lipid homeostasis. Handb Exp Pharmacol 233: ‐51, 71, 2016.
 337.Samols E, Stagner JI, Ewart RBL, Marks V. The order of islet microvascular cellular perfusion is B→A→D in the perfused rat pancreas. J Clin Investig 82: 350‐353, 1988.
 338.Santos RM, Rosario LM, Nadal A, Garcia‐Sancho J, Soria B, Valdeolmillos M. Widespread synchronous [Ca2+]i oscillations due to bursting electrical activity in single pancreatic islets. Pflugers Arch : Eur J Physiol 418: 417‐422, 1991.
 339.Satin LS, Cook DL. Voltage‐gated Ca2+ current in pancreatic B‐cells. Pflugers Arch 404: 385‐387, 1985.
 340.Satin LS, Zhang Q, Rorsman P. “Take me to your leader”: An electrophysiological appraisal of the role of hub cells in pancreatic islets. Diabetes 69: 830‐836, 2020.
 341.Schirra J, Nicolaus M, Woerle HJ, Struckmeier C, Katschinski M, Goke B. GLP‐1 regulates gastroduodenal motility involving cholinergic pathways. Neurogastroenterol Motil 21: 609‐618, e21‐622, 2009.
 342.Schmidt PT, Naslund E, Gryback P, Jacobsson H, Holst JJ, Hilsted L, Hellstrom PM. A role for pancreatic polypeptide in the regulation of gastric emptying and short‐term metabolic control. J Clin Endocrinol Metab 90: 5241‐5246, 2005.
 343.Schou KB, Pedersen LB, Christensen ST. Ins and outs of GPCR signaling in primary cilia. EMBO Rep 16: 1099‐1113, 2015.
 344.Schraenen A, de Faudeur G, Thorrez L, Lemaire K, Van Wichelen G, Granvik M, Van Lommel L, in't Veld P, Schuit F. mRNA expression analysis of cell cycle genes in islets of pregnant mice. Diabetologia 53: 2579‐2588, 2010.
 345.Schuit F, De Vos A, Farfari S, Moens K, Pipeleers D, Brun T, Prentki M. Metabolic fate of glucose in purified islet cells. Glucose‐regulated anaplerosis in beta cells. J Biol Chem 272: 18572‐18579, 1997.
 346.Schuit FC, Derde MP, Pipeleers DG. Sensitivity of rat pancreatic A and B cells to somatostatin. Diabetologia 32: 207‐212, 1989.
 347.Segerstolpe A, Palasantza A, Eliasson P, Andersson EM, Andreasson AC, Sun X, Picelli S, Sabirsh A, Clausen M, Bjursell MK, Smith DM, Kasper M, Ammala C, Sandberg R. Single‐cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab 24: 593‐607, 2016.
 348.Seghers V, Nakazaki M, DeMayo F, Aguilar‐Bryan L, Bryan J. Sur1 knockout mice. A model for K(ATP) channel‐independent regulation of insulin secretion. J Biol Chem 275: 9270‐9277, 2000.
 349.Semino MC, de Gagliardino EE, Gagliardino JJ. Islet cells‐tight junctions: Changes in its number induced by glucose. Acta Physiol Pharmacol Latinoam 37: 533‐539, 1987.
 350.Serre‐Beinier V, Le Gurun S, Belluardo N, Trovato‐Salinaro A, Charollais A, Haefliger JA, Condorelli DF, Meda P. Cx36 preferentially connects beta‐cells within pancreatic islets. Diabetes 49: 727‐734, 2000.
 351.Shah P, Vella A, Basu A, Basu R, Schwenk WF, Rizza RA. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetees mellitus. J Clin Endocrinol Metab 85: 4053‐4059, 2000.
 352.Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Robertson RP, Secchi A, Brendel MD, Berney T, Brennan DC, Cagliero E, Alejandro R, Ryan EA, DiMercurio B, Morel P, Polonsky KS, Reems JA, Bretzel RG, Bertuzzi F, Froud T, Kandaswamy R, Sutherland DE, Eisenbarth G, Segal M, Preiksaitis J, Korbutt GS, Barton FB, Viviano L, Seyfert‐Margolis V, Bluestone J, Lakey JR. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355: 1318‐1330, 2006.
