New insights into the architecture of the islet of Langerhans: a focused cross-species assessment

Diabetologia

Volumn 58, Issue 10, 2015, Pages 2218-2228

  Arrojo e Drigo, Rafael ^a   Ali, Yusuf ^a   Diez, Juan ^a   Srinivasan, Dinesh Kumar ^a   Berggren, Per Olof ^a,b,c   Boehm, Bernhard O ^a,b,d  

^a NANYANG TECHNOLOGICAL UNIVERSITY   (Singapore)

^b IMPERIAL COLLEGE LONDON   (United Kingdom)

^c KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

^d UNIVERSITY HOSPITAL ULM   (Germany)

Author keywords

Cross species assessment; Intra islet signalling; Islet cell architecture; Islets of Langerhans; Non human primates; Review

Indexed keywords

4 AMINOBUTYRIC ACID; ACETYLCHOLINE; ADENOSINE TRIPHOSPHATE; GLUCAGON; GLUTAMIC ACID; INSULIN; SOMATOSTATIN;

CELL STRUCTURE; CROSS BREEDING; CYTOARCHITECTURE; HUMAN; INSULIN DEPENDENT DIABETES MELLITUS; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS ISLET; PANCREAS ISLET CELL; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; ANATOMY AND HISTOLOGY; ANIMAL; PHYSIOLOGY; SPECIES DIFFERENCE;

ANIMALS; HUMANS; ISLETS OF LANGERHANS; SPECIES SPECIFICITY;

EID: 84942197026     PISSN: 0012186X     EISSN: 14320428     Source Type: Journal    
DOI: 10.1007/s00125-015-3699-0     Document Type: Review

References (138)

