Skip to main content

Advertisement

Springer Nature Link
Log in

Beta cell connectivity in pancreatic islets: a type 2 diabetes target?

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

An Author Correction to this article was published on 15 February 2018

This article has been updated

Abstract

Beta cell connectivity describes the phenomenon whereby the islet context improves insulin secretion by providing a three-dimensional platform for intercellular signaling processes. Thus, the precise flow of information through homotypically interconnected beta cells leads to the large-scale organization of hormone release activities, influencing cell responses to glucose and other secretagogues. Although a phenomenon whose importance has arguably been underappreciated in islet biology until recently, a growing number of studies suggest that such cell–cell communication is a fundamental property of this micro-organ. Hence, connectivity may plausibly be targeted by both environmental and genetic factors in type 2 diabetes mellitus (T2DM) to perturb normal beta cell function and insulin release. Here, we review the mechanisms that contribute to beta cell connectivity, discuss how these may fail during T2DM, and examine approaches to restore insulin secretion by boosting cell communication.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Change history

  • 15 February 2018

    The original version of this article unfortunately contained a mistake. Legends of Figures 1 and 2 were interchanged. The correct versions are given below.

Abbreviations

AC:

Adenyl cyclase

ACh:

Acetylcholine

ADP:

Adenosine diphosphate

ATP:

Adenosine triphosphate

cAMP:

Cyclic adenosine monophosphate

Cx36:

Connexin 36

Epac:

Exchange protein activated by cAMP

fMCI:

Functional multicellular calcium imaging

GABA:

Gamma aminobutyric acid

GIP:

Glucose-dependent insulinotropic polypeptide

GJ:

Gap junction

GLP-1:

Glucagon-like peptide-1

GWAS:

Genome-wide association studies

GPCR:

G protein-coupled receptor

KATP :

ATP-sensitive K+ channel

SST:

Somatostatin

SNP:

Single nucleotide polymorphism

T2DM:

Type 2 diabetes mellitus

VDCC:

Voltage-dependent Ca2+-channel

References

  1. International Diabetes Federation (2013) IDF Diabetes Atlas, 6th edn. International Diabetes Federation, Brussels, Belgium

  2. Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52(9):1766–1777. doi:10.1007/s00125-009-1440-6

    Article  CAS  PubMed  Google Scholar 

  3. Stitt AW (2010) AGEs and diabetic retinopathy. Invest Ophthalmol Vis Sci 51(10):4867–4874. doi:10.1167/iovs.10-5881

    Article  PubMed  Google Scholar 

  4. van de Bunt M, Gloyn AL (2012) A tale of two glucose transporters: how GLUT2 re-emerged as a contender for glucose transport into the human beta cell. Diabetologia 55(9):2312–2315. doi:10.1007/s00125-012-2612-3

    Article  CAS  PubMed  Google Scholar 

  5. Iynedjian PB (1993) Mammalian glucokinase and its gene. Biochem J 293(Pt 1):1–13

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Prentki M, Matschinsky FM, Madiraju SR (2013) Metabolic signaling in fuel-induced insulin secretion. Cell Metab 18(2):162–185. doi:10.1016/j.cmet.2013.05.018

    Article  CAS  PubMed  Google Scholar 

  7. Rutter GA (2001) Nutrient-secretion coupling in the pancreatic islet beta-cell: recent advances. Mol Aspects Med 22(6):247–284

    Article  CAS  PubMed  Google Scholar 

  8. Tarasov AI, Semplici F, Ravier MA, Bellomo EA, Pullen TJ, Gilon P, Sekler I, Rizzuto R, Rutter GA (2012) The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic beta-cells. PLoS ONE 7(7):e39722. doi:10.1371/journal.pone.0039722

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Kennedy HJ, Pouli AE, Ainscow EK, Jouaville LS, Rizzuto R, Rutter GA (1999) Glucose generates sub-plasma membrane ATP microdomains in single islet beta-cells. Potential role for strategically located mitochondria. J Biol Chem 274(19):13281–13291

    Article  CAS  PubMed  Google Scholar 

  10. Ashcroft FM, Harrison DE, Ashcroft SJ (1984) Glucose induces closure of single potassium channels in isolated rat pancreatic beta-cells. Nature 312(5993):446–448

    Article  CAS  PubMed  Google Scholar 

  11. Ashcroft FM, Gribble FM (1999) ATP-sensitive K+ channels and insulin secretion: their role in health and disease. Diabetologia 42(8):903–919. doi:10.1007/s001250051247

    Article  CAS  PubMed  Google Scholar 

  12. Ammala C, Ashcroft FM, Rorsman P (1993) Calcium-independent potentiation of insulin release by cyclic AMP in single beta-cells. Nature 363(6427):356–358. doi:10.1038/363356a0

    Article  CAS  PubMed  Google Scholar 

  13. Henquin JC (2000) Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49(11):1751–1760

    Article  CAS  PubMed  Google Scholar 

  14. Rutter GA, Tsuboi T, Ravier MA (2006) Ca2+ microdomains and the control of insulin secretion. Cell Calcium 40(5–6):539–551. doi:10.1016/j.ceca.2006.08.015

    Article  CAS  PubMed  Google Scholar 

  15. Emmanouilidou E, Teschemacher AG, Pouli AE, Nicholls LI, Seward EP, Rutter GA (1999) Imaging Ca2+ concentration changes at the secretory vesicle surface with a recombinant targeted cameleon. Curr Biol 9(16):915–918

    Article  CAS  PubMed  Google Scholar 

  16. Tsuboi T, Rutter GA (2003) Multiple forms of “kiss-and-run” exocytosis revealed by evanescent wave microscopy. Curr Biol 13(7):563–567

    Article  CAS  PubMed  Google Scholar 

  17. Rutter GA, Varadi A, Tsuboi T, Parton L, Ravier M (2006) Insulin secretion in health and disease: genomics, proteomics and single vesicle dynamics. Biochem Soc Trans 34(Pt 2):247–250. doi:10.1042/BST20060247

    Article  CAS  PubMed  Google Scholar 

  18. Serre-Beinier V, Mas C, Calabrese A, Caton D, Bauquis J, Caille D, Charollais A, Cirulli V, Meda P (2002) Connexins and secretion. Biol Cell 94(7–8):477–492 S0248490002000242

    Article  CAS  PubMed  Google Scholar 

  19. Bavamian S, Klee P, Britan A, Populaire C, Caille D, Cancela J, Charollais A, Meda P (2007) Islet-cell-to-cell communication as basis for normal insulin secretion. Diabetes Obes Metab 9(Suppl 2):118–132. doi:10.1111/j.1463-1326.2007.00780.x

    Article  CAS  PubMed  Google Scholar 

  20. Bosco D, Haefliger JA, Meda P (2011) Connexins: key mediators of endocrine function. Physiol Rev 91(4):1393–1445. doi:10.1152/physrev.00027.2010

    Article  CAS  PubMed  Google Scholar 

  21. Meda P (2013) Protein-mediated interactions of pancreatic islet cells. Scientifica (Cairo) 2013:621249. doi:10.1155/2013/621249

    Google Scholar 

  22. Farnsworth NL, Benninger RK (2014) New insights into the role of connexins in pancreatic islet function and diabetes. FEBS Lett 588(8):1278–1287. doi:10.1016/j.febslet.2014.02.035

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Salomon D, Meda P (1986) Heterogeneity and contact-dependent regulation of hormone secretion by individual B cells. Exp Cell Res 162(2):507–520