 353.Sharma N, Berbari NF, Yoder BK. Ciliary dysfunction in developmental abnormalities and diseases. Curr Top Dev Biol 85: 371‐427, 2008.
 354.Sherman A, Rinzel J, Keizer J. Emergence of organized bursting in clusters of pancreatic beta‐cells by channel sharing. Biophys J 54: 411‐425, 1988.
 355.Shiota C, Larsson O, Shelton KD, Shiota M, Efanov AM, Hoy M, Lindner J, Kooptiwut S, Juntti‐Berggren L, Gromada J, Berggren PO, Magnuson MA. Sulfonylurea receptor type 1 knock‐out mice have intact feeding‐stimulated insulin secretion despite marked impairment in their response to glucose. J Biol Chem 277: 37176‐37183, 2002.
 356.Short KW, Head WS, Piston DW. Connexin 36 mediates blood cell flow in mouse pancreatic islets. Am J Physiol Endocrinol Metab 306: E324‐E331, 2014.
 357.Simpson N, Maffei A, Freeby M, Burroughs S, Freyberg Z, Javitch J, Leibel RL, Harris PE. Dopamine‐mediated autocrine inhibitory circuit regulating human insulin secretion in vitro. Mol Endocrinol 26: 1757‐1772, 2012.
 358.Singla V, Reiter JF. The primary cilium as the cell's antenna: Signaling at a sensory organelle. Science 313: 629‐633, 2006.
 359.Skaggs BJ, Gorre ME, Ryvkin A, Burgess MR, Xie Y, Han Y, Komisopoulou E, Brown LM, Loo JA, Landaw EM, Sawyers CL, Graeber TG. Phosphorylation of the ATP‐binding loop directs oncogenicity of drug‐resistant BCR‐ABL mutants. Proc Natl Acad Sci USA 103: 19466‐19471, 2006.
 360.Sliwinska‐Mosson M, Marek G, Milnerowicz H. The role of pancreatic polypeptide in pancreatic diseases. Adv Clin Exp Med 26: 1447‐1455, 2017.
 361.Slucca M, Harmon JS, Oseid EA, Bryan J, Robertson RP. ATP‐sensitive K+ channel mediates the zinc switch‐off signal for glucagon response during glucose deprivation. Diabetes 59: 128‐134, 2010.
 362.Smolen P, Rinzel J, Sherman A. Why pancreatic islets burst but single beta cells do not. The heterogeneity hypothesis. Biophys J 64: 1668‐1680, 1993.
 363.Song SH, Kjems L, Ritzel R, McIntyre SM, Johnson ML, Veldhuis JD, Butler PC. Pulsatile insulin secretion by human pancreatic islets. J Clin Endocrinol Metab 87: 213‐221, 2002.
 364.Song SH, McIntyre SS, Shah H, Veldhuis JD, Hayes PC, Butler PC. Direct measurement of pulsatile insulin secretion from the portal vein in human subjects. J Clin Endocrinol Metab 85: 4491‐4499, 2000.
 365.Sorenson RL, Garry DG, Brelje TC. Structural and functional considerations of GABA in islets of Langerhans: Beta‐cells and nerves. Diabetes 40: 1365‐1374, 1991.
 366.Soria B, Andreu E, Berna G, Fuentes E, Gil A, Leon‐Quinto T, Martin F, Montanya E, Nadal A, Reig JA, Ripoll C, Roche E, Sanchez‐Andres JV, Segura J. Engineering pancreatic islets. Pflugers Arch 440: 1‐18, 2000.
 367.Sorrenson B, Cognard E, Lee KL, Dissanayake WC, Fu Y, Han W, Hughes WE, Shepherd PR. A critical role for β‐catenin in modulating levels of insulin secretion from β‐cells by regulating actin cytoskeleton and insulin vesicle localization. J Biol Chem 291: 25888‐25900, 2016.