1. Sullivan LH (1896) The tall office building artistically considered. Lippincotts Mag 57:403–409
2. Langerhans P (1869) Beitraege zur mikroskopischen Anatomie der Bauchspeicheldruese. Friedrich-Wilhelm-Universitaet zu Berlin, Inaugural Dissertation (in German)
3. Laguesse É (1893) Sur la formation des ilots de Langerhans dans le pancreas. Compt Rend Soc Biol 5:819–820 (in French)
4. Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110
5. de Koning EJ, Bodkin NL, Hansen BC, Clark A (1993) Diabetes mellitus in Macaca mulatta monkeys is characterised by islet amyloidosis and reduction in beta-cell population. Diabetologia 36:378–384
6. Willcox A, Richardson SJ, Bone AJ, Foulis AK, Morgan NG (2010) Evidence of increased islet cell proliferation in patients with recent-onset type 1 diabetes. Diabetologia 53:2020–2028
7. Nyman LR, Ford E, Powers AC, Piston DW (2010) Glucose-dependent blood flow dynamics in murine pancreatic islets in vivo. Am J Physiol Endocrinol Metab 298:E807–E814
8. Rodriguez-Diaz R, Abdulreda MH, Formoso AL et al (2011) Innervation patterns of autonomic axons in the human endocrine pancreas. Cell Metab 14:45–54
9. Suckale J, Solimena M (2010) The insulin secretory granule as a signaling hub. Trends Endocrinol Metab 21:599–609
10. Rutter GA, Hodson DJ (2013) Minireview: intraislet regulation of insulin secretion in humans. Mol Endocrinol 27:1984–1995
11. Speier S, Nyqvist D, Cabrera O et al (2008) Noninvasive in vivo imaging of pancreatic islet cell biology. Nat Med 14:574–578
12. Unger RH, Orci L (2010) Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci U S A 107:16009–16012
13. Fiori JL, Shin YK, Kim W et al (2013) Resveratrol prevents beta-cell dedifferentiation in nonhuman primates given a high-fat/high-sugar diet. Diabetes 62:3500–3513
14. 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 U S A 103:2334–2339
15. Stewart AF (2014) Betatrophin versus bitter-trophin and the elephant in the room: time for a new normal in beta-cell regeneration research. Diabetes 63:1198–1199
16. Reed JC, Herold KC (2015) Thinking bedside at the bench: the NOD mouse model of T1DM. Nat Rev Endocrinol 11:308–314
17. Rodriguez-Diaz R, Dando R, Jacques-Silva MC et al (2011) Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat Med 17:888–892
18. Kim A, Miller K, Jo J, Kilimnik G, Wojcik P, Hara M (2009) Islet architecture: a comparative study. Islets 1:129–136
19. Seok J, Warren HS, Cuenca AG et al (2013) Genomic responses in mouse models poorly mimic human inflammatory diseases. Proc Natl Acad Sci U S A 110:3507–3512
20. Westermark P, Andersson A, Westermark GT (2011) Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiol Rev 91:795–826
21. Mezza T, Kulkarni RN (2014) The regulation of pre- and post-maturational plasticity of mammalian islet cell mass. Diabetologia 57:1291–1303
22. Wang P, Medarova Z, Moore A (2011) Molecular imaging: a promising tool to monitor islet transplantation. J Transl 2011:202915
23. Leibiger IB, Caicedo A, Berggren PO (2012) Non-invasive in vivo imaging of pancreatic beta-cell function and survival – a perspective. Acta Physiol 204:178–185
24. Brissova M, Fowler MJ, Nicholson WE et al (2005) Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem: Off J Histochem Soc 53:1087–1097
25. Andralojc KM, Mercalli A, Nowak KW et al (2009) Ghrelin-producing epsilon cells in the developing and adult human pancreas. Diabetologia 52:486–493
26. Wang X, Zielinski MC, Misawa R et al (2013) Quantitative analysis of pancreatic polypeptide cell distribution in the human pancreas. PLoS One 8:e55501
27. Rodriguez-Diaz R, Caicedo A (2014) Neural control of the endocrine pancreas. Best Pract Res Clin Endocrinol Metab 28:745–756
28. Westwell-Roper CY, Ehses JA, Verchere CB (2014) Resident macrophages mediate islet amyloid polypeptide-induced islet IL-1β production and β-cell dysfunction. Diabetes 63:1698–1711
29. Bonner-Weir S, Orci L (1982) New perspectives on the microvasculature of the islets of Langerhans in the rat. Diabetes 31:883–889
30. Donath MY, Burcelin R (2013) GLP-1 effects on islets: hormonal, neuronal, or paracrine? Diabetes Care 36(Suppl 2):S145–S148
31. Lammert E, Cleaver O, Melton D (2001) Induction of pancreatic differentiation by signals from blood vessels. Science 294:564–567
32. Lammert E, Gu G, McLaughlin M et al (2003) Role of VEGF-A in vascularization of pancreatic islets. Curr Biol: CB 13:1070–1074