    Article  CAS  PubMed  Google Scholar 

  24. Caton D, Calabrese A, Mas C, Serre-Beinier V, Wonkam A, Meda P (2002) Beta-cell crosstalk: a further dimension in the stimulus-secretion coupling of glucose-induced insulin release. Diabetes Metab 28(6 Pt 2):3S45–3S53 discussion 43S108-112

    CAS  PubMed  Google Scholar 

  25. Steiner DJ, Kim A, Miller K, Hara M (2010) Pancreatic islet plasticity: interspecies comparison of islet architecture and composition. Islets 2(3):135–145

    Article  PubMed Central  PubMed  Google Scholar 

  26. Hodson DJ, Mitchell RK, Marselli L, Pullen TJ, Brias SG, Semplici F, Everett KL, Cooper DM, Bugliani M, Marchetti P, Lavallard V, Bosco D, Piemonti L, Johnson PR, Hughes SJ, Li D, Li WH, Shapiro AM, Rutter GA (2014) ADCY5 couples glucose to insulin secretion in human islets. Diabetes. doi:10.2337/db13-1607

    PubMed Central  PubMed  Google Scholar 

  27. 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 (2013) Lipotoxicity disrupts incretin-regulated human beta cell connectivity. J Clin Invest 123(10):4182–4194. doi:10.1172/JCI68459

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Rutter GA, Hodson DJ (2013) Minireview: intraislet regulation of insulin secretion in humans. Mol Endocrinol 27(12):1984–1995. doi:10.1210/me.2013-1278

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Stozer A, Gosak M, Dolensek J, Perc M, Marhl M, Rupnik MS, Korosak D (2013) Functional connectivity in islets of Langerhans from mouse pancreas tissue slices. PLoS Comput Biol 9(2):e1002923. doi:10.1371/journal.pcbi.1002923

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Stozer A, Dolensek J, Rupnik MS (2013) Glucose-stimulated calcium dynamics in islets of Langerhans in acute mouse pancreas tissue slices. PLoS ONE 8(1):e54638. doi:10.1371/journal.pone.0054638

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Benninger RK, Piston DW (2014) Cellular communication and heterogeneity in pancreatic islet insulin secretion dynamics. Trends Endocrinol Metab. doi:10.1016/j.tem.2014.02.005

    PubMed Central  PubMed  Google Scholar 

  32. Orci L, Unger RH (1975) Functional subdivision of islets of Langerhans and possible role of D cells. Lancet 2(7947):1243–1244

    Article  CAS  PubMed  Google Scholar 

  33. Cabrera O, Berman DM, Kenyon NS, Ricordi C, Berggren PO, Caicedo A (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci USA 103(7):2334–2339. doi:10.1073/pnas.0510790103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  34. Nyman LR, Wells KS, Head WS, McCaughey M, Ford E, Brissova M, Piston DW, Powers AC (2008) Real-time, multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets. J Clin Invest 118(11):3790–3797. doi:10.1172/JCI36209

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Cleaver O, Dor Y (2012) Vascular instruction of pancreas development. Development 139(16):2833–2843. doi:10.1242/dev.065953

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Brissova M, Fowler MJ, Nicholson WE, Chu A, Hirshberg B, Harlan DM, Powers AC (2005) Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 53(9):1087–1097. doi:10.1369/jhc.5C6684.2005

    Article  CAS  PubMed  Google Scholar 

  37. Bosco D, Armanet M, Morel P, Niclauss N, Sgroi A, Muller YD, Giovannoni L, Parnaud G, Berney T (2010) Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59(5):1202–1210. doi:10.2337/db09-1177

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Kilimnik G, Zhao B, Jo J, Periwal V, Witkowski P, Misawa R, Hara M (2011) Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes. PLoS ONE 6(11):e27445. doi:10.1371/journal.pone.0027445

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Halban PA, Wollheim CB, Blondel B, Meda P, Niesor EN, Mintz DH (1982) The possible importance of contact between pancreatic islet cells for the control of insulin release. Endocrinology 111(1):86–94. doi:10.1210/endo-111-1-86

    Article  CAS  PubMed  Google Scholar 

  40. Hauge-Evans AC, Squires PE, Persaud SJ, Jones PM (1999) Pancreatic beta-cell-to-beta-cell interactions are required for integrated responses to nutrient stimuli: enhanced Ca2+ and insulin secretory responses of MIN6 pseudoislets. Diabetes 48(7):1402–1408

    Article  CAS  PubMed  Google Scholar 

  41. Squires PE, Hauge-Evans AC, Persaud SJ, Jones PM (2000) Synchronization of Ca(2+)-signals within insulin-secreting pseudoislets: effects of gap-junctional uncouplers. Cell Calcium 27(5):287–296. doi:10.1054/ceca.2000.0117

    Article  CAS  PubMed  Google Scholar 

  42. Hodson DJ, Molino F, Fontanaud P, Bonnefont X, Mollard P (2010) Investigating and Modelling Pituitary Endocrine Network Function. J Neuroendocrinol 22:1217–1225. doi:10.1111/j.1365-2826.2010.02052.x

    Article  CAS  PubMed  Google Scholar 

  43. Takahashi N, Kishimoto T, Nemoto T, Kadowaki T, Kasai H (2002) Fusion pore dynamics and insulin granule exocytosis in the pancreatic islet. Science 297(5585):1349–1352. doi:10.1126/science.1073806

    Article  CAS  PubMed  Google Scholar 

  44. Li D, Chen S, Bellomo EA, Tarasov AI, Kaut C, Rutter GA, Li WH (2011) Imaging dynamic insulin release using a fluorescent zinc indicator for monitoring induced exocytotic release (ZIMIR). Proc Natl Acad Sci USA 108(52):21063–21068. doi:10.1073/pnas.1109773109

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Low JT, Mitchell JM, Do OH, Bax J, Rawlings A, Zavortink M, Morgan G, Parton RG, Gaisano HY, Thorn P (2013) Glucose principally regulates insulin secretion in mouse islets by controlling the numbers of granule fusion events per cell. Diabetologia 56(12):2629–2637. doi:10.1007/s00125-013-3019-5

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Pancholi J, Hodson DJ, Jobe K, Rutter GA, Goldup SM, Watkinson M (2014) Biologically targeted probes for Zn2+: a diversity oriented modular “click-SNAr-click” approach. Chem Sci. doi:10.1039/c4sc01249f

    PubMed Central  PubMed  Google Scholar 

  47. Akemann W, Mutoh H, Perron A, Rossier J, Knopfel T (2010) Imaging brain electric signals with genetically targeted voltage-sensitive fluorescent proteins. Nat Methods 7(8):643–649. doi:10.1038/nmeth.1479

    Article  CAS  PubMed  Google Scholar 

  48. Hodson DJ, Romano N, Schaeffer M, Fontanaud P, Lafont C, Fiordelisio T, Mollard P (2012) Coordination of calcium signals by pituitary endocrine cells in situ. Cell Calcium 51(3–4):222–230. doi:10.1016/j.ceca.2011.11.007

    Article  CAS  PubMed  Google Scholar 

  49. Dolensek J, Stozer A, Skelin Klemen M, Miller EW, Slak Rupnik M (2013) The relationship between membrane potential and calcium dynamics in glucose-stimulated beta cell syncytium in acute mouse pancreas tissue slices. PLoS ONE 8(12):e82374. doi:10.1371/journal.pone.0082374