 368.Speier S, Gjinovci A, Charollais A, Meda P, Rupnik M. Cx36‐mediated coupling reduces beta‐cell heterogeneity, confines the stimulating glucose concentration range, and affects insulin release kinetics. Diabetes 56: 1078‐1086, 2007.
 369.Spigelman AF, Dai X, MacDonald PE. Voltage‐dependent K+ channels are positive regulators of alpha cell action potential generation and glucagon secretion in mice and humans. Diabetologia 53: 1917‐1926, 2010.
 370.St Clair JR, Ramirez D, Passman S, Benninger RKP. Contrast‐enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models. Nat Commun 9: 1742, 2018.
 371.Stagner JI, Samols E. The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41: 93‐97, 1992.
 372.Stagner JI, Samols E, Bonner‐Weir S. Beta→alpha→delta Pancreatic islet cellular perfusion in dogs. Diabetes 37: 1715‐1721, 1988.
 373.Stagner JI, Samols E, Koerker DJ, Goodner CJ. Perfusion with anti‐insulin gamma globulin indicates a B to A to D cellular perfusion sequence in the pancreas of the rhesus monkey, macaca mulatta. Pancreas 7: 26‐29, 1992.
 374.Stefan Y, Meda P, Neufeld M, Orci L. Stimulation of insulin secretion reveals heterogeneity of pancreatic B cells in vivo. J Clin Invest 80: 175‐183, 1987.
 375.Steiner DJ, Kim A, Miller K, Hara M. Pancreatic islet plasticity: Interspecies comparison of islet architecture and composition. Islets 2: 135‐145, 2010.
 376.Strowski MZ, Cashen DE, Birzin ET, Yang L, Singh V, Jacks TM, Nowak KW, Rohrer SP, Patchett AA, Smith RG, Schaeffer JM. Antidiabetic activity of a highly potent and selective nonpeptide somatostatin receptor subtype‐2 agonist. Endocrinology 147: 4664‐4673, 2006.
 377.Strowski MZ, Kohler M, Chen HY, Trumbauer ME, Li Z, Szalkowski D, Gopal‐Truter S, Fisher JK, Schaeffer JM, Blake AD, Zhang BB, Wilkinson HA. Somatostatin receptor subtype 5 regulates insulin secretion and glucose homeostasis. Mol Endocrinol 17: 93‐106, 2003.
 378.Strowski MZ, Parmar RM, Blake AD, Schaeffer JM. Somatostatin inhibits insulin and glucagon secretion via two receptors subtypes: An in vitro study of pancreatic islets from somatostatin receptor 2 knockout mice. Endocrinology 141: 111‐117, 2000.
 379.Svendsen B, Larsen O, Gabe MBN, Christiansen CB, Rosenkilde MM, Drucker DJ, Holst JJ. Insulin secretion depends on intra‐islet glucagon signaling. Cell Rep 25: 1127‐1134.e2, 2018.
 380.Taborsky GJ Jr, Ahren B, Havel PJ. Autonomic mediation of glucagon secretion during hypoglycemia: Implications for impaired alpha‐cell responses in type 1 diabetes. Diabetes 47: 995‐1005, 1998.
 381.Taneera J, Jin Z, Jin Y, Muhammed SJ, Zhang E, Lang S, Salehi A, Korsgren O, Renstrm E, Groop L, Birnir B. Gamma‐aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes. Diabetologia 55: 1985‐1994, 2012.
 382.Tang SC, Jessup CF, Campbell‐Thompson M. The role of accessory cells in islet homeostasis. Curr Diab Rep 18: 117, 2018.
 383.Tang SC, Peng SJ, Chien HJ. Imaging of the islet neural network. Diabetes Obes Metab 16 (Suppl 1): 77‐86, 2014.
 384.Thomas‐Reetz A, Hell JW, During MJ, Walch‐Solimena C, Jahn R, De Camilli P. A gamma‐aminobutyric acid transporter driven by a proton pump is present in synaptic‐like microvesicles of pancreatic beta cells. Proc Natl Acad Sci USA 90: 5317‐5321, 1993.