33. Gorden DL, Mandriota SJ, Montesano R, Orci L, Pepper MS (1997) Vascular endothelial growth factor is increased in devascularized rat islets of Langerhans in vitro. Transplantation 63:436–443
34. Samols E, Stagner JI, Ewart RB, Marks V (1988) The order of islet microvascular cellular perfusion is B–A–D in the perfused rat pancreas. J Clin Invest 82:350–353
35. Olsson R, Carlsson PO (2011) A low-oxygenated subpopulation of pancreatic islets constitutes a functional reserve of endocrine cells. Diabetes 60:2068–2075
36. Lau J, Svensson J, Grapensparr L, Johansson A, Carlsson PO (2012) Superior beta cell proliferation, function and gene expression in a subpopulation of rat islets identified by high blood perfusion. Diabetologia 55:1390–1399
37. Almaca J, Molina J, Arrojo EDR et al (2014) Young capillary vessels rejuvenate aged pancreatic islets. Proc Natl Acad Sci U S A 111:17612–17617
38. Meissner HP (1976) Electrophysiological evidence for coupling between beta cells of pancreatic islets. Nature 262:502–504
39. 2+ and insulin oscillations, and basal insulin release. Diabetes 54:1798–1807
40. Kilimnik G, Jo J, Periwal V, Zielinski MC, Hara M (2012) Quantification of islet size and architecture. Islets 4:167–172
41. Wang X, Misawa R, Zielinski MC et al (2013) Regional differences in islet distribution in the human pancreas – preferential beta-cell loss in the head region in patients with type 2 diabetes. PLoS One 8:e67454
42. Bonner-Weir S, Sullivan BA, Weir GC (2015) Human islet morphology revisited: human and rodent islets are not so different after all. J Histochem Cytochem. doi:10.1369/0022155415570969
43. Bosco D, Armanet M, Morel P et al (2010) Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59:1202–1210
44. Meier JJ, Kohler CU, Alkhatib B et al (2010) Beta-cell development and turnover during prenatal life in humans. Eur J Endocrinol Eur Fed Endocr Soc 162:559–568
45. Gregg BE, Moore PC, Demozay D et al (2012) Formation of a human beta-cell population within pancreatic islets is set early in life. J Clin Endocrinol Metab 97:3197–3206
46. In’t Veld P, Lammert E (2015) The dark side of islet vasculature. Diabetologia 58:4–6
47. Stagner JI, Samols E (1992) The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41:93–97
48. Stagner JI, Samols E, Koerker DJ, Goodner CJ (1992) 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
49. Virtanen I, Banerjee M, Palgi J et al (2008) Blood vessels of human islets of Langerhans are surrounded by a double basement membrane. Diabetologia 51:1181–1191
50. Stozer A, Gosak M, Dolensek J et al (2013) Functional connectivity in islets of Langerhans from mouse pancreas tissue slices. PLoS Comput Biol 9:e1002923
51. Schaeffer M, Hodson DJ, Lafont C, Mollard P (2011) Endocrine cells and blood vessels work in tandem to generate hormone pulses. J Mol Endocrinol 47:R59–R66
52. 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 63:2714–2726
53. Cabrera O, Jacques-Silva MC, Speier S et al (2008) Glutamate is a positive autocrine signal for glucagon release. Cell Metab 7:545–554
54. 3 receptors constitute a positive autocrine signal for insulin release in the human pancreatic beta cell. Proc Natl Acad Sci U S A 107:6465–6470
55. Fernandez-Alvarez J, Hillaire-Buys D, Loubatières-Mariani MM, Gomis R, Petit P (2001) P2 receptor agonists stimulate insulin release from human pancreatic islets. Pancreas 22:69–71
56. Purwana I, Zheng J, Li X et al (2014) GABA promotes human beta-cell proliferation and modulates glucose homeostasis. Diabetes 63:4197–4205
57. Taneera J, Jin Z, Jin Y et al (2012) γ-Aminobutyric acid (GABA) signalling in human pancreatic islets is altered in type 2 diabetes. Diabetologia 55:1985–1994
58. Tian J, Dang H, Chen Z et al (2013) γ-Aminobutyric acid regulates both the survival and replication of human beta-cells. Diabetes 62:3760–3765
59. Trus MD, Hintz CS, Weinstein JB, Williams AD, Pagliara AS, Matschinsky FM (1979) A comparison of the effects of glucose and acetylcholine on insulin release and intermediary metabolism in rat pancreatic islets. J Biol Chem 254:3921–3929
60. Renuka TR, Robinson R, Paulose CS (2006) Increased insulin secretion by muscarinic M1 and M3 receptor function from rat pancreatic islets in vitro. Neurochem Res 31:313–320