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Schlegel W, Winiger BP, Mollard P, Vacher P, Wuarin F, Zahnd GR, Wollheim CB, Dufy B (1987) Oscillations of cytosolic Ca2+ in pituitary cells due to action potentials. Nature 329(6141):719–721. doi:10.1038/329719a0

    Article  CAS  PubMed  Google Scholar 

  51. Peterlin ZA, Kozloski J, Mao BQ, Tsiola A, Yuste R (2000) Optical probing of neuronal circuits with calcium indicators. Proc Natl Acad Sci USA 97(7):3619–3624

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  52. Cossart R, Ikegaya Y, Yuste R (2005) Calcium imaging of cortical networks dynamics. Cell Calcium 37(5):451–457. doi:10.1016/j.ceca.2005.01.013

    Article  CAS  PubMed  Google Scholar 

  53. Ikegaya Y, Le Bon-Jego M, Yuste R (2005) Large-scale imaging of cortical network activity with calcium indicators. Neurosci Res 52(2):132–138. doi:10.1016/j.neures.2005.02.004

    Article  CAS  PubMed  Google Scholar 

  54. Hodson DJ, Schaeffer M, Romano N, Fontanaud P, Lafont C, Birkenstock J, Molino F, Christian H, Lockey J, Carmignac D, Fernandez-Fuente M, Le Tissier P, Mollard P (2012) Existence of long-lasting experience-dependent plasticity in endocrine cell networks. Nature Commun 3:605. doi:10.1038/ncomms1612

    Article  CAS  Google Scholar 

  55. Hodson DJ, Tarasov AI, Gimeno Brias S, Mitchell RK, Johnston NR, Haghollahi S, Cane MC, Bugliani M, Marchetti P, Bosco D, Johnson PR, Hughes SJ, Rutter GA (2014) Incretin-modulated beta cell energetics in intact islets of Langerhans. Mol Endocrinol 28(6):860–871. doi:10.1210/me.2014-1038

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Alon U (2007) Network motifs: theory and experimental approaches. Nat Rev Genet 8(6):450–461. doi:10.1038/nrg2102

    Article  CAS  PubMed  Google Scholar 

  57. Bullmore E, Sporns O (2009) Complex brain networks: graph theoretical analysis of structural and functional systems. Nat Rev Neurosci 10(3):186–198. doi:10.1038/nrn2575

    Article  CAS  PubMed  Google Scholar 

  58. Price DJ (1965) Networks of Scientific Papers. Science 149:510–515

    Article  CAS  PubMed  Google Scholar 

  59. Barabasi AL, Albert R (1999) Emergence of scaling in random networks. Science 286(5439):509–512

    Article  CAS  PubMed  Google Scholar 

  60. Barabasi AL (2009) Scale-free networks: a decade and beyond. Science 325(5939):412–413. doi:10.1126/science.1173299

    Article  CAS  PubMed  Google Scholar 

  61. Bonifazi P, Goldin M, Picardo MA, Jorquera I, Cattani A, Bianconi G, Represa A, Ben-Ari Y, Cossart R (2009) GABAergic hub neurons orchestrate synchrony in developing hippocampal networks. Science 326(5958):1419–1424. doi:10.1126/science.1175509

    Article  CAS  PubMed  Google Scholar 

  62. Mollard P, Hodson DJ, Lafont C, Rizzoti K, Drouin J (2012) A tridimensional view of pituitary development and function. Trends Endocrinol Metab. doi:10.1016/j.tem.2012.02.004

    PubMed  Google Scholar 

  63. Le Tissier PR, Hodson DJ, Lafont C, Fontanaud P, Schaeffer M, Mollard P (2012) Anterior pituitary cell networks. Front Neuroendocrinol 33(3):252–266. doi:10.1016/j.yfrne.2012.08.002

    Article  CAS  PubMed  Google Scholar 

  64. Caicedo A (2013) Paracrine and autocrine interactions in the human islet: more than meets the eye. Semin Cell Dev Biol 24(1):11–21. doi:10.1016/j.semcdb.2012.09.007

    Article  CAS  PubMed  Google Scholar 

  65. Serre-Beinier V, Le Gurun S, Belluardo N, Trovato-Salinaro A, Charollais A, Haefliger JA, Condorelli DF, Meda P (2000) Cx36 preferentially connects beta-cells within pancreatic islets. Diabetes 49(5):727–734

    Article  CAS  PubMed  Google Scholar 

  66. Condorelli DF, Belluardo N, Trovato-Salinaro A, Mudo G (2000) Expression of Cx36 in mammalian neurons. Brain Res Brain Res Rev 32(1):72–85 S0165017399000685

    Article  CAS  PubMed  Google Scholar 

  67. Charpantier E, Cancela J, Meda P (2007) Beta cells preferentially exchange cationic molecules via connexin 36 gap junction channels. Diabetologia 50(11):2332–2341. doi:10.1007/s00125-007-0807-9

    Article  CAS  PubMed  Google Scholar 

  68. Ravier MA, Guldenagel M, Charollais A, Gjinovci A, Caille D, Sohl G, Wollheim CB, Willecke K, Henquin JC, Meda P (2005) Loss of connexin36 channels alters beta-cell coupling, islet synchronization of glucose-induced Ca2+ and insulin oscillations, and basal insulin release. Diabetes 54(6):1798–1807

    Article  CAS  PubMed  Google Scholar 

  69. Speier S, Gjinovci A, Charollais A, Meda P, Rupnik M (2007) Cx36-mediated coupling reduces beta-cell heterogeneity, confines the stimulating glucose concentration range, and affects insulin release kinetics. Diabetes 56(4):1078–1086. doi:10.2337/db06-0232

    Article  CAS  PubMed  Google Scholar 

  70. Rocheleau JV, Remedi MS, Granada B, Head WS, Koster JC, Nichols CG, Piston DW (2006) Critical role of gap junction coupled KATP channel activity for regulated insulin secretion. PLoS Biol 4(2):e26 05-PLBI-RA-0819R2

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Head WS, Orseth ML, Nunemaker CS, Satin LS, Piston DW, Benninger RK (2012) Connexin-36 gap junctions regulate in vivo first- and second-phase insulin secretion dynamics and glucose tolerance in the conscious mouse. Diabetes 61(7):1700–1707. doi:10.2337/db11-1312

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  72. Serre-Beinier V, Bosco D, Zulianello L, Charollais A, Caille D, Charpantier E, Gauthier BR, Diaferia GR, Giepmans BN, Lupi R, Marchetti P, Deng S, Buhler L, Berney T, Cirulli V, Meda P (2009) Cx36 makes channels coupling human pancreatic beta-cells, and correlates with insulin expression. Hum Mol Genet 18(3):428–439. doi:10.1093/hmg/ddn370

    Article  CAS  PubMed  Google Scholar 

  73. Farnsworth NL, Hemmati A, Pozzoli M, Benninger RK (2014) Fluorescence recovery after photobleaching reveals regulation and distribution of Cx36 gap junction coupling within mouse islets of langerhans. J Physiol. doi:10.1113/jphysiol.2014.276733

    PubMed Central  PubMed  Google Scholar 

  74. Ahren B (2000) Autonomic regulation of islet hormone secretion–implications for health and disease. Diabetologia 43(4):393–410. doi:10.1007/s001250051322