 385.Thomas‐Reetz AC, De Camilli P. A role for synaptic vesicles in non‐neuronal cells: Clues from pancreatic beta cells and from chromaffin cells. FASEB J 8: 209‐216, 1994.
 386.Tiscornia OM, Negri GA, Otero G, Lopez Mingorance FN, Waisman H, Tiscornia‐Wasserman PG. Pancreatic polypeptide: A review of its involvement in neuro‐endocrine reflexes, islet‐acinar interactions and ethanol‐evoked physiopatologic pancreatic gland changes. Acta Gastroenterol Latinoam 45: 155‐164, 2015.
 387.Tominaga M, Komiya I, Johnson JH, Inman L, Alam T, Moltz J, Crider B, Stefan Y, Baetens D, McCorkle K, Orci L, Unger RH. Loss of insulin response to glucose but not arginine during the development of autoimmune diabetes in BB/W rats: Relationships to islet volume and glucose transport rate. Proc Natl Acad Sci USA 83: 9749‐9753, 1986.
 388.Tong Q, Ouedraogo R, Kirchgessner AL. Localization and function of group III metabotropic glutamate receptors in rat pancreatic islets. Am J Physiol Endocrinol Metab 282: E1324‐E1333, 2002.
 389.Tsuchitani M, Sato J, Kokoshima H. A comparison of the anatomical structure of the pancreas in experimental animals. J Toxicol Pathol 29: 147‐154, 2016.
 390.Tsui H, Razavi R, Chan Y, Yantha J, Dosch HM. ‘Sensing’ autoimmunity in type 1 diabetes. Trends Mol Med 13: 405‐413, 2007.
 391.Uehara S, Muroyama A, Echigo N, Morimoto R, Otsuka M, Yatsushiro S, Moriyama Y. Metabotropic glutamate receptor type 4 is involved in autoinhibitory cascade for glucagon secretion by alpha‐cells of islet of Langerhans. Diabetes 53: 998‐1006, 2004.
 392.Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: A pathophysiologic and therapeutic makeover. J Clin Invest 122: 4‐12, 2012.
 393.Unger RH, Orci L. Physiology and pathophysiology of glucagon. Physiol Rev 56: 778‐826, 1976.
 394.Unger RH, Orci L. Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci USA 107: 16009‐16012, 2010.
 395.Ustione A, Piston DW. Dopamine synthesis and D3 receptor activation in pancreatic beta‐cells regulates insulin secretion and intracellular [Ca(2+)] oscillations. Mol Endocrinol 26: 1928‐1940, 2012.
 396.Ustione A, Piston DW, Harris PE. Minireview: Dopaminergic regulation of insulin secretion from the pancreatic islet. Mol Endocrinol 27: 1198‐1207, 2013.
 397.van der Meulen T, Donaldson CJ, Caceres E, Hunter AE, Cowing‐Zitron C, Pound LD, Adams MW, Zembrzycki A, Grove KL, Huising MO. Urocortin3 mediates somatostatin‐dependent negative feedback control of insulin secretion. Nat Med 21: 769‐776, 2015.
 398.Van Schravendijk CF, Kiekens R, Pipeleers DG. Pancreatic beta cell heterogeneity in glucose‐induced insulin secretion. J Biol Chem 267: 21344‐21348, 1992.
 399.Veedfald S, Plamboeck A, Deacon CF, Hartmann B, Knop FK, Vilsboll T, Holst JJ. Cephalic phase secretion of insulin and other enteropancreatic hormones in humans. Am J Physiol Gastrointest Liver Physiol 310: G43‐G51, 2016.
 400.Veedfald S, Plamboeck A, Hartmann B, Svendsen LB, Vilsboll T, Knop FK, Holst JJ. Pancreatic polypeptide responses to isoglycemic oral and intravenous glucose in humans with and without intact vagal innervation. Peptides 71: 229‐231, 2015.
 401.Veedfald S, Vedtofte L, Skov‐Jeppesen K, Deacon CF, Hartmann B, Vilsboll T, Knop FK, Christensen MB, Holst JJ. Glucose‐dependent insulinotropic polypeptide is a pancreatic polypeptide secretagogue in humans. J Clin Endocrinol Metab 105: dgz097, 2020.