61. Markmann JF, Deng S, Huang X et al (2003) Insulin independence following isolated islet transplantation and single islet infusions. Ann Surg 237:741–749, discussion 749-750
62. Burnstock G, Verkhratsky A (2009) Evolutionary origins of the purinergic signalling system. Acta Physiol 195:415–447
63. + channels in pancreatic B-cells. Nature 311:271–273
64. MacDonald PE, Braun M, Galvanovskis J, Rorsman P (2006) Release of small transmitters through kiss-and-run fusion pores in rat pancreatic beta cells. Cell Metab 4:283–290
65. Obermuller S, Lindqvist A, Karanauskaite J, Galvanovskis J, Rorsman P, Barg S (2005) Selective nucleotide-release from dense-core granules in insulin-secreting cells. J Cell Sci 118:4271–4282
66. 1 receptor is involved in the maintenance of glucose homeostasis and in insulin secretion in mice. Purinergic Signal 1:145–151
67. Petit P, Manteghetti M, Puech R, Loubatieres-Mariani MM (1987) ATP and phosphate-modified adenine nucleotide analogues. Effects on insulin secretion and calcium uptake. Biochem Pharmacol 36:377–380
68. Poulsen CR, Bokvist K, Olsen HL et al (1999) Multiple sites of purinergic control of insulin secretion in mouse pancreatic beta-cells. Diabetes 48:2171–2181
69. 2+ release in human pancreatic beta cells. Diabetologia 57:2535–2545
70. Roberts E, Frankel S (1950) γ-Aminobutyric acid in brain: its formation from glutamic acid. J Biol Chem 187:55–63
71. A receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 56:141–148
72. Braun M, Wendt A, Birnir B et al (2004) Regulated exocytosis of GABA-containing synaptic-like microvesicles in pancreatic beta-cells. J Gen Physiol 123:191–204
73. A-receptor chloride channels. Nature 341:233–236
74. Soltani N, Qiu H, Aleksic M et al (2011) GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc Natl Acad Sci U S A 108:11692–11697
75. Kim J, Richter W, Aanstoot HJ et al (1993) Differential expression of GAD65 and GAD67 in human, rat, and mouse pancreatic islets. Diabetes 42:1799–1808
76. Braun M, Ramracheya R, Bengtsson M et al (2010) γ-Aminobutyric acid (GABA) is an autocrine excitatory transmitter in human pancreatic beta-cells. Diabetes 59:1694–1701
77. Meldrum BS (2000) Glutamate as a neurotransmitter in the brain: review of physiology and pathology. J Nutr 130:1007S–1015S
78. Inagaki N, Kuromi H, Gonoi T et al (1995) Expression and role of ionotropic glutamate receptors in pancreatic islet cells. FASEB J: Off Publ Fed Am Soc Exp Biol 9:686–691
79. Muroyama A, Uehara S, Yatsushiro S et al (2004) A novel variant of ionotropic glutamate receptor regulates somatostatin secretion from delta-cells of islets of Langerhans. Diabetes 53:1743–1753
80. Hayashi M, Yamada H, Uehara S et al (2003) Secretory granule-mediated co-secretion of l-glutamate and glucagon triggers glutamatergic signal transmission in islets of Langerhans. J Biol Chem 278:1966–1974
81. Feldmann N, del Rio RM, Gjinovci A, Tamarit-Rodriguez J, Wollheim CB, Wiederkehr A (2011) Reduction of plasma membrane glutamate transport potentiates insulin but not glucagon secretion in pancreatic islet cells. Mol Cell Endocrinol 338:46–57
82. Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA (1922) Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 12:141–146
83. Uhles S, Moede T, Leibiger B, Berggren PO, Leibiger IB (2003) Isoform-specific insulin receptor signaling involves different plasma membrane domains. J Cell Biol 163:1327–1337
84. Kulkarni RN, Bruning JC, Winnay JN, Postic C, Magnuson MA, Kahn CR (1999) Tissue-specific knockout of the insulin receptor in pancreatic beta cells creates an insulin secretory defect similar to that in type 2 diabetes. Cell 96:329–339
85. Martinez SC, Cras-Meneur C, Bernal-Mizrachi E, Permutt MA (2006) Glucose regulates Foxo1 through insulin receptor signaling in the pancreatic islet beta-cell. Diabetes 55:1581–1591
86. + channels in pancreatic beta-cells through a phosphatidylinositol 3-kinase-dependent pathway. Diabetes 50:2192–2198
87. Kawamori D, Kurpad AJ, Hu J et al (2009) Insulin signaling in alpha cells modulates glucagon secretion in vivo. Cell Metab 9:350–361
88. Wu H, MacFarlane WM, Tadayyon M, Arch JR, James RF, Docherty K (1999) Insulin stimulates pancreatic-duodenal homoeobox factor-1 (PDX1) DNA-binding activity and insulin promoter activity in pancreatic beta cells. Biochem J 344:813–818
89. Persaud SJ, Asare-Anane H, Jones PM (2002) Insulin receptor activation inhibits insulin secretion from human islets of Langerhans. FEBS Lett 510:225–228
90. Brunicardi FC, Kleinman R, Moldovan S et al (2001) Immunoneutralization of somatostatin, insulin, and glucagon causes alterations in islet cell secretion in the isolated perfused human pancreas. Pancreas 23:302–308
91. Ramnanan CJ, Edgerton DS, Kraft G, Cherrington AD (2011) Physiologic action of glucagon on liver glucose metabolism. Diabetes Obes Metab 13(Suppl 1):118–125
92. Gelling RW, Du XQ, Dichmann DS et al (2003) Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 100:1438–1443
93. Moens K, Flamez D, Van Schravendijk C, Ling Z, Pipeleers D, Schuit F (1998) Dual glucagon recognition by pancreatic beta-cells via glucagon and glucagon-like peptide 1 receptors. Diabetes 47:66–72
94. Huypens P, Ling Z, Pipeleers D, Schuit F (2000) Glucagon receptors on human islet cells contribute to glucose competence of insulin release. Diabetologia 43:1012–1019
95. Moens K, Heimberg H, Flamez D et al (1996) Expression and functional activity of glucagon, glucagon-like peptide I, and glucose-dependent insulinotropic peptide receptors in rat pancreatic islet cells. Diabetes 45:257–261
96. Kieffer TJ, Heller RS, Unson CG, Weir GC, Habener JF (1996) Distribution of glucagon receptors on hormone-specific endocrine cells of rat pancreatic islets. Endocrinology 137:5119–5125
97. Sorensen H, Winzell MS, Brand CL et al (2006) Glucagon receptor knockout mice display increased insulin sensitivity and impaired beta-cell function. Diabetes 55:3463–3469
98. Leibiger B, Moede T, Muhandiramlage TP et al (2012) Glucagon regulates its own synthesis by autocrine signaling. Proc Natl Acad Sci U S A 109:20925–20930
99. Gahete MD, Cordoba-Chacon J, Duran-Prado M et al (2010) Somatostatin and its receptors from fish to mammals. Ann N Y Acad Sci 1200:43–52
100. Hauge-Evans AC, King AJ, Carmignac D et al (2009) Somatostatin secreted by islet delta-cells fulfills multiple roles as a paracrine regulator of islet function. Diabetes 58:403–411
101. Kumar U, Sasi R, Suresh S et al (1999) 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
102. Wang XP, Yang J, Norman MA, Magnusson J, DeMayo FJ, Brunicardi FC (2005) SSTR5 ablation in islet results in alterations in glucose homeostasis in mice. FEBS Lett 579:3107–3114
103. Zhang Y, Zhang Y, Bone RN et al (2012) Regeneration of pancreatic non-beta endocrine cells in adult mice following a single diabetes-inducing dose of streptozotocin. PLoS One 7:e36675
104. Plesner A, Ten Holder JT, Verchere CB (2014) Islet remodeling in female mice with spontaneous autoimmune and streptozotocin-induced diabetes. PLoS One 9:e102843
105. Dufrane D, Maillart JF, Aouassar N, Goebbels RM, Guiot Y, Gianello P (2009) Native pancreatic alpha-cell adaptation in streptozotocin-induced diabetic primates: importance for pig islet xenotransplantation. Xenotransplantation 16:152–163
106. Meier JJ, Bhushan A, Butler AE, Rizza RA, Butler PC (2005) Sustained beta cell apoptosis in patients with long-standing type 1 diabetes: indirect evidence for islet regeneration? Diabetologia 48:2221–2228
107. Walker JN, Johnson PR, Shigeto M, Hughes SJ, Clark A, Rorsman P (2011) Glucose-responsive beta cells in islets isolated from a patient with long-standing type 1 diabetes mellitus. Diabetologia 54:200–202
108. Carlsson PO, Andersson A, Jansson L (1996) Pancreatic islet blood flow in normal and obese-hyperglycemic (ob/ob) mice. Am J Physiol 271:E990–E995
109. Ilegems E, Dicker A, Speier S et al (2013) Reporter islets in the eye reveal the plasticity of the endocrine pancreas. Proc Natl Acad Sci U S A 110:20581–20586
110. Nakamura M, Kitamura H, Konishi S et al (1995) The endocrine pancreas of spontaneously diabetic db/db mice: microangiopathy as revealed by transmission electron microscopy. Diabetes Res Clin Pract 30:89–100
111. Dai C, Brissova M, Reinert RB et al (2013) Pancreatic islet vasculature adapts to insulin resistance through dilation and not angiogenesis. Diabetes 62:4144–4153
112. Paulsen SJ, Jelsing J, Madsen AN et al (2010) Characterization of beta-cell mass and insulin resistance in diet-induced obese and diet-resistant rats. Obesity (Silver Spring) 18:266–273
113. Ribeiro RA, Santos-Silva JC, Vettorazzi JF et al (2012) Taurine supplementation prevents morpho-physiological alterations in high-fat diet mice pancreatic beta-cells. Amino Acids 43:1791–1801
114. Okada T, Liew CW, Hu J et al (2007) Insulin receptors in beta-cells are critical for islet compensatory growth response to insulin resistance. Proc Natl Acad Sci U S A 104:8977–8982
115. Halban PA, Polonsky KS, Bowden DW et al (2014) β-Cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care 37:1751–1758
116. Mezza T, Muscogiuri G, Sorice GP et al (2014) Insulin resistance alters islet morphology in nondiabetic humans. Diabetes 63:994–1007
117. Talchai C, Xuan S, Lin HV, Sussel L, Accili D (2012) Pancreatic beta cell dedifferentiation as a mechanism of diabetic beta cell failure. Cell 150:1223–1234
118. Weir GC, Bonner-Weir S (2004) Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes 5(Suppl 3):S16–S21
119. UKPDS (1995) U.K. prospective diabetes study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes 44:1249–1258
120. Abdulreda MH, Faleo G, Molano RD et al (2011) High-resolution, noninvasive longitudinal live imaging of immune responses. Proc Natl Acad Sci U S A 108:12863–12868
121. Rodriguez-Diaz R, Speier S, Molano RD et al (2012) Noninvasive in vivo model demonstrating the effects of autonomic innervation on pancreatic islet function. Proc Natl Acad Sci U S A 109:21456–21461
122. + T cells. J Exp Med 197:643–656
123. Akirav EM, Baquero MT, Opare-Addo LW et al (2011) Glucose and inflammation control islet vascular density and beta-cell function in NOD mice: control of islet vasculature and vascular endothelial growth factor by glucose. Diabetes 60:876–883
124. Reddy S, Pathipati P, Bai Y, Robinson E, Ross JM (2005) Histopathological changes in insulin, glucagon and somatostatin cells in the islets of NOD mice during cyclophosphamide-accelerated diabetes: a combined immunohistochemical and histochemical study. J Mol Histol 36:289–300
125. Esterhazy D, Stutzer I, Wang H et al (2011) Bace2 is a beta cell-enriched protease that regulates pancreatic beta cell function and mass. Cell Metab 14:365–377
126. Devedjian JC, George M, Casellas A et al (2000) Transgenic mice overexpressing insulin-like growth factor-II in beta cells develop type 2 diabetes. J Clin Invest 105:731–740
127. Guillam MT, Hummler E, Schaerer E et al (1997) Early diabetes and abnormal postnatal pancreatic islet development in mice lacking Glut-2. Nat Genet 17:327–330
128. Höög A, Sandberg-Nordqvist AC, Abdel-Halim SM et al (1996) Increased amounts of a high molecular weight insulin-like growth factor II (IGF-II) peptide and IGF-II messenger ribonucleic acid in pancreatic islets of diabetic Goto-Kakizaki rats. Endocrinology 137:2415–2423
129. Agudo J, Ayuso E, Jimenez V et al (2012) Vascular endothelial growth factor-mediated islet hypervascularization and inflammation contribute to progressive reduction of beta-cell mass. Diabetes 61:2851–2861
130. Guardado-Mendoza R, Davalli AM, Chavez AO et al (2009) Pancreatic islet amyloidosis, beta-cell apoptosis, and alpha-cell proliferation are determinants of islet remodeling in type-2 diabetic baboons. Proc Natl Acad Sci U S A 106:13992–13997
131. Guardado-Mendoza R, Jimenez-Ceja L, Majluf-Cruz A et al (2013) Impact of obesity severity and duration on pancreatic beta- and alpha-cell dynamics in normoglycemic non-human primates. Int J Obes (Lond) 37:1071–1078
132. Jurgens CA, Toukatly MN, Fligner CL et al (2011) β-Cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol 178:2632–2640
133. Henquin JC, Rahier J (2011) Pancreatic alpha cell mass in European subjects with type 2 diabetes. Diabetologia 54:1720–1725
134. Tomita T (2012) Islet amyloid polypeptide in pancreatic islets from type 2 diabetic subjects. Islets 4:223–232
135. Yoneda S, Uno S, Iwahashi H et al (2013) Predominance of beta-cell neogenesis rather than replication in humans with an impaired glucose tolerance and newly diagnosed diabetes. J Clin Endocrinol Metab 98:2053–2061
136. Rahier J, Guiot Y, Goebbels RM, Sempoux C, Henquin JC (2008) Pancreatic beta-cell mass in European subjects with type 2 diabetes. Diabetes Obes Metab 10(Suppl 4):32–42
137. Marselli L, Suleiman M, Masini M et al (2014) Are we overestimating the loss of beta cells in type 2 diabetes? Diabetologia 57:362–365
138. Butcher MJ, Hallinger D, Garcia E et al (2014) Association of proinflammatory cytokines and islet resident leucocytes with islet dysfunction in type 2 diabetes. Diabetologia 57:491–501