    Article  CAS  PubMed  Google Scholar 

  75. Zhang M, Fendler B, Peercy B, Goel P, Bertram R, Sherman A, Satin L (2008) Long lasting synchronization of calcium oscillations by cholinergic stimulation in isolated pancreatic islets. Biophys J 95(10):4676–4688. doi:10.1529/biophysj.107.125088

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  76. Fendler B, Zhang M, Satin L, Bertram R (2009) Synchronization of pancreatic islet oscillations by intrapancreatic ganglia: a modeling study. Biophys J 97(3):722–729. doi:10.1016/j.bpj.2009.05.016

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Ahren B, Holst JJ (2001) The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia. Diabetes 50(5):1030–1038

    Article  CAS  PubMed  Google Scholar 

  78. Filipsson K, Kvist-Reimer M, Ahren B (2001) The neuropeptide pituitary adenylate cyclase-activating polypeptide and islet function. Diabetes 50(9):1959–1969

    Article  CAS  PubMed  Google Scholar 

  79. Kurose T, Seino Y, Nishi S, Tsuji K, Taminato T, Tsuda K, Imura H (1990) Mechanism of sympathetic neural regulation of insulin, somatostatin, and glucagon secretion. Am J Physiol 258(1 Pt 1):E220–E227

    CAS  PubMed  Google Scholar 

  80. Nilsson T, Arkhammar P, Rorsman P, Berggren PO (1988) Inhibition of glucose-stimulated insulin release by alpha 2-adrenoceptor activation is parallelled by both a repolarization and a reduction in cytoplasmic free Ca2+ concentration. J Biol Chem 263(4):1855–1860

    CAS  PubMed  Google Scholar 

  81. Kuo WN, Hodgins DS, Kuo JF (1973) Adenylate cyclase in islets of Langerhans. Isolation of islets and regulation of adenylate cyclase activity by various hormones and agents. J Biol Chem 248(8):2705–2711

    CAS  PubMed  Google Scholar 

  82. Asensio C, Jimenez M, Kuhne F, Rohner-Jeanrenaud F, Muzzin P (2005) The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes 54(12):3490–3495

    Article  CAS  PubMed  Google Scholar 

  83. Rodriguez-Diaz R, Abdulreda MH, Formoso AL, Gans I, Ricordi C, Berggren PO, Caicedo A (2011) Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab 14(1):45–54. doi:10.1016/j.cmet.2011.05.008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Rodriguez-Diaz R, Dando R, Jacques-Silva MC, Fachado A, Molina J, Abdulreda MH, Ricordi C, Roper SD, Berggren PO, Caicedo A (2011) Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat Med 17(7):888–892. doi:10.1038/nm.2371

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Molina J, Rodriguez-Diaz R, Fachado A, Jacques-Silva MC, Berggren PO, Caicedo A (2014) control of insulin secretion by cholinergic signaling in the human pancreatic islet. Diabetes. doi:10.2337/db13-1371

    PubMed Central  Google Scholar 

  86. Martin F, Soria B (1996) Glucose-induced [Ca2+]i oscillations in single human pancreatic islets. Cell Calcium 20(5):409–414

    Article  CAS  PubMed  Google Scholar 

  87. diIorio P, Rittenhouse AR, Bortell R, Jurczyk A (2014) Role of cilia in normal pancreas function and in diseased states. Birth Defects Res C Embryo Today 102(2):126–138. doi:10.1002/bdrc.21064

    Article  CAS  PubMed  Google Scholar 

  88. Oh EC, Katsanis N (2012) Cilia in vertebrate development and disease. Development 139(3):443–448. doi:10.1242/dev.050054

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Cano DA, Sekine S, Hebrok M (2006) Primary cilia deletion in pancreatic epithelial cells results in cyst formation and pancreatitis. Gastroenterology 131(6):1856–1869. doi:10.1053/j.gastro.2006.10.050

    Article  CAS  PubMed  Google Scholar 

  90. Ait-Lounis A, Baas D, Barras E, Benadiba C, Charollais A, Nlend Nlend R, Liegeois D, Meda P, Durand B, Reith W (2007) Novel function of the ciliogenic transcription factor RFX3 in development of the endocrine pancreas. Diabetes 56(4):950–959. doi:10.2337/db06-1187

    Article  CAS  PubMed  Google Scholar 

  91. Granot Z, Swisa A, Magenheim J, Stolovich-Rain M, Fujimoto W, Manduchi E, Miki T, Lennerz JK, Stoeckert CJ Jr, Meyuhas O, Seino S, Permutt MA, Piwnica-Worms H, Bardeesy N, Dor Y (2009) LKB1 regulates pancreatic beta cell size, polarity, and function. Cell Metab 10(4):296–308. doi:10.1016/j.cmet.2009.08.010

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  92. Green JA, Mykytyn K (2014) Neuronal primary cilia: an underappreciated signaling and sensory organelle in the brain. Neuropsychopharmacology 39(1):244–245. doi:10.1038/npp.2013.203

    Article  CAS  PubMed  Google Scholar 

  93. Wang J, Silva M, Haas LA, Morsci NS, Nguyen KC, Hall DH, Barr MM (2014) C. elegans ciliated sensory neurons release extracellular vesicles that function in animal communication. Curr Biol 24(5):519–525. doi:10.1016/j.cub.2014.01.002

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  94. Yang YH, Szabat M, Bragagnini C, Kott K, Helgason CD, Hoffman BG, Johnson JD (2011) Paracrine signalling loops in adult human and mouse pancreatic islets: netrins modulate beta cell apoptosis signalling via dependence receptors. Diabetologia 54(4):828–842. doi:10.1007/s00125-010-2012-5

    Article  CAS  PubMed  Google Scholar 

  95. Ren J, Sherman A, Bertram R, Goforth PB, Nunemaker CS, Waters CD, Satin LS (2013) Slow oscillations of KATP conductance in mouse pancreatic islets provide support for electrical bursting driven by metabolic oscillations. Am J Physiol Endocrinol Metab 305(7):E805–E817. doi:10.1152/ajpendo.00046.2013

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  96. Merrins MJ, Fendler B, Zhang M, Sherman A, Bertram R, Satin LS (2010) Metabolic oscillations in pancreatic islets depend on the intracellular Ca2+ level but not Ca2+ oscillations. Biophys J 99(1):76–84. doi:10.1016/j.bpj.2010.04.012

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  97. Nunemaker CS, Satin LS (2004) Comparison of metabolic oscillations from mouse pancreatic beta cells and islets. Endocrine 25(1):61–67. doi:10.1385/ENDO:25:1:61

    Article  CAS  PubMed  Google Scholar 

  98. Li J, Shuai HY, Gylfe E, Tengholm A (2013) Oscillations of sub-membrane ATP in glucose-stimulated beta cells depend on negative feedback from Ca(2+). Diabetologia 56(7):1577–1586. doi:10.1007/s00125-013-2894-0

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  99. Bennett BD, Jetton TL, Ying G, Magnuson MA, Piston DW (1996) Quantitative subcellular imaging of glucose metabolism within intact pancreatic islets. J Biol Chem 271(7):3647–3651

    Article  CAS  PubMed  Google Scholar 

  100. Piston DW, Knobel SM (1999) Quantitative imaging of metabolism by two-photon excitation microscopy. Methods Enzymol 307:351–368

    Article  CAS  PubMed  Google Scholar 

  101. Nunemaker CS, Dishinger JF, Dula SB, Wu R, Merrins MJ, Reid KR, Sherman A, Kennedy RT, Satin LS (2009) Glucose metabolism, islet architecture, and genetic homogeneity in imprinting of [Ca2+](i) and insulin rhythms in mouse islets. PLoS ONE 4(12):e8428. doi:10.1371/journal.pone.0008428

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  102. Kohen E, Kohen C, Thorell B, Mintz DH, Rabinovitch A (1979) Intercellular communication in pancreatic islet monolayer cultures: a microfluorometric study. Science 204(4395):862–865

    Article  CAS  PubMed  Google Scholar 

  103. Meda P, Amherdt M, Perrelet A, Orci L (1981) Metabolic coupling between cultured pancreatic b-cells. Exp Cell Res 133(2):421–430

    Article  CAS  PubMed  Google Scholar 

  104. Reimann F, Gribble FM (2002) Glucose-sensing in glucagon-like peptide-1-secreting cells. Diabetes 51(9):2757–2763

    Article  CAS  PubMed  Google Scholar 

  105. Tolhurst G, Reimann F, Gribble FM (2009) Nutritional regulation of glucagon-like peptide-1 secretion. J Physiol 587(Pt 1):27–32. doi:10.1113/jphysiol.2008.164012

    Article  CAS  PubMed  Google Scholar 

  106. Parker HE, Wallis K, le Roux CW, Wong KY, Reimann F, Gribble FM (2012) Molecular mechanisms underlying bile acid-stimulated glucagon-like peptide-1 secretion. Br J Pharmacol 165(2):414–423. doi:10.1111/j.1476-5381.2011.01561.x

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  107. Gomez E, Pritchard C, Herbert TP (2002) cAMP-dependent protein kinase and Ca2+ influx through L-type voltage-gated calcium channels mediate Raf-independent activation of extracellular regulated kinase in response to glucagon-like peptide-1 in pancreatic beta-cells. J Biol Chem 277(50):48146–48151. doi:10.1074/jbc.M209165200

    Article  CAS  PubMed  Google Scholar 

  108. Leech CA, Dzhura I, Chepurny OG, Kang G, Schwede F, Genieser HG, Holz GG (2011) Molecular physiology of glucagon-like peptide-1 insulin secretagogue action in pancreatic beta cells. Prog Biophys Mol Biol 107(2):236–247. doi:10.1016/j.pbiomolbio.2011.07.005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  109. Ravier MA, Leduc M, Richard J, Linck N, Varrault A, Pirot N, Roussel MM, Bockaert J, Dalle S, Bertrand G (2013) beta-Arrestin2 plays a key role in the modulation of the pancreatic beta cell mass in mice. Diabetologia. doi:10.1007/s00125-013-3130-7

    PubMed  Google Scholar 

  110. Tsuboi T, da Xavier Silva G, Holz GG, Jouaville LS, Thomas AP, Rutter GA (2003) Glucagon-like peptide-1 mobilizes intracellular Ca2+ and stimulates mitochondrial ATP synthesis in pancreatic MIN6 beta-cells. Biochem J 369(Pt 2):287–299. doi:10.1042/BJ20021288

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  111. Peyot ML, Gray JP, Lamontagne J, Smith PJ, Holz GG, Madiraju SR, Prentki M, Heart E (2009) Glucagon-like peptide-1 induced signaling and insulin secretion do not drive fuel and energy metabolism in primary rodent pancreatic beta-cells. PLoS ONE 4(7):e6221. doi:10.1371/journal.pone.0006221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  112. Berg J, Hung YP, Yellen G (2009) A genetically encoded fluorescent reporter of ATP:ADP ratio. Nat Methods 6(2):161–166. doi:10.1038/nmeth.1288

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  113. Hodson DJ, Mitchell RK, Johnston N, Thorens B, Ferrer J, Rutter GA (2014) Optical control of beta cell function. Diabet Med 31:6

    Article  Google Scholar 

  114. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, Creutzfeldt W (1986) Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab 63(2):492–498. doi:10.1210/jcem-63-2-492

    Article  CAS  PubMed  Google Scholar 

  115. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W (1993) Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 91(1):301–307. doi:10.1172/JCI116186

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  116. Kjems LL, Holst JJ, Volund A, Madsbad S (2003) The influence of GLP-1 on glucose-stimulated insulin secretion: effects on beta-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52(2):380–386

    Article  CAS  PubMed  Google Scholar 

  117. Meier JJ, Nauck MA (2010) Is the diminished incretin effect in type 2 diabetes just an epi-phenomenon of impaired beta-cell function? Diabetes 59(5):1117–1125. doi:10.2337/db09-1899

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  118. Muscelli E, Mari A, Casolaro A, Camastra S, Seghieri G, Gastaldelli A, Holst JJ, Ferrannini E (2008) Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes 57(5):1340–1348. doi:10.2337/db07-1315

    Article  CAS  PubMed  Google Scholar 

  119. Knop FK, Aaboe K, Vilsboll T, Volund A, Holst JJ, Krarup T, Madsbad S (2012) Impaired incretin effect and fasting hyperglucagonaemia characterizing type 2 diabetic subjects are early signs of dysmetabolism in obesity. Diabetes Obes Metab 14(6):500–510. doi:10.1111/j.1463-1326.2011.01549.x

    Article  CAS  PubMed  Google Scholar 

  120. Allagnat F, Alonso F, Martin D, Abderrahmani A, Waeber G, Haefliger JA (2008) ICER-1gamma overexpression drives palmitate-mediated connexin36 down-regulation in insulin-secreting cells. J Biol Chem 283(9):5226–5234. doi:10.1074/jbc.M708181200

    Article  CAS  PubMed  Google Scholar 

  121. Haefliger JA, Martin D, Favre D, Petremand Y, Mazzolai L, Abderrahmani A, Meda P, Waeber G, Allagnat F (2013) Reduction of connexin36 content by ICER-1 contributes to insulin-secreting cells apoptosis induced by oxidized LDL particles. PLoS ONE 8(1):e55198. doi:10.1371/journal.pone.0055198

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  122. Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, Friedman GD (1987) Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia 30(10):763–768

    Article  CAS  PubMed  Google Scholar 

  123. Pierce M, Keen H, Bradley C (1995) Risk of diabetes in offspring of parents with non-insulin-dependent diabetes. Diabet Med 12(1):6–13. doi:10.1111/j.1464-5491.1995.tb02054.x

    Article  CAS  PubMed  Google Scholar 

  124. Medici F, Hawa M, Ianari A, Pyke DA, Leslie RD (1999) Concordance rate for type II diabetes mellitus in monozygotic twins: actuarial analysis. Diabetologia 42(2):146–150. doi:10.1007/s001250051132

    Article  CAS  PubMed  Google Scholar 

  125. Rutter GA (2014) Understanding genes identified by genome-wide association studies for type 2 diabetes. Diabet Med. doi:10.1111/dme.12579

    PubMed  Google Scholar 

  126. McCarthy MI (2010) Genomics, type 2 diabetes, and obesity. N Engl J Med 363(24):2339–2350. doi:10.1056/NEJMra0906948

    Article  CAS  PubMed  Google Scholar 

  127. Lyssenko V, Lupi R, Marchetti P, Del Guerra S, Orho-Melander M, Almgren P, Sjogren M, Ling C, Eriksson KF, Lethagen AL, Mancarella R, Berglund G, Tuomi T, Nilsson P, Del Prato S, Groop L (2007) Mechanisms by which common variants in the TCF7L2 gene increase risk of type 2 diabetes. J Clin Invest 117(8):2155–2163. doi:10.1172/JCI30706

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  128. Salonen JT, Uimari P, Aalto JM, Pirskanen M, Kaikkonen J, Todorova B, Hypponen J, Korhonen VP, Asikainen J, Devine C, Tuomainen TP, Luedemann J, Nauck M, Kerner W, Stephens RH, New JP, Ollier WE, Gibson JM, Payton A, Horan MA, Pendleton N, Mahoney W, Meyre D, Delplanque J, Froguel P, Luzzatto O, Yakir B, Darvasi A (2007) Type 2 diabetes whole-genome association study in four populations: the DiaGen consortium. Am J Hum Genet 81(2):338–345. doi:10.1086/520599

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  129. Vaxillaire M, Veslot J, Dina C, Proenca C, Cauchi S, Charpentier G, Tichet J, Fumeron F, Marre M, Meyre D, Balkau B, Froguel P (2008) Impact of common type 2 diabetes risk polymorphisms in the DESIR prospective study. Diabetes 57(1):244–254. doi:10.2337/db07-0615

    Article  CAS  PubMed  Google Scholar 

  130. Palmer ND, Lehtinen AB, Langefeld CD, Campbell JK, Haffner SM, Norris JM, Bergman RN, Goodarzi MO, Rotter JI, Bowden DW (2008) Association of TCF7L2 gene polymorphisms with reduced acute insulin response in Hispanic Americans. J Clin Endocrinol Metab 93(1):304–309. doi:10.1210/jc.2007-1225

    Article  CAS  PubMed  Google Scholar 

  131. Schafer SA, Tschritter O, Machicao F, Thamer C, Stefan N, Gallwitz B, Holst JJ, Dekker JM, t Hart LM, Nijpels G, van Haeften TW, Haring HU, Fritsche A (2007) Impaired glucagon-like peptide-1-induced insulin secretion in carriers of transcription factor 7-like 2 (TCF7L2) gene polymorphisms. Diabetologia 50(12):2443–2450. doi:10.1007/s00125-007-0753-6

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  132. Pilgaard K, Jensen CB, Schou JH, Lyssenko V, Wegner L, Brons C, Vilsboll T, Hansen T, Madsbad S, Holst JJ, Volund A, Poulsen P, Groop L, Pedersen O, Vaag AA (2009) The T allele of rs7903146 TCF7L2 is associated with impaired insulinotropic action of incretin hormones, reduced 24 h profiles of plasma insulin and glucagon, and increased hepatic glucose production in young healthy men. Diabetologia 52(7):1298–1307. doi:10.1007/s00125-009-1307-x

    Article  CAS  PubMed  Google Scholar 

  133. da Silva Xavier G, Loder MK, McDonald A, Tarasov AI, Carzaniga R, Kronenberger K, Barg S, Rutter GA (2009) TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells. Diabetes 58(4):894–905. doi:10.2337/db08-1187

    Article  CAS  Google Scholar 

  134. Shu L, Sauter NS, Schulthess FT, Matveyenko AV, Oberholzer J, Maedler K (2008) Transcription factor 7-like 2 regulates beta-cell survival and function in human pancreatic islets. Diabetes 57(3):645–653. doi:10.2337/db07-0847

    Article  CAS  PubMed  Google Scholar 

  135. da Silva Xavier G, Mondragon A, Sun G, Chen L, McGinty JA, French PM, Rutter GA (2012) Abnormal glucose tolerance and insulin secretion in pancreas-specific Tcf7l2-null mice. Diabetologia 55(10):2667–2676. doi:10.1007/s00125-012-2600-7

    Article  CAS  Google Scholar 

  136. da Silva Xavier G, Mondragon A, Mitchell RK, Hodson DJ, Ferrer J, Thoren B, Chen L, McGinty JA, French PM, Rutter GA (2014) Defective glucose homeostasis in mice inactivated selectively for Tcf7l2 in the adult beta cell with an Ins1-controlled Cre. In: EASD, Vienna. Diabetologia. http://www.easdvirtualmeeting.org/resources/17180 (in press)

  137. Boj SF, van Es JH, Huch M, Li VS, Jose A, Hatzis P, Mokry M, Haegebarth A, van den Born M, Chambon P, Voshol P, Dor Y, Cuppen E, Fillat C, Clevers H (2012) Diabetes risk gene and Wnt effector Tcf7l2/TCF4 controls hepatic response to perinatal and adult metabolic demand. Cell 151(7):1595–1607. doi:10.1016/j.cell.2012.10.053

    Article  CAS  PubMed  Google Scholar 

  138. Shu L, Matveyenko AV, Kerr-Conte J, Cho JH, McIntosh CH, Maedler K (2009) Decreased TCF7L2 protein levels in type 2 diabetes mellitus correlate with downregulation of GIP- and GLP-1 receptors and impaired beta-cell function. Hum Mol Genet 18(13):2388–2399. doi:10.1093/hmg/ddp178

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  139. Rosengren AH, Braun M, Mahdi T, Andersson SA, Travers ME, Shigeto M, Zhang E, Almgren P, Ladenvall C, Axelsson AS, Edlund A, Pedersen MG, Jonsson A, Ramracheya R, Tang Y, Walker JN, Barrett A, Johnson PR, Lyssenko V, McCarthy MI, Groop L, Salehi A, Gloyn AL, Renstrom E, Rorsman P, Eliasson L (2012) Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type 2 diabetes. Diabetes 61(7):1726–1733. doi:10.2337/db11-1516

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  140. Loder MK, da Silva Xavier G, McDonald A, Rutter GA (2008) TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic beta-cells. Biochem Soc Trans 36(Pt 3):357–359. doi:10.1042/BST0360357

    Article  CAS  PubMed  Google Scholar 

  141. Zhou Y, Park SY, Su J, Bailey K, Ottosson-Laakso E, Shcherbina L, Oskolkov N, Zhang E, Thevenin T, Fadista J, Bennet H, Vikman P, Wierup N, Fex M, Rung J, Wollheim C, Nobrega M, Renstrom E, Groop L, Hansson O (2014) TCF7L2 is a master regulator of insulin production and processing. Hum Mol Genet. doi:10.1093/hmg/ddu359

    Google Scholar 

  142. Yoshimura M, Cooper DM (1992) Cloning and expression of a Ca(2+)-inhibitable adenylyl cyclase from NCB-20 cells. Proc Natl Acad Sci USA 89(15):6716–6720

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  143. Yan L, Vatner DE, O’Connor JP, Ivessa A, Ge H, Chen W, Hirotani S, Ishikawa Y, Sadoshima J, Vatner SF (2007) Type 5 adenylyl cyclase disruption increases longevity and protects against stress. Cell 130(2):247–258. doi:10.1016/j.cell.2007.05.038

    Article  CAS  PubMed  Google Scholar 

  144. Holz GG, Leech CA, Chepurny OG (2014) New insights concerning the molecular basis for defective glucoregulation in soluble adenylyl cyclase knockout mice. Biochim Biophys Acta. doi:10.1016/j.bbadis.2014.06.023

    PubMed Central  Google Scholar 

  145. Leech CA, Castonguay MA, Habener JF (1999) Expression of adenylyl cyclase subtypes in pancreatic beta-cells. Biochem Biophys Res Commun 254(3):703–706. doi:10.1006/bbrc.1998.9906

    Article  CAS  PubMed  Google Scholar 

  146. Dupuis J, Langenberg C, Prokopenko I, Saxena R, Soranzo N, Jackson AU, Wheeler E, Glazer NL, Bouatia-Naji N, Gloyn AL, Lindgren CM, Magi R, Morris AP, Randall J, Johnson T, Elliott P, Rybin D, Thorleifsson G, Steinthorsdottir V, Henneman P, Grallert H, Dehghan A, Hottenga JJ, Franklin CS, Navarro P, Song K, Goel A, Perry JR, Egan JM, Lajunen T, Grarup N, Sparso T, Doney A, Voight BF, Stringham HM, Li M, Kanoni S, Shrader P, Cavalcanti-Proenca C, Kumari M, Qi L, Timpson NJ, Gieger C, Zabena C, Rocheleau G, Ingelsson E, An P, O’Connell J, Luan J, Elliott A, McCarroll SA, Payne F, Roccasecca RM, Pattou F, Sethupathy P, Ardlie K, Ariyurek Y, Balkau B, Barter P, Beilby JP, Ben-Shlomo Y, Benediktsson R, Bennett AJ, Bergmann S, Bochud M, Boerwinkle E, Bonnefond A, Bonnycastle LL, Borch-Johnsen K, Bottcher Y, Brunner E, Bumpstead SJ, Charpentier G, Chen YD, Chines P, Clarke R, Coin LJ, Cooper MN, Cornelis M, Crawford G, Crisponi L, Day IN, de Geus EJ, Delplanque J, Dina C, Erdos MR, Fedson AC, Fischer-Rosinsky A, Forouhi NG, Fox CS, Frants R, Franzosi MG, Galan P, Goodarzi MO, Graessler J, Groves CJ, Grundy S, Gwilliam R, Gyllensten U, Hadjadj S, Hallmans G, Hammond N, Han X, Hartikainen AL, Hassanali N, Hayward C, Heath SC, Hercberg S, Herder C, Hicks AA, Hillman DR, Hingorani AD, Hofman A, Hui J, Hung J, Isomaa B, Johnson PR, Jorgensen T, Jula A, Kaakinen M, Kaprio J, Kesaniemi YA, Kivimaki M, Knight B, Koskinen S, Kovacs P, Kyvik KO, Lathrop GM, Lawlor DA, Le Bacquer O, Lecoeur C, Li Y, Lyssenko V, Mahley R, Mangino M, Manning AK, Martinez-Larrad MT, McAteer JB, McCulloch LJ, McPherson R, Meisinger C, Melzer D, Meyre D, Mitchell BD, Morken MA, Mukherjee S, Naitza S, Narisu N, Neville MJ, Oostra BA, Orru M, Pakyz R, Palmer CN, Paolisso G, Pattaro C, Pearson D, Peden JF, Pedersen NL, Perola M, Pfeiffer AF, Pichler I, Polasek O, Posthuma D, Potter SC, Pouta A, Province MA, Psaty BM, Rathmann W, Rayner NW, Rice K, Ripatti S, Rivadeneira F, Roden M, Rolandsson O, Sandbaek A, Sandhu M, Sanna S, Sayer AA, Scheet P, Scott LJ, Seedorf U, Sharp SJ, Shields B, Sigurethsson G, Sijbrands EJ, Silveira A, Simpson L, Singleton A, Smith NL, Sovio U, Swift A, Syddall H, Syvanen AC, Tanaka T, Thorand B, Tichet J, Tonjes A, Tuomi T, Uitterlinden AG, van Dijk KW, van Hoek M, Varma D, Visvikis-Siest S, Vitart V, Vogelzangs N, Waeber G, Wagner PJ, Walley A, Walters GB, Ward KL, Watkins H, Weedon MN, Wild SH, Willemsen G, Witteman JC, Yarnell JW, Zeggini E, Zelenika D, Zethelius B, Zhai G, Zhao JH, Zillikens MC, Borecki IB, Loos RJ, Meneton P, Magnusson PK, Nathan DM, Williams GH, Hattersley AT, Silander K, Salomaa V, Smith GD, Bornstein SR, Schwarz P, Spranger J, Karpe F, Shuldiner AR, Cooper C, Dedoussis GV, Serrano-Rios M, Morris AD, Lind L, Palmer LJ, Hu FB, Franks PW, Ebrahim S, Marmot M, Kao WH, Pankow JS, Sampson MJ, Kuusisto J, Laakso M, Hansen T, Pedersen O, Pramstaller PP, Wichmann HE, Illig T, Rudan I, Wright AF, Stumvoll M, Campbell H, Wilson JF, Bergman RN, Buchanan TA, Collins FS, Mohlke KL, Tuomilehto J, Valle TT, Altshuler D, Rotter JI, Siscovick DS, Penninx BW, Boomsma DI, Deloukas P, Spector TD, Frayling TM, Ferrucci L, Kong A, Thorsteinsdottir U, Stefansson K, van Duijn CM, Aulchenko YS, Cao A, Scuteri A, Schlessinger D, Uda M, Ruokonen A, Jarvelin MR, Waterworth DM, Vollenweider P, Peltonen L, Mooser V, Abecasis GR, Wareham NJ, Sladek R, Froguel P, Watanabe RM, Meigs JB, Groop L, Boehnke M, McCarthy MI, Florez JC, Barroso I (2010) New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 42(2):105–116. doi:10.1038/ng.520

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  147. Rees SD, Hydrie MZ, O’Hare JP, Kumar S, Shera AS, Basit A, Barnett AH, Kelly MA (2011) Effects of 16 genetic variants on fasting glucose and type 2 diabetes in South Asians: ADCY5 and GLIS3 variants may predispose to type 2 diabetes. PLoS ONE 6(9):e24710. doi:10.1371/journal.pone.0024710

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  148. Hodson DJ, Mitchell RK, Marselli L, Pullen TJ, Gimeno Brias S, Semplici F, Everett KL, Cooper DMF, Bugliani M, Marchetti P, Lavallard V, Bosco D, Piemonti L, Johnson PR, Hughes SJ, Li D, Li WH, Shapiro AMJ, Rutter GA (2014) ADCY5 couples glucose to insulin secretion in human islets Diabetes. (in press)

  149. Wagner R, Dudziak K, Herzberg-Schafer SA, Machicao F, Stefan N, Staiger H, Haring HU, Fritsche A (2011) Glucose-raising genetic variants in MADD and ADCY5 impair conversion of proinsulin to insulin. PLoS ONE 6(8):e23639. doi:10.1371/journal.pone.0023639

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  150. Mears D, Sheppard NF Jr, Atwater I, Rojas E (1995) Magnitude and modulation of pancreatic beta-cell gap junction electrical conductance in situ. J Membr Biol 146(2):163–176

    Article  CAS  PubMed  Google Scholar 

  151. Lemaire K, Ravier MA, Schraenen A, Creemers JW, Van de Plas R, Granvik M, Van Lommel L, Waelkens E, Chimienti F, Rutter GA, Gilon P, in’t Veld PA, Schuit FC (2009) Insulin crystallization depends on zinc transporter ZnT8 expression, but is not required for normal glucose homeostasis in mice. Proc Natl Acad Sci USA 106(35):14872–14877. doi:10.1073/pnas.0906587106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  152. Nicolson TJ, Bellomo EA, Wijesekara N, Loder MK, Baldwin JM, Gyulkhandanyan AV, Koshkin V, Tarasov AI, Carzaniga R, Kronenberger K, Taneja TK, da Silva Xavier G, Libert S, Froguel P, Scharfmann R, Stetsyuk V, Ravassard P, Parker H, Gribble FM, Reimann F, Sladek R, Hughes SJ, Johnson PR, Masseboeuf M, Burcelin R, Baldwin SA, Liu M, Lara-Lemus R, Arvan P, Schuit FC, Wheeler MB, Chimienti F, Rutter GA (2009) Insulin storage and glucose homeostasis in mice null for the granule zinc transporter ZnT8 and studies of the type 2 diabetes-associated variants. Diabetes 58(9):2070–2083. doi:10.2337/db09-0551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  153. Wijesekara N, Dai FF, Hardy AB, Giglou PR, Bhattacharjee A, Koshkin V, Chimienti F, Gaisano HY, Rutter GA, Wheeler MB (2010) Beta cell-specific ZnT8 deletion in mice causes marked defects in insulin processing, crystallisation and secretion. Diabetologia 53(8):1656–1668. doi:10.1007/s00125-010-1733-9

    Article  CAS  PubMed  Google Scholar 

  154. Rutter GA (2010) Think zinc: new roles for zinc in the control of insulin secretion. Islets 2(1):49–50. doi:10.4161/isl.2.1.10259

    Article  PubMed  Google Scholar 

  155. Tamaki M, Fujitani Y, Hara A, Uchida T, Tamura Y, Takeno K, Kawaguchi M, Watanabe T, Ogihara T, Fukunaka A, Shimizu T, Mita T, Kanazawa A, Imaizumi MO, Abe T, Kiyonari H, Hojyo S, Fukada T, Kawauchi T, Nagamatsu S, Hirano T, Kawamori R, Watada H (2013) The diabetes-susceptible gene SLC30A8/ZnT8 regulates hepatic insulin clearance. J Clin Invest 123(10):4513–4524. doi:10.1172/JCI68807

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  156. Flannick J, Thorleifsson G, Beer NL, Jacobs SB, Grarup N, Burtt NP, Mahajan A, Fuchsberger C, Atzmon G, Benediktsson R, Blangero J, Bowden DW, Brandslund I, Brosnan J, Burslem F, Chambers J, Cho YS, Christensen C, Douglas DA, Duggirala R, Dymek Z, Farjoun Y, Fennell T, Fontanillas P, Forsen T, Gabriel S, Glaser B, Gudbjartsson DF, Hanis C, Hansen T, Hreidarsson AB, Hveem K, Ingelsson E, Isomaa B, Johansson S, Jorgensen T, Jorgensen ME, Kathiresan S, Kong A, Kooner J, Kravic J, Laakso M, Lee JY, Lind L, Lindgren CM, Linneberg A, Masson G, Meitinger T, Mohlke KL, Molven A, Morris AP, Potluri S, Rauramaa R, Ribel-Madsen R, Richard AM, Rolph T, Salomaa V, Segre AV, Skarstrand H, Steinthorsdottir V, Stringham HM, Sulem P, Tai ES, Teo YY, Teslovich T, Thorsteinsdottir U, Trimmer JK, Tuomi T, Tuomilehto J, Vaziri-Sani F, Voight BF, Wilson JG, Boehnke M, McCarthy MI, Njolstad PR, Pedersen O, Groop L, Cox DR, Stefansson K, Altshuler D (2014) Loss-of-function mutations in SLC30A8 protect against type 2 diabetes. Nat Genet 46(4):357–363. doi:10.1038/ng.2915

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  157. Gerber PA, Bellomo EA, Hodson DJ, Meur G, Solomou A, Mitchell RK, Hollinshead M, Chimienti F, Bosco D, Hughes SJ, Johnson PR, Rutter GA (2014) Hypoxia lowers SLC30A8/ZnT8 expression and free cytosolic Zn2+ in pancreatic beta cells. Diabetologia. doi:10.1007/s00125-014-3266-0

    PubMed Central  PubMed  Google Scholar 

  158. Sun Z, Zhang DQ, McMahon DG (2009) Zinc modulation of hemi-gap-junction channel currents in retinal horizontal cells. J Neurophysiol 101(4):1774–1780. doi:10.1152/jn.90581.2008

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  159. Lurtz MM, Louis CF (2007) Intracellular calcium regulation of connexin43. Am J Physiol Cell Physiol 293(6):C1806–C1813. doi:10.1152/ajpcell.00630.2006

    Article  CAS  PubMed  Google Scholar 

  160. Bavamian S, Pontes H, Cancela J, Charollais A, Startchik S, Van de Ville D, Meda P (2012) The intercellular synchronization of Ca2+ oscillations evaluates Cx36-dependent coupling. PLoS ONE 7(7):e41535. doi:10.1371/journal.pone.0041535

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  161. Amisten S, Salehi A, Rorsman P, Jones PM, Persaud SJ (2013) An atlas and functional analysis of G-protein coupled receptors in human islets of Langerhans. Pharmacol Ther 139(3):359–391. doi:10.1016/j.pharmthera.2013.05.004

    Article  CAS  PubMed  Google Scholar 

  162. Zhou K, Pearson ER (2013) Insights from genome-wide association studies of drug response. Annu Rev Pharmacol Toxicol 53:299–310. doi:10.1146/annurev-pharmtox-011112-140237

    Article  CAS  PubMed  Google Scholar 

  163. Meda P, Michaels RL, Halban PA, Orci L, Sheridan JD (1983) In vivo modulation of gap junctions and dye coupling between B-cells of the intact pancreatic islet. Diabetes 32(9):858–868

    Article  CAS  PubMed  Google Scholar 

  164. Donnelly LA, Doney ASF, Hattersley AT, Morris AD, Pearson ER (2006) The effect of obesity on glycaemic response to metformin or sulphonylureas in type 2 diabetes. Diabet Med 23(2):128–133. doi:10.1111/j.1464-5491.2005.01755.x

    Article  CAS  PubMed  Google Scholar 

  165. Kim S, Putrino D, Ghosh S, Brown EN (2011) A Granger causality measure for point process models of ensemble neural spiking activity. PLoS Comput Biol 7(3):e1001110. doi:10.1371/journal.pcbi.1001110

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

The writing of this review article was supported by a Diabetes UK R.D. Lawrence Research Fellowship (12/0004431) to D.J.H. and Wellcome Trust Senior Investigator (WT098424AIA), MRC Programme (MR/J0003042/1), Diabetes UK Project Grant (11/0004210) and Royal Society Wolfson Research Merit Awards to G.A.R. The work leading to this publication has received support from the Innovative Medicines Initiative Joint Undertaking under grant agreement n° 155005 (IMIDIA), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in-kind contribution (G.A.R.). Lastly, we thank Miss Maria Paiva Pessoa for assistance with the figures.

Conflict of interest

The authors have nothing to disclose.

Author information

Authors and Affiliations

  1. Section of Cell Biology, Department of Medicine, Imperial College London, Imperial Centre for Translational and Experimental Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Guy A. Rutter & David J. Hodson

Authors
  1. Guy A. Rutter
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. David J. Hodson
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Guy A. Rutter.

Additional information

A correction to this article is available online at https://doi.org/10.1007/s00018-018-2767-2.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rutter, G.A., Hodson, D.J. Beta cell connectivity in pancreatic islets: a type 2 diabetes target?. Cell. Mol. Life Sci. 72, 453–467 (2015). https://doi.org/10.1007/s00018-014-1755-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-014-1755-4

Keywords