Apoptosis

, 14:1389 | Cite as

Beta cell apoptosis in diabetes

  • Helen E. Thomas
  • Mark D. McKenzie
  • Eveline Angstetra
  • Peter D. Campbell
  • Thomas W. Kay
Diabetes and Apoptosis

Abstract

Apoptosis of beta cells is a feature of both type 1 and type 2 diabetes as well as loss of islets after transplantation. In type 1 diabetes, beta cells are destroyed by immunological mechanisms. In type 2 diabetes abnormal levels of metabolic factors contribute to beta cell failure and subsequent apoptosis. Loss of beta cells after islet transplantation is due to many factors including the stress associated with islet isolation, primary graft non-function and allogeneic graft rejection. Irrespective of the exact mediators, highly conserved intracellular pathways of apoptosis are triggered. This review will outline the molecular mediators of beta cell apoptosis and the intracellular pathways activated.

Keywords

Diabetes Pancreatic beta cells Islet transplantation Apoptosis 

Abbreviations

T1DM

Type 1 diabetes mellitus

CTL

Cytotoxic T lymphocyte

β2m

β2-microglobulin

NOD

Non-obese diabetic

TNF

Tumor necrosis factor

TNFR

TNF receptor

FasL

Fas Ligand

FADD

Fas-associated death domain

BH3

Bcl-homology domain 3

ALPS

Autoimmune lymphoproliferation syndrome

lpr

Lyphoproliferation

gld

Generalized lymphoproliferative disease

IL-1

Interleukin-1

IL-1R

IL-1 receptor

IFN

Interferon

IFNγR

IFNγ receptor

IGRP

Islet-specific glucose-6-phosphatase catalytic subunit-related protein

SOCS

Suppressor of cytokine signaling

JNK

c-Jun N-terminal kinase

NO

Nitric oxide

iNOS

Inducible NO synthase

XIAP

X-linked inhibitor of apoptosis

ROS

Reactive oxygen species

Gpx

Glutathione peroxidase

SOD

Superoxide dismutase

IBMIR

Instant blood-mediated inflammatory reaction

IAPP

Islet amyloid polypeptide

TXNIP

Thioredoxin-interacting protein

T2DM

Type 2 diabetes mellitus

CHOP

C/EBP homologous protein

ER

Endoplasmic reticulum

PERK

PKR-like ER kinase

Notes

Acknowledgments

We thank Dr. Janette Allison for critical reading of the manuscript. This work was supported by the National Health and Medical Research Council of Australia, the Juvenile Diabetes Research Foundation and the Australian Government through the Department of Health and Ageing.