 402.Velazco‐Cruz L, Goedegebuure MM, Millman JR. Advances toward engineering functionally mature human pluripotent stem cell‐derived beta cells. Front Bioeng Biotechnol 8: 786, 2020.
 403.Vieira E, Salehi A, Gylfe E. Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic alpha cells. Diabetologia 50: 370‐379, 2007.
 404.Vierra NC, Dickerson MT, Jordan KL, Dadi PK, Kadare KA, Altman MK, Milian SC, Jacobson DA. TALK‐1 reduces delta‐cell endoplasmic reticulum and cytoplasmic calcium levels limiting somatostatin secretion. Mol Metab 9: 84‐97, 2018.
 405.Volta F, Gerdes JM. The role of primary cilia in obesity and diabetes. Ann N Y Acad Sci 1391: 71‐84, 2017.
 406.Volta F, Scerbo MJ, Seelig A, Wagner R, O'Brien N, Gerst F, Fritsche A, Haring HU, Zeigerer A, Ullrich S, Gerdes JM. Glucose homeostasis is regulated by pancreatic beta‐cell cilia via endosomal EphA‐processing. Nat Commun 10: 5686, 2019.
 407.Wakae‐Takada N, Xuan S, Watanabe K, Meda P, Leibel RL. Molecular basis for the regulation of islet beta cell mass in mice: The role of E‐cadherin. Diabetologia 56: 856‐866, 2013.
 408.Walker JN, Ramracheya R, Zhang Q, Johnson PRV, Braun M, Rorsman P. Regulation of glucagon secretion by glucose: Paracrine, intrinsic or both? Diabetes Obes Metab 13: 95‐105, 2011.
 409.Walker JT, Haliyur R, Nelson HA, Ishahak M, Poffenberger G, Aramandla R, Reihsmann C, Luchsinger JR, Saunders DC, Wang P, Garcia‐Ocana A, Bottino R, Agarwal A, Powers AC, Brissova M. Integrated human pseudoislet system and microfluidic platform demonstrate differences in GPCR signaling in islet cells. JCI Insight 5: e137017, 2020.
 410.Wang M, Li J, Lim GE, Johnson JD. Is dynamic autocrine insulin signaling possible? A mathematical model predicts picomolar concentrations of extracellular monomeric insulin within human pancreatic islets. PLoS One 8: e64860, 2013.
 411.Wang MY, Chen L, Clark GO, Lee Y, Stevens RD, Ilkayeva OR, Wenner BR, Bain JR, Charron MJ, Newgard CB, Unger RH. Leptin therapy in insulin‐deficient type I diabetes. Proc Natl Acad Sci USA 107: 4813‐4819, 2010.
 412.Wang MY, Yan H, Shi Z, Evans MR, Yu X, Lee Y, Chen S, Williams A, Philippe J, Roth MG, Unger RH. Glucagon receptor antibody completely suppresses type 1 diabetes phenotype without insulin by disrupting a novel diabetogenic pathway. Proc Natl Acad Sci USA 112: 2503‐2508, 2015.
 413.Wang Q, Ren L, Wan Y, Prud'homme GJ. GABAergic regulation of pancreatic islet cells: Physiology and antidiabetic effects. J Cell Physiol 234: 14432‐14444, 2019.
 414.Watts M, Sherman A. Modeling the pancreatic alpha‐cell: Dual mechanisms of glucose suppression of glucagon secretion. Biophys J 106: 741‐751, 2014.
 415.Weckbecker G, Lewis I, Albert R, Schmid HA, Hoyer D, Bruns C. Opportunities in somatostatin research: Biological, chemical and therapeutic aspects. Nat Rev Drug Discov 2: 999‐1017, 2003.
 416.Weir GC, Clore ET, Zmachinski CJ, Bonner‐Weir S. Islet secretion in a new experimental model for non‐insulin‐dependent diabetes. Diabetes 30: 590‐595, 1981.
 417.Weir GC, Samols E, Day JA, Patel YC. Glucose and glucagon stimulate the secretion of somatostatin from the perfused canine pancreas. Metabolism 27: 1223‐1226, 1978.
 418.Wendt A, Birnir B, Buschard K, Gromada J, Salehi A, Sewing S, Rorsman P, Braun M. Glucose inhibition of glucagon secretion from rat alpha‐cells is mediated by GABA released from neighboring beta‐cells. Diabetes 53: 1038‐1045, 2004.
 419.Wendt A, Eliasson L. Pancreatic alpha‐cells ‐ the unsung heroes in islet function. Semin Cell Dev Biol 103: 41‐50, 2020.
 420.Westacott MJ, Farnsworth NL, St Clair JR, Poffenberger G, Heintz A, Ludin NW, Hart NJ, Powers AC, Benninger RKP. Age‐dependent decline in the coordinated [Ca(2+)] and insulin secretory dynamics in human pancreatic islets. Diabetes 66: 2436‐2445, 2017.
 421.Westacott MJ, Ludin NWF, Benninger RKP. Spatially organized beta‐cell subpopulations control electrical dynamics across islets of Langerhans. Biophys J 113: 1093‐1108, 2017.
 422.Wheway G, Nazlamova L, Hancock JT. Signaling through the primary cilium. Front Cell Dev Biol 6: 8, 2018.
 423.Xia W, Pessentheiner AR, Hofer DC, Amor M, Schreiber R, Schoiswohl G, Eichmann TO, Walenta E, Itariu B, Prager G, Hackl H, Stulnig T, Kratky D, Rlicke T, Bogner‐Strauss JG. Loss of ABHD15 impairs the anti‐lipolytic action of insulin by altering PDE3B stability and contributes to insulin resistance. Cell Rep 23: 1948‐1961, 2018.
 424.Xin Y, Kim J, Okamoto H, Ni M, Wei Y, Adler C, Murphy AJ, Yancopoulos GD, Lin C, Gromada J. RNA sequencing of single human islet cells reveals type 2 diabetes genes. Cell Metab 24: 608‐615, 2016.
 425.Xu E, Kumar M, Zhang Y, Ju W, Obata T, Zhang N, Liu S, Wendt A, Deng S, Ebina Y, Wheeler MB, Braun M, Wang Q. Intra‐islet insulin suppresses glucagon release via GABA‐GABAA receptor system. Cell Metab 3: 47‐58, 2006.
 426.Xu SFS, Andersen DB, Izarzugaza JMG, Kuhre RE, Holst JJ. In the rat pancreas, somatostatin tonically inhibits glucagon secretion and is required for glucose‐induced inhibition of glucagon secretion. Acta Physiol (Oxf) 229: e13464, 2020.
 427.Yamagata K, Nammo T, Moriwaki M, Ihara A, Iizuka K, Yang Q, Satoh T, Li M, Uenaka R, Okita K, Iwahashi H, Zhu Q, Cao Y, Imagawa A, Tochino Y, Hanafusa T, Miyagawa J‐I, Matsuzawa Y. Overexpression of dominant‐negative mutant hepatocyte nuclear factor‐1α in pancreatic β‐cells causes abnormal islet architecture with decreased expression of E‐cadherin, reduced β‐cell proliferation, and diabetes. Diabetes 51: 114‐123, 2002.
 428.Yamamoto M, Kataoka K. Electron microscopic observation of the primary cilium in the pancreatic islets. Arch Histol Jpn 49: 449‐457, 1986.
 429.Yaney GC, Corkey BE. Fatty acid metabolism and insulin secretion in pancreatic beta cells. Diabetologia 46: 1297‐1312, 2003.
 430.Yoshimoto Y, Fukuyama Y, Horio Y, Inanobe A, Gotoh M, Kurachi Y. Somatostatin induces hyperpolarization in pancreatic islet alpha cells by activating a G protein‐gated K+ channel. FEBS Lett 444: 265‐269, 1999.
 431.Young A. Inhibition of glucagon secretion. Adv Pharmacol 52: 151‐171, 2005.
 432.Yu B‐S, Wang A‐R. Glucagon‐like peptide 1 drugs as second‐line therapy for type 2 diabetes. World J Pediatr 4: 8‐13, 2008.
 433.Yu Q, Lai BK, Ahooghalandari P, Helander A, Gylfe E, Gilon P, Tengholm A. Gamma‐hydroxybutyrate does not mediate glucose inhibition of glucagon secretion. J Biol Chem 295 (16): 5419‐5426, 2020.
 434.Yu Q, Shuai H, Ahooghalandari P, Gylfe E, Tengholm A. Glucose controls glucagon secretion by directly modulating cAMP in alpha cells. Diabetologia 62: 1212‐1224, 2019.
 435.Yu X, Park BH, Wang MY, Wang ZV, Unger RH. Making insulin‐deficient type 1 diabetic rodents thrive without insulin. Proc Natl Acad Sci USA 105: 14070‐14075, 2008.
 436.Yue JTY, Burdett E, Coy DH, Giacca A, Efendic S, Vranic M. Somatostatin receptor type 2 antagonism improves glucagon and corticosterone counterregulatory responses to hypoglycemia in streptozotocin‐induced diabetic rats. Diabetes 61: 197‐207, 2012.
 437.Yue JTY, Riddell MC, Burdett E, Coy DH, Efendic S, Vranic M. Amelioration of hypoglycemia via somatostatin receptor type 2 antagonism in recurrently hypoglycemic diabetic rats. Diabetes 62: 2215‐2222, 2013.
 438.Zawalich WS, Yamazaki H, Zawalich KC, Cline G. Comparative effects of amino acids and glucose on insulin secretion from isolated rat or mouse islets. J Endocrinol 183: 309‐319, 2004.
 439.Zhang M, Fendler B, Peercy B, Goel P, Bertram R, Sherman A, Satin L. Long lasting synchronization of calcium oscillations by cholinergic stimulation in isolated pancreatic islets. Biophys J 95: 4676‐4688, 2008.
 440.Zhang Q, Bengtsson M, Partridge C, Salehi A, Braun M, Cox R, Eliasson L, Johnson PRV, Renstrm E, Schneider T, Berggren P‐O, Gpel S, Ashcroft FM, Rorsman P. R‐type Ca2+‐channel‐evoked CICR regulates glucose‐induced somatostatin secretion. Nat Cell Biol 9: 453‐460, 2007.
 441.Zhang Q, Ramracheya R, Lahmann C, Tarasov A, Bengtsson M, Braha O, Braun M, Brereton M, Collins S, Galvanovskis J, Gonzalez A, Groschner LN, Rorsman NJ, Salehi A, Travers ME, Walker JN, Gloyn AL, Gribble F, Johnson PR, Reimann F, Ashcroft FM, Rorsman P. Role of KATP channels in glucose‐regulated glucagon secretion and impaired counterregulation in type 2 diabetes. Cell Metab 18: 871‐882, 2013.
 442.Zhao L, Wang L, Aierken R, Wang W, Wang X, Li M. Characterization of insulin and glucagon genes and their producing endocrine cells from pygmy sperm whale (Kogia breviceps). Front Endocrinol (Lausanne) 11: 174, 2020.
 443.Zhou H, Tran POT, Yang S, Zhang T, LeRoy E, Oseid E, Robertson RP. Regulation of alpha‐cell function by the beta‐cell during hypoglycemia in wistar rats: The switch‐off hypothesis. Diabetes 53: 1482‐1487, 2004.
 444.Zhou H, Zhang T, Harmon JS, Bryan J, Robertson RP. Zinc, not insulin, regulates the rat alpha‐cell response to hypoglycemia in vivo. Diabetes 56: 1107‐1112, 2007.

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Article Title: Intercellular Communication in the Islet of Langerhans in Health and Disease
 

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Xue W. Ng, Yong H. Chung, David W. Piston. Intercellular Communication in the Islet of Langerhans in Health and Disease. Compr Physiol 2021, 11: 2191-2225. doi: 10.1002/cphy.c200026