References

  1. 1.
    Augstein P, Elefanty AG, Allison J et al (1998) Apoptosis and beta-cell destruction in pancreatic islets of NOD mice with spontaneous and cyclophosphamide-accelerated diabetes. Diabetologia 41:1381–1388. doi:10.1007/s001250051080 PubMedCrossRefGoogle Scholar
  2. 2.
    Butler AE, Janson J, Bonner-Weir S et al (2003) Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes 52:102–110. doi:10.2337/diabetes.52.1.102 PubMedCrossRefGoogle Scholar
  3. 3.
    Kurrer MO, Pakala SV, Hanson HL et al (1997) Beta cell apoptosis in T cell-mediated autoimmune diabetes. Proc Natl Acad Sci USA 94:213–218. doi:10.1073/pnas.94.1.213 PubMedCrossRefGoogle Scholar
  4. 4.
    O’Brien BA, Harmon BV, Cameron DP et al (1997) Apoptosis is the mode of beta-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. Diabetes 46:750–757. doi:10.2337/diabetes.46.5.750 PubMedCrossRefGoogle Scholar
  5. 5.
    Cnop M, Welsh N, Jonas JC et al (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107. doi:10.2337/diabetes.54.suppl_2.S97 PubMedCrossRefGoogle Scholar
  6. 6.
    Foulis AK, Farquharson MA, Hardman R (1987) Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type 1 (insulin-dependent) diabetes mellitus. Diabetologia 30:333–343. doi:10.1007/BF00299027 PubMedCrossRefGoogle Scholar
  7. 7.
    Bottazzo GF, Dean BM, McNally JM et al (1985) In situ characterization of autoimmune phenomena and expression of HLA molecules in the pancreas in diabetic insulitis. N Engl J Med 313:353–360PubMedGoogle Scholar
  8. 8.
    Hanninen A, Jalkanen S, Salmi M et al (1992) Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest 90:1901–1910. doi:10.1172/JCI116067 PubMedCrossRefGoogle Scholar
  9. 9.
    Itoh N, Hanafusa T, Miyazaki A et al (1993) Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion molecules in pancreas biopsy specimens from newly diagnosed insulin-dependent diabetes mellitus patients. J Clin Invest 92:2313–2322. doi:10.1172/JCI116835 PubMedCrossRefGoogle Scholar
  10. 10.
    Moriwaki M, Itoh N, Miyagawa J et al (1999) Fas and Fas ligand expression in inflamed islets in pancreas sections of patients with recent-onset type I diabetes mellitus. Diabetologia 42:1332–1340. doi:10.1007/s001250051446 PubMedCrossRefGoogle Scholar
  11. 11.
    Santamaria P, Nakhleh RE, Sutherland DE et al (1992) Characterization of T lymphocytes infiltrating human pancreas allograft affected by isletitis and recurrent diabetes. Diabetes 41:53–61. doi:10.2337/diabetes.41.1.53 PubMedCrossRefGoogle Scholar
  12. 12.
    Sibley RK, Sutherland DE, Goetz F et al (1985) Recurrent diabetes mellitus in the pancreas iso- and allograft. A light and electron microscopic and immunohistochemical analysis of four cases. Lab Invest 53:132–144PubMedGoogle Scholar
  13. 13.
    Dubois-LaForgue D, Carel JC, Bougneres PF et al (1999) T-cell response to proinsulin and insulin in type 1 and pretype 1 diabetes. J Clin Immunol 19:127–134. doi:10.1023/A:1020558601175 PubMedCrossRefGoogle Scholar
  14. 14.
    Hassainya Y, Garcia-Pons F, Kratzer R et al (2005) Identification of naturally processed HLA-A2–restricted proinsulin epitopes by reverse immunology. Diabetes 54:2053–2059. doi:10.2337/diabetes.54.7.2053 PubMedCrossRefGoogle Scholar
  15. 15.
    Mallone R, Martinuzzi E, Blancou P et al (2007) CD8+T-cell responses identify beta-cell autoimmunity in human type 1 diabetes. Diabetes 56:613–621. doi:10.2337/db06-1419 PubMedCrossRefGoogle Scholar
  16. 16.
    Ouyang Q, Standifer NE, Qin H et al (2006) Recognition of HLA class I-restricted beta-cell epitopes in type 1 diabetes. Diabetes 55:3068–3074. doi:10.2337/db06-0065 PubMedCrossRefGoogle Scholar
  17. 17.
    Panina-Bordignon P, Lang R, van Endert PM et al (1995) Cytotoxic T cells specific for glutamic acid decarboxylase in autoimmune diabetes. J Exp Med 181:1923–1927. doi:10.1084/jem.181.5.1923 PubMedCrossRefGoogle Scholar
  18. 18.
    Pinkse GG, Tysma OH, Bergen CA et al (2005) Autoreactive CD8 T cells associated with beta cell destruction in type 1 diabetes. Proc Natl Acad Sci USA 102:18425–18430. doi:10.1073/pnas.0508621102 PubMedCrossRefGoogle Scholar
  19. 19.
    Toma A, Haddouk S, Briand JP et al (2005) Recognition of a subregion of human proinsulin by class I-restricted T cells in type 1 diabetic patients. Proc Natl Acad Sci USA 102:10581–10586. doi:10.1073/pnas.0504230102 PubMedCrossRefGoogle Scholar
  20. 20.
    Katz J, Benoist C, Mathis D (1993) Major histocompatibility complex class I molecules are required for the development of insulitis in non-obese diabetic mice. Eur J Immunol 23:3358–3360. doi:10.1002/eji.1830231244 PubMedCrossRefGoogle Scholar
  21. 21.
    Serreze DV, Leiter EH, Christianson GJ et al (1994) Major histocompatibility complex class I-deficient NOD-beta 2-m null mice are diabetes and insulitis resistant. Diabetes 43:505–509. doi:10.2337/diabetes.43.3.505 PubMedCrossRefGoogle Scholar
  22. 22.
    Sumida T, Furukawa M, Sakamoto A et al (1994) Prevention of insulitis and diabetes in beta 2-microglobulin-deficient non-obese diabetic mice. Int Immunol 6:1445–1449. doi:10.1093/intimm/6.9.1445 PubMedCrossRefGoogle Scholar
  23. 23.
    Wicker LS, Leiter EH, Todd JA et al (1994) Beta 2-microglobulin-deficient NOD mice do not develop insulitis or diabetes. Diabetes 43:500–504. doi:10.2337/diabetes.43.3.500 PubMedCrossRefGoogle Scholar
  24. 24.
    Hamilton-Williams EE, Palmer SE, Charlton B et al (2003) Beta cell MHC class I is a late requirement for diabetes. Proc Natl Acad Sci USA 100:6688–6693. doi:10.1073/pnas.1131954100 PubMedCrossRefGoogle Scholar
  25. 25.
    Graser RT, DiLorenzo TP, Wang F et al (2000) Identification of a CD8 T cell that can independently mediate autoimmune diabetes development in the complete absence of CD4 T cell helper functions. J Immunol 164:3913–3918PubMedGoogle Scholar
  26. 26.
    Verdaguer J, Schmidt D, Amrani A et al (1997) Spontaneous autoimmune diabetes in monoclonal T cell nonobese diabetic mice. J Exp Med 186:1663–1676. doi:10.1,084/jem.186.10.1,663 PubMedCrossRefGoogle Scholar
  27. 27.
    Wong FS, Visintin I, Wen L et al (1996) CD8 T cell clones from young nonobese diabetic (NOD) islets can transfer rapid onset of diabetes in NOD mice in the absence of CD4 cells. J Exp Med 183:67–76. doi:10.1,084/jem.183.1.67 PubMedCrossRefGoogle Scholar
  28. 28.
    De Berardinis P, Londei M, Kahan M et al (1988) The majority of the activated T cells in the blood of insulin-dependent diabetes mellitus (IDDM) patients are CD4+. Clin Exp Immunol 73:255–259PubMedGoogle Scholar
  29. 29.
    Katz JD, Wang B, Haskins K et al (1993) Following a diabetogenic T cell from genesis through pathogenesis. Cell 74:1089–1100. doi:10.1,016/0,092-8,674(93)90,730-E PubMedCrossRefGoogle Scholar
  30. 30.
    Mora C, Wong FS, Chang CH et al (1999) Pancreatic infiltration but not diabetes occurs in the relative absence of MHC class II-restricted CD4 T cells: studies using NOD/CIITA-deficient mice. J Immunol 162:4576–4588PubMedGoogle Scholar
  31. 31.
    Wong FS, Visintin I, Wen L et al (1998) The role of lymphocyte subsets in accelerated diabetes in nonobese diabetic-rat insulin promoter-B7–1 (NOD-RIP-B7–1) mice. J Exp Med 187:1985–1993. doi:10.1,084/jem.187.12.1,985 PubMedCrossRefGoogle Scholar
  32. 32.
    Kagi D, Odermatt B, Seiler P et al (1997) Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J Exp Med 186:989–997. doi:10.1,084/jem.186.7.989 PubMedCrossRefGoogle Scholar
  33. 33.
    Wang B, Gonzalez A, Benoist C et al (1996) The role of CD8+T cells in the initiation of insulin-dependent diabetes mellitus. Eur J Immunol 26:1762–1769. doi:10.1,002/eji.1,830,260,815 PubMedCrossRefGoogle Scholar
  34. 34.
    Christianson SW, Shultz LD, Leiter EH (1993) Adoptive transfer of diabetes into immunodeficient NOD-scid/scid mice. Relative contributions of CD4+and CD8+T-cells from diabetic versus prediabetic NOD.NON-Thy-1a donors. Diabetes 42:44–55. doi:10.2,337/diabetes.42.1.44 PubMedCrossRefGoogle Scholar
  35. 35.
    Peterson JD, Haskins K (1996) Transfer of diabetes in the NOD-scid mouse by CD4 T-cell clones. Differential requirement for CD8 T-cells. Diabetes 45:328–336. doi:10.2,337/diabetes.45.3.328 PubMedCrossRefGoogle Scholar
  36. 36.
    Cullen SP, Martin SJ (2008) Mechanisms of granule-dependent killing. Cell Death Differ 15:251–262. doi:10.1,038/sj.cdd.4,402,244 PubMedCrossRefGoogle Scholar
  37. 37.
    Trapani JA, Smyth MJ (2002) Functional significance of the perforin/granzyme cell death pathway. Nat Rev Immunol 2:735–747. doi:10.1,038/nri911 PubMedCrossRefGoogle Scholar
  38. 38.
    Dudek NL, Thomas HE, Mariana L et al (2006) Cytotoxic T-cells from T-cell receptor transgenic NOD8.3 mice destroy beta-cells via the perforin and Fas pathways. Diabetes 55:2412–2418. doi:10.2,337/db06-0,109 PubMedCrossRefGoogle Scholar
  39. 39.
    Kreuwel HT, Morgan DJ, Krahl T et al (1999) Comparing the relative role of perforin/granzyme versus Fas/Fas ligand cytotoxic pathways in CD8+T cell-mediated insulin-dependent diabetes mellitus. J Immunol 163:4335–4341PubMedGoogle Scholar
  40. 40.
    McKenzie MD, Dudek NL, Mariana L et al (2006) Perforin and Fas induced by IFNgamma and TNFalpha mediate beta cell death by OT-I CTL. Int Immunol 18:837–846. doi:10.1,093/intimm/dxl020 PubMedCrossRefGoogle Scholar
  41. 41.
    Campbell PD, Estella E, Dudek NL et al (2008) Cytotoxic T-lymphocyte-mediated killing of human pancreatic islet cells in vitro. Hum Immunol 69:543–551. doi:10.1,016/j.humimm.2,008.06.008 PubMedCrossRefGoogle Scholar
  42. 42.
    Amrani A, Verdaguer J, Anderson B et al (1999) Perforin-independent beta-cell destruction by diabetogenic CD8(+) T lymphocytes in transgenic nonobese diabetic mice. J Clin Invest 103:1201–1209. doi:10.1,172/JCI6266 PubMedCrossRefGoogle Scholar
  43. 43.
    Sutton VR, Davis JE, Cancilla M et al (2000) Initiation of apoptosis by granzyme B requires direct cleavage of bid, but not direct granzyme B-mediated caspase activation. J Exp Med 192:1403–1414. doi:10.1,084/jem.192.10.1,403 PubMedCrossRefGoogle Scholar
  44. 44.
    Strasser A (2005) The role of BH3-only proteins in the immune system. Nat Rev Immunol 5:189–200. doi:10.1,038/nri1568 PubMedCrossRefGoogle Scholar
  45. 45.
    Estella E, McKenzie MD, Catterall T et al (2006) Granzyme B-mediated death of pancreatic beta-cells requires the proapoptotic BH3-only molecule bid. Diabetes 55:2212–2219. doi:10.2,337/db06-0,129 PubMedCrossRefGoogle Scholar
  46. 46.
    Wajant H (2002) The Fas signaling pathway: more than a paradigm. Science 296:1635–1636. doi:10.1,126/science.1,071,553 PubMedCrossRefGoogle Scholar
  47. 47.
    Suda T, Takahashi T, Golstein P et al (1993) Molecular cloning and expression of the Fas ligand, a novel member of the tumor necrosis factor family. Cell 75:1169–1178. doi:10.1,016/0,092-8,674(93)90,326-L PubMedCrossRefGoogle Scholar
  48. 48.
    Watanabe-Fukunaga R, Brannan CI, Itoh N et al (1992) The cDNA structure, expression, and chromosomal assignment of the mouse Fas antigen. J Immunol 148:1274–1279PubMedGoogle Scholar
  49. 49.
    Waring P, Mullbacher A (1999) Cell death induced by the Fas/Fas ligand pathway and its role in pathology. Immunol Cell Biol 77:312–317. doi:10.1,046/j.1,440-1711.1,999.00837.x PubMedCrossRefGoogle Scholar
  50. 50.
    Rieux-Laucat F, Le Deist F, Hivroz C et al (1995) Mutations in Fas associated with human lymphoproliferative syndrome and autoimmunity. Science 268:1347–1349. doi:10.1126/science.7539157 PubMedCrossRefGoogle Scholar
  51. 51.
    Watanabe-Fukunaga R, Brannan CI, Copeland NG et al (1992) Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356:314–317. doi:10.1038/356314a0 PubMedCrossRefGoogle Scholar
  52. 52.
    Roths JB, Murphy ED, Eicher EM (1984) A new mutation, gld, that produces lymphoproliferation and autoimmunity in C3H/HeJ mice. J Exp Med 159:1–20. doi:10.1084/jem.159.1.1 PubMedCrossRefGoogle Scholar
  53. 53.
    Sneller MC, Wang J, Dale JK et al (1997) Clincal, immunologic, and genetic features of an autoimmune lymphoproliferative syndrome associated with abnormal lymphocyte apoptosis. Blood 89:1341–1348PubMedGoogle Scholar
  54. 54.
    Suarez-Pinzon W, Sorensen O, Bleackley RC et al (1999) Beta-cell destruction in NOD mice correlates with Fas (CD95) expression on beta-cells and proinflammatory cytokine expression in islets. Diabetes 48:21–28. doi:10.2337/diabetes.48.1.21 PubMedCrossRefGoogle Scholar
  55. 55.
    Thomas HE, Darwiche R, Corbett JA et al (1999) Evidence that beta cell death in the nonobese diabetic mouse is Fas independent. J Immunol 163:1562–1569PubMedGoogle Scholar
  56. 56.
    Yamada K, Takane-Gyotoku N, Yuan X et al (1996) Mouse islet cell lysis mediated by interleukin-1-induced Fas. Diabetologia 39:1306–1312. doi:10.1007/s001250050574 PubMedCrossRefGoogle Scholar
  57. 57.
    Loweth AC, Williams GT, James RF et al (1998) Human islets of langerhans express Fas ligand and undergo apoptosis in response to interleukin-1beta and Fas ligation. Diabetes 47:727–732. doi:10.2337/diabetes.47.5.727 PubMedCrossRefGoogle Scholar
  58. 58.
    Angstetra E, Graham KL, Emmett S et al (2009) In vivo effects of cytokines on pancreatic beta-cells in models of type I diabetes dependent on CD4(+) T lymphocytes. Immunol Cell Biol 87:178–185. doi:10.1038/icb.2008.81 PubMedCrossRefGoogle Scholar
  59. 59.
    Darwiche R, Chong MM, Santamaria P et al (2003) Fas is detectable on beta cells in accelerated, but not spontaneous, diabetes in nonobese diabetic mice. J Immunol 170:6292–6297PubMedGoogle Scholar
  60. 60.
    Stassi G, Todaro M, Richiusa P et al (1995) Expression of apoptosis-inducing CD95 (Fas/Apo-1) on human beta-cells sorted by flow-cytometry and cultured in vitro. Transpl Proc 27:3271–3275Google Scholar
  61. 61.
    Liadis N, Salmena L, Kwan E et al (2007) Distinct in vivo roles of caspase-8 in beta-cells in physiological and diabetes models. Diabetes 56:2302–2311. doi:10.2337/db06-1771 PubMedCrossRefGoogle Scholar
  62. 62.
    McKenzie MD, Carrington EM, Kaufmann T et al (2008) Proapoptotic BH3-only protein Bid is essential for death receptor-induced apoptosis of pancreatic beta-cells. Diabetes 57:1284–1292. doi:10.2337/db07-1692 PubMedCrossRefGoogle Scholar
  63. 63.
    Amrani A, Verdaguer J, Thiessen S et al (2000) IL-1alpha, IL-1beta, and IFN-gamma mark beta cells for Fas-dependent destruction by diabetogenic CD4(+) T lymphocytes. J Clin Invest 105:459–468. doi:10.1172/JCI8185 PubMedCrossRefGoogle Scholar
  64. 64.
    Apostolou I, Hao Z, Rajewsky K et al (2003) Effective destruction of Fas-deficient insulin-producing beta cells in type 1 diabetes. J Exp Med 198:1103–1106. doi:10.1084/jem.20030698 PubMedCrossRefGoogle Scholar
  65. 65.
    Savinov AY, Tcherepanov A, Green EA et al (2003) Contribution of Fas to diabetes development. Proc Natl Acad Sci USA 100:628–632. doi:10.1073/pnas.0237359100 PubMedCrossRefGoogle Scholar
  66. 66.
    Allison J, Thomas HE, Catterall T et al (2005) Transgenic expression of dominant-negative Fas-associated death domain protein in beta cells protects against Fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice. J Immunol 175:293–301PubMedGoogle Scholar
  67. 67.
    Allison J, Strasser A (1998) Mechanisms of beta cell death in diabetes: a minor role for CD95. Proc Natl Acad Sci USA 95:13818–13822. doi:10.1073/pnas.95.23.13818 PubMedCrossRefGoogle Scholar
  68. 68.
    Pakala SV, Chivetta M, Kelly CB et al (1999) In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor alpha. J Exp Med 189:1053–1062. doi:10.1084/jem.189.7.1053 PubMedCrossRefGoogle Scholar
  69. 69.
    Chervonsky AV, Wang Y, Wong FS et al (1997) The role of Fas in autoimmune diabetes. Cell 89:17–24. doi:10.1016/S0092-8674(00)80178-6 PubMedCrossRefGoogle Scholar
  70. 70.
    Itoh N, Imagawa A, Hanafusa T et al (1997) Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J Exp Med 186:613–618. doi:10.1084/jem.186.4.613 PubMedCrossRefGoogle Scholar
  71. 71.
    Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485. doi:10.1146/annurev.immunol.23.021704.115643 PubMedCrossRefGoogle Scholar
  72. 72.
    Mohamood AS, Guler ML, Xiao Z et al (2007) Protection from autoimmune diabetes and T-cell lymphoproliferation induced by FasL mutation are differentially regulated and can be uncoupled pharmacologically. Am J Pathol 171:97–106. doi:10.2353/ajpath.2007.070148 PubMedCrossRefGoogle Scholar
  73. 73.
    Nakayama M, Nagata M, Yasuda H et al (2002) Fas/Fas ligand interactions play an essential role in the initiation of murine autoimmune diabetes. Diabetes 51:1391–1397. doi:10.2337/diabetes.51.5.1391 PubMedCrossRefGoogle Scholar
  74. 74.
    Suarez-Pinzon WL, Power RF, Rabinovitch A (2000) Fas ligand-mediated mechanisms are involved in autoimmune destruction of islet beta cells in non-obese diabetic mice. Diabetologia 43:1149–1156. doi:10.1007/s001250051506 PubMedCrossRefGoogle Scholar
  75. 75.
    Vence L, Benoist C, Mathis D (2004) Fas deficiency prevents type 1 diabetes by inducing hyporesponsiveness in islet beta-cell-reactive T-cells. Diabetes 53:2797–2803. doi:10.2337/diabetes.53.11.2797 PubMedCrossRefGoogle Scholar
  76. 76.
    Mandrup-Poulsen T, Bendtzen K, Nerup J et al (1986) Affinity-purified human interleukin I is cytotoxic to isolated islets of langerhans. Diabetologia 29:63–67. doi:10.1007/BF02427283 PubMedCrossRefGoogle Scholar
  77. 77.
    Mandrup-Poulsen T, Bendtzen K, Nielsen JH et al (1985) Cytokines cause functional and structural damage to isolated islets of langerhans. Allergy 40:424–429. doi:10.1111/j.1398-9995.1985.tb02681.x PubMedCrossRefGoogle Scholar
  78. 78.
    Mandrup-Poulsen T (1996) The role of interleukin-1 in the pathogenesis of IDDM. Diabetologia 39:1005–1029. doi:10.1007/BF00400649 PubMedCrossRefGoogle Scholar
  79. 79.
    Arnush M, Heitmeier MR, Scarim AL et al (1998) IL-1 produced and released endogenously within human islets inhibits beta cell function. J Clin Invest 102:516–526. doi:10.1172/JCI844 PubMedCrossRefGoogle Scholar
  80. 80.
    Thomas HE, Darwiche R, Corbett JA et al (2002) Interleukin-1 plus gamma-interferon-induced pancreatic beta-cell dysfunction is mediated by beta-cell nitric oxide production. Diabetes 51:311–316. doi:10.2337/diabetes.51.2.311 PubMedCrossRefGoogle Scholar
  81. 81.
    Dogusan Z, Garcia M, Flamez D et al (2008) Double-stranded RNA induces pancreatic beta-cell apoptosis by activation of the toll-like receptor 3 and interferon regulatory factor 3 pathways. Diabetes 57:1236–1245. doi:10.2337/db07-0844 PubMedCrossRefGoogle Scholar
  82. 82.
    Darville MI, Eizirik DL (1998) Regulation by cytokines of the inducible nitric oxide synthase promoter in insulin-producing cells. Diabetologia 41:1101–1108. doi:10.1007/s001250051036 PubMedCrossRefGoogle Scholar
  83. 83.
    Chong MM, Thomas HE, Kay TW (2001) Gamma-interferon signaling in pancreatic beta-cells is persistent but can be terminated by overexpression of suppressor of cytokine signaling-1. Diabetes 50:2744–2751. doi:10.2337/diabetes.50.12.2744 PubMedCrossRefGoogle Scholar
  84. 84.
    Thomas HE, Angstetra E, Fernandes RV et al (2006) Perturbations in nuclear factor-kappaB or c-Jun N-terminal kinase pathways in pancreatic beta cells confer susceptibility to cytokine-induced cell death. Immunol Cell Biol 84:20–27. doi:10.1111/j.1440-1711.2005.01397.x PubMedCrossRefGoogle Scholar
  85. 85.
    Ammendrup A, Maillard A, Nielsen K et al (2000) The c-Jun amino-terminal kinase pathway is preferentially activated by interleukin-1 and controls apoptosis in differentiating pancreatic beta-cells. Diabetes 49:1468–1476. doi:10.2337/diabetes.49.9.1468 PubMedCrossRefGoogle Scholar
  86. 86.
    Bonny C, Oberson A, Negri S et al (2001) Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death. Diabetes 50:77–82. doi:10.2337/diabetes.50.1.77 PubMedCrossRefGoogle Scholar
  87. 87.
    Bonny C, Oberson A, Steinmann M et al (2000) IB1 reduces cytokine-induced apoptosis of insulin-secreting cells. J Biol Chem 275:16466–16472. doi:10.1074/jbc.M908297199 PubMedCrossRefGoogle Scholar
  88. 88.
    Ferdaoussi M, Abdelli S, Yang JY et al (2008) Exendin-4 protects beta-cells from interleukin-1 beta-induced apoptosis by interfering with the c-Jun NH2-terminal kinase pathway. Diabetes 57:1205–1215. doi:10.2337/db07-1214 PubMedCrossRefGoogle Scholar
  89. 89.
    Li L, El-Kholy W, Rhodes CJ et al (2005) Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B. Diabetologia 48:1339–1349. doi:10.1007/s00125-005-1787-2 PubMedCrossRefGoogle Scholar
  90. 90.
    Chong MM, Thomas HE, Kay TW (2002) Suppressor of cytokine signaling-1 regulates the sensitivity of pancreatic beta cells to tumor necrosis factor. J Biol Chem 277:27945–27952. doi:10.1074/jbc.M110214200 PubMedCrossRefGoogle Scholar
  91. 91.
    Saldeen J, Lee JC, Welsh N (2001) Role of p38 mitogen-activated protein kinase (p38 MAPK) in cytokine-induced rat islet cell apoptosis. Biochem Pharmacol 61:1561–1569. doi:10.1016/S0006-2952(01)00605-0 PubMedCrossRefGoogle Scholar
  92. 92.
    Green EA, Eynon EE, Flavell RA (1998) Local expression of TNFalpha in neonatal NOD mice promotes diabetes by enhancing presentation of islet antigens. Immunity 9:733–743. doi:10.1016/S1074-7613(00)80670-6 PubMedCrossRefGoogle Scholar
  93. 93.
    Higuchi Y, Herrera P, Muniesa P et al (1992) Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. J Exp Med 176:1719–1731. doi:10.1084/jem.176.6.1719 PubMedCrossRefGoogle Scholar
  94. 94.
    Picarella DE, Kratz A, Li CB et al (1993) Transgenic tumor necrosis factor (TNF)-alpha production in pancreatic islets leads to insulitis, not diabetes. Distinct patterns of inflammation in TNF-alpha and TNF-beta transgenic mice. J Immunol 150:4136–4150PubMedGoogle Scholar
  95. 95.
    Beg AA, Baltimore D (1996) An essential role for NF-kappaB in preventing TNF-alpha-induced cell death. Science 274:782–784. doi:10.1126/science.274.5288.782 PubMedCrossRefGoogle Scholar
  96. 96.
    Baker MS, Chen X, Cao XC et al (2001) Expression of a dominant negative inhibitor of NF-kappaB protects MIN6 beta-cells from cytokine-induced apoptosis. J Surg Res 97:117–122. doi:10.1006/jsre.2001.6121 PubMedCrossRefGoogle Scholar
  97. 97.
    Giannoukakis N, Rudert WA, Trucco M et al (2000) Protection of human islets from the effects of interleukin-1beta by adenoviral gene transfer of an Ikappa B repressor. J Biol Chem 275:36509–36513. doi:10.1074/jbc.M005943200 PubMedCrossRefGoogle Scholar
  98. 98.
    Heimberg H, Heremans Y, Jobin C et al (2001) Inhibition of cytokine-induced NF-kappaB activation by adenovirus-mediated expression of a NF-kappaB super-repressor prevents beta-cell apoptosis. Diabetes 50:2219–2224. doi:10.2337/diabetes.50.10.2219 PubMedCrossRefGoogle Scholar
  99. 99.
    Chang I, Kim S, Kim JY et al (2003) Nuclear factor kappaB protects pancreatic beta-cells from tumor necrosis factor-alpha-mediated apoptosis. Diabetes 52:1169–1175. doi:10.2337/diabetes.52.5.1169 PubMedCrossRefGoogle Scholar
  100. 100.
    Liuwantara D, Elliot M, Smith MW et al (2006) Nuclear factor-kappaB regulates beta-cell death: a critical role for A20 in beta-cell protection. Diabetes 55:2491–2501. doi:10.2337/db06-0142 PubMedCrossRefGoogle Scholar
  101. 101.
    Stephens LA, Thomas HE, Ming L et al (1999) Tumor necrosis factor-alpha-activated cell death pathways in NIT-1 insulinoma cells and primary pancreatic beta cells. Endocrinology 140:3219–3227. doi:10.1210/en.140.7.3219 PubMedCrossRefGoogle Scholar
  102. 102.
    Kim S, Millet I, Kim HS et al (2007) NF-kappa B prevents beta cell death and autoimmune diabetes in NOD mice. Proc Natl Acad Sci USA 104:1913–1918. doi:10.1073/pnas.0610690104 PubMedCrossRefGoogle Scholar
  103. 103.
    Eldor R, Yeffet A, Baum K et al (2006) Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents. Proc Natl Acad Sci USA 103:5072–5077. doi:10.1073/pnas.0508166103 PubMedCrossRefGoogle Scholar
  104. 104.
    Gysemans CA, Ladriere L, Callewaert H et al (2005) Disruption of the gamma-interferon signaling pathway at the level of signal transducer and activator of transcription-1 prevents immune destruction of beta-cells. Diabetes 54:2396–2403. doi:10.2337/diabetes.54.8.2396 PubMedCrossRefGoogle Scholar
  105. 105.
    Kim S, Kim HS, Chung KW et al (2007) Essential role for signal transducer and activator of transcription-1 in pancreatic beta-cell death and autoimmune type 1 diabetes of nonobese diabetic mice. Diabetes 56:2561–2568. doi:10.2337/db06-1372 PubMedCrossRefGoogle Scholar
  106. 106.
    Grey ST, Arvelo MB, Hasenkamp W et al (1999) A20 inhibits cytokine-induced apoptosis and nuclear factor kappaB-dependent gene activation in islets. J Exp Med 190:1135–1146. doi:10.1084/jem.190.8.1135 PubMedCrossRefGoogle Scholar
  107. 107.
    Kim HS, Kim S, Lee MS (2005) IFN-gamma sensitizes MIN6N8 insulinoma cells to TNF-alpha-induced apoptosis by inhibiting NF-kappaB-mediated XIAP upregulation. Biochem Biophys Res Commun 336:847–853. doi:10.1016/j.bbrc.2005.08.183 PubMedCrossRefGoogle Scholar
  108. 108.
    Emamaullee JA, Rajotte RV, Liston P et al (2005) XIAP overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes. Diabetes 54:2541–2548. doi:10.2337/diabetes.54.9.2541 PubMedCrossRefGoogle Scholar
  109. 109.
    Plesner A, Liston P, Tan R et al (2005) The X-linked inhibitor of apoptosis protein enhances survival of murine islet allografts. Diabetes 54:2533–2540. doi:10.2337/diabetes.54.9.2533 PubMedCrossRefGoogle Scholar
  110. 110.
    Thomas HE, Irawaty W, Darwiche R et al (2004) IL-1 receptor deficiency slows progression to diabetes in the NOD mouse. Diabetes 53:113–121. doi:10.2337/diabetes.53.1.113 PubMedCrossRefGoogle Scholar
  111. 111.
    Cailleau C, Diu-Hercend A, Ruuth E et al (1997) Treatment with neutralizing antibodies specific for IL-1beta prevents cyclophosphamide-induced diabetes in nonobese diabetic mice. Diabetes 46:937–940. doi:10.2337/diabetes.46.6.937 PubMedCrossRefGoogle Scholar
  112. 112.
    Nicoletti F, Di Marco R, Barcellini W et al (1994) Protection from experimental autoimmune diabetes in the non-obese diabetic mouse with soluble interleukin-1 receptor. Eur J Immunol 24:1843–1847. doi:10.1002/eji.1830240818 PubMedCrossRefGoogle Scholar
  113. 113.
    Sandberg JO, Eizirik DL, Sandler S (1997) IL-1 receptor antagonist inhibits recurrence of disease after syngeneic pancreatic islet transplantation to spontaneously diabetic non-obese diabetic (NOD) mice. Clin Exp Immunol 108:314–317. doi:10.1046/j.1365-2249.1997.3771275.x PubMedCrossRefGoogle Scholar
  114. 114.
    O’Sullivan BJ, Thomas HE, Pai S et al (2006) IL-1 beta breaks tolerance through expansion of CD25+effector T cells. J Immunol 176:7278–7287PubMedGoogle Scholar
  115. 115.
    Kagi D, Ho A, Odermatt B et al (1999) TNF receptor 1-dependent beta cell toxicity as an effector pathway in autoimmune diabetes. J Immunol 162:4598–4605PubMedGoogle Scholar
  116. 116.
    Hultgren B, Huang X, Dybdal N et al (1996) Genetic absence of gamma-interferon delays but does not prevent diabetes in NOD mice. Diabetes 45:812–817. doi:10.2337/diabetes.45.6.812 PubMedCrossRefGoogle Scholar
  117. 117.
    Kanagawa O, Xu G, Tevaarwerk A et al (2000) Protection of nonobese diabetic mice from diabetes by gene(s) closely linked to IFN-gamma receptor loci. J Immunol 164:3919–3923PubMedGoogle Scholar
  118. 118.
    Serreze DV, Post CM, Chapman HD et al (2000) Interferon-gamma receptor signaling is dispensable in the development of autoimmune type 1 diabetes in NOD mice. Diabetes 49:2007–2011. doi:10.2337/diabetes.49.12.2007 PubMedCrossRefGoogle Scholar
  119. 119.
    Thomas HE, Parker JL, Schreiber RD et al (1998) IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes. J Clin Invest 102:1249–1257. doi:10.1172/JCI2899 PubMedCrossRefGoogle Scholar
  120. 120.
    Nakazawa T, Satoh J, Takahashi K et al (2001) Complete suppression of insulitis and diabetes in NOD mice lacking interferon regulatory factor-1. J Autoimmun 17:119–125. doi:10.1006/jaut.2001.0531 PubMedCrossRefGoogle Scholar
  121. 121.
    Chong MM, Chen Y, Darwiche R et al (2004) Suppressor of cytokine signaling-1 overexpression protects pancreatic beta cells from CD8(+) T cell-mediated autoimmune destruction. J Immunol 172:5714–5721PubMedGoogle Scholar
  122. 122.
    Flodstrom-Tullberg M, Yadav D, Hagerkvist R et al (2003) Target cell expression of suppressor of cytokine signaling-1 prevents diabetes in the NOD mouse. Diabetes 52:2696–2700. doi:10.2337/diabetes.52.11.2696 PubMedCrossRefGoogle Scholar
  123. 123.
    Ott M, Gogvadze V, Orrenius S et al (2007) Mitochondria, oxidative stress and cell death. Apoptosis 12:913–922. doi:10.1007/s10495-007-0756-2 PubMedCrossRefGoogle Scholar
  124. 124.
    Guichard C, Moreau R, Pessayre D et al (2008) NOX family NADPH oxidases in liver and in pancreatic islets: a role in the metabolic syndrome and diabetes? Biochem Soc Trans 36:920–929. doi:10.1042/BST0360920 PubMedCrossRefGoogle Scholar
  125. 125.
    Eizirik DL, Pipeleers DG, Ling Z et al (1994) Major species differences between humans and rodents in the susceptibility to pancreatic beta-cell injury. Proc Natl Acad Sci USA 91:9253–9256. doi:10.1073/pnas.91.20.9253 PubMedCrossRefGoogle Scholar
  126. 126.
    Grankvist K, Marklund SL, Taljedal IB (1981) CuZn-superoxide dismutase, Mn-superoxide dismutase, catalase and glutathione peroxidase in pancreatic islets and other tissues in the mouse. Biochem J 199:393–398PubMedGoogle Scholar
  127. 127.
    Lenzen S, Drinkgern J, Tiedge M (1996) Low antioxidant enzyme gene expression in pancreatic islets compared with various other mouse tissues. Free Radic Biol Med 20:463–466. doi:10.1016/0891-5849(96)02051-5 PubMedCrossRefGoogle Scholar
  128. 128.
    Tiedge M, Lortz S, Drinkgern J et al (1997) Relation between antioxidant enzyme gene expression and antioxidative defense status of insulin-producing cells. Diabetes 46:1733–1742. doi:10.2337/diabetes.46.11.1733 PubMedCrossRefGoogle Scholar
  129. 129.
    Welsh N, Margulis B, Borg LA et al (1995) Differences in the expression of heat-shock proteins and antioxidant enzymes between human and rodent pancreatic islets: implications for the pathogenesis of insulin-dependent diabetes mellitus. Mol Med 1:806–820PubMedGoogle Scholar
  130. 130.
    Li X, Chen H, Epstein PN (2004) Metallothionein protects islets from hypoxia and extends islet graft survival by scavenging most kinds of reactive oxygen species. J Biol Chem 279:765–771. doi:10.1074/jbc.M307907200 PubMedCrossRefGoogle Scholar
  131. 131.
    Lortz S, Tiedge M, Nachtwey T et al (2000) Protection of insulin-producing RINm5F cells against cytokine-mediated toxicity through overexpression of antioxidant enzymes. Diabetes 49:1123–1130. doi:10.2337/diabetes.49.7.1123 PubMedCrossRefGoogle Scholar
  132. 132.
    Chen H, Li X, Epstein PN (2005) MnSOD and catalase transgenes demonstrate that protection of islets from oxidative stress does not alter cytokine toxicity. Diabetes 54:1437–1446. doi:10.2337/diabetes.54.5.1437 PubMedCrossRefGoogle Scholar
  133. 133.
    Mysore TB, Shinkel TA, Collins J et al (2005) Overexpression of glutathione peroxidase with two isoforms of superoxide dismutase protects mouse islets from oxidative injury and improves islet graft function. Diabetes 54:2109–2116. doi:10.2337/diabetes.54.7.2109 PubMedCrossRefGoogle Scholar
  134. 134.
    Heineke EW, Johnson MB, Dillberger JE et al (1993) Antioxidant MDL 29, 311 prevents diabetes in nonobese diabetic and multiple low-dose STZ-injected mice. Diabetes 42:1721–1730. doi:10.2337/diabetes.42.12.1721 PubMedCrossRefGoogle Scholar
  135. 135.
    Piganelli JD, Flores SC, Cruz C et al (2002) A metalloporphyrin-based superoxide dismutase mimic inhibits adoptive transfer of autoimmune diabetes by a diabetogenic T-cell clone. Diabetes 51:347–355. doi:10.2337/diabetes.51.2.347 PubMedCrossRefGoogle Scholar
  136. 136.
    Hotta M, Tashiro F, Ikegami H et al (1998) Pancreatic beta cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes. J Exp Med 188:1445–1451. doi:10.1084/jem.188.8.1445 PubMedCrossRefGoogle Scholar
  137. 137.
    Li X, Chen H, Epstein PN (2006) Metallothionein and catalase sensitize to diabetes in nonobese diabetic mice: reactive oxygen species may have a protective role in pancreatic beta-cells. Diabetes 55:1592–1604. doi:10.2337/db05-1357 PubMedCrossRefGoogle Scholar
  138. 138.
    Irie J, Shimada A, Oikawa Y et al (2004) N-acetyl-cysteine accelerates transfer of diabetes into non-obese diabetic scid mice. Diabetologia 47:1803–1809. doi:10.1007/s00125-004-1529-x PubMedCrossRefGoogle Scholar
  139. 139.
    Goldstein BJ, Mahadev K, Wu X (2005) Redox paradox: insulin action is facilitated by insulin-stimulated reactive oxygen species with multiple potential signaling targets. Diabetes 54:311–321. doi:10.2337/diabetes.54.2.311 PubMedCrossRefGoogle Scholar
  140. 140.
    Mahadev K, Motoshima H, Wu X et al (2004) The NAD(P)H oxidase homolog Nox4 modulates insulin-stimulated generation of H2O2 and plays an integral role in insulin signal transduction. Mol Cell Biol 24:1844–1854. doi:10.1128/MCB.24.5.1844-1854.2004 PubMedCrossRefGoogle Scholar
  141. 141.
    Castrillo A, Bodelon OG, Bosca L (2000) Inhibitory effect of IGF-I on type 2 nitric oxide synthase expression in Ins-1 cells and protection against activation-dependent apoptosis: involvement of phosphatidylinositol 3-kinase. Diabetes 49:209–217. doi:10.2337/diabetes.49.2.209 PubMedCrossRefGoogle Scholar
  142. 142.
    Chen W, Salojin KV, Mi QS et al (2004) Insulin-like growth factor (IGF)-I/IGF-binding protein-3 complex: therapeutic efficacy and mechanism of protection against type 1 diabetes. Endocrinology 145:627–638. doi:10.1210/en.2003-1274 PubMedCrossRefGoogle Scholar
  143. 143.
    Harrison M, Dunger AM, Berg S et al (1998) Growth factor protection against cytokine-induced apoptosis in neonatal rat islets of langerhans: role of Fas. FEBS Lett 435:207–210. doi:10.1016/S0014-5793(98)01051-5 PubMedCrossRefGoogle Scholar
  144. 144.
    Thomas D, Yang H, Boffa DJ et al (2002) Proapoptotic Bax is hyperexpressed in isolated human islets compared with antiapoptotic Bcl-2. Transplantation 74:1489–1496. doi:10.1097/00007890-200212150-00003 PubMedCrossRefGoogle Scholar
  145. 145.
    Kobayash H, Doi R, Hosotani R et al (2000) Immunohistochemical analysis of apoptosis-related proteins in human embryonic and fetal pancreatic tissues. Int J Pancreatol 27:113–122. doi:10.1385/IJGC:27:2:113 PubMedCrossRefGoogle Scholar
  146. 146.
    Naik P, Karrim J, Hanahan D (1996) The rise and fall of apoptosis during multistage tumorigenesis: down-modulation contributes to tumor progression from angiogenic progenitors. Genes Dev 10:2105–2116. doi:10.1101/gad.10.17.2105 PubMedCrossRefGoogle Scholar
  147. 147.
    Dupraz P, Rinsch C, Pralong WF et al (1999) Lentivirus-mediated Bcl-2 expression in betaTC-tet cells improves resistance to hypoxia and cytokine-induced apoptosis while preserving in vitro and in vivo control of insulin secretion. Gene Ther 6:1160–1169. doi:10.1038/sj.gt.3300922 PubMedCrossRefGoogle Scholar
  148. 148.
    Iwahashi H, Hanafusa T, Eguchi Y et al (1996) Cytokine-induced apoptotic cell death in a mouse pancreatic beta-cell line: inhibition by Bcl-2. Diabetologia 39:530–536. doi:10.1007/BF00403299 PubMedCrossRefGoogle Scholar
  149. 149.
    Liu Y, Rabinovitch A, Suarez-Pinzon W et al (1996) Expression of the bcl-2 gene from a defective HSV-1 amplicon vector protects pancreatic beta-cells from apoptosis. Hum Gene Ther 7:1719–1726. doi:10.1089/hum.1996.7.14-1719 PubMedCrossRefGoogle Scholar
  150. 150.
    Rabinovitch A, Suarez-Pinzon W, Strynadka K et al (1999) Transfection of human pancreatic islets with an anti-apoptotic gene (bcl-2) protects beta-cells from cytokine-induced destruction. Diabetes 48:1223–1229. doi:10.2337/diabetes.48.6.1223 PubMedCrossRefGoogle Scholar
  151. 151.
    Saldeen J (2000) Cytokines induce both necrosis and apoptosis via a common Bcl-2-inhibitable pathway in rat insulin-producing cells. Endocrinology 141:2003–2010. doi:10.1210/en.141.6.2003 PubMedCrossRefGoogle Scholar
  152. 152.
    Sutherland RM, Allison J, Thomas HE et al (2004) Bcl-2 protection of islet allografts is unmasked by costimulation blockade. Transplantation 77:1610–1613. doi:10.1097/01.TP.0000132283.95107.9C PubMedCrossRefGoogle Scholar
  153. 153.
    Barbu AR, Akusjarvi G, Welsh N (2002) Adenoviral-induced islet cell cytotoxicity is not counteracted by Bcl-2 overexpression. Mol Med 8:733–741PubMedGoogle Scholar
  154. 154.
    Tran VV, Chen G, Newgard CB et al (2003) Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy. Diabetes 52:1423–1432. doi:10.2337/diabetes.52.6.1423 PubMedCrossRefGoogle Scholar
  155. 155.
    Allison J, Thomas H, Beck D et al (2000) Transgenic overexpression of human Bcl-2 in islet beta cells inhibits apoptosis but does not prevent autoimmune destruction. Int Immunol 12:9–17. doi:10.1093/intimm/12.1.9 PubMedCrossRefGoogle Scholar
  156. 156.
    Farilla L, Bulotta A, Hirshberg B et al (2003) Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 144:5149–5158. doi:10.1210/en.2003-0323 PubMedCrossRefGoogle Scholar
  157. 157.
    Ranta F, Avram D, Berchtold S et al (2006) Dexamethasone induces cell death in insulin-secreting cells, an effect reversed by exendin-4. Diabetes 55:1380–1390. doi:10.2337/db05-1220 PubMedCrossRefGoogle Scholar
  158. 158.
    Shapiro AM, Lakey JR, Ryan EA et al (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 343:230–238. doi:10.1056/NEJM200007273430401 PubMedCrossRefGoogle Scholar
  159. 159.
    Biarnes M, Montolio M, Nacher V et al (2002) Beta-cell death and mass in syngeneically transplanted islets exposed to short- and long-term hyperglycemia. Diabetes 51:66–72. doi:10.2337/diabetes.51.1.66 PubMedCrossRefGoogle Scholar
  160. 160.
    Hering BJ, Kandaswamy R, Ansite JD et al (2005) Single-donor, marginal-dose islet transplantation in patients with type 1 diabetes. JAMA 293:830–835. doi:10.1001/jama.293.7.830 PubMedCrossRefGoogle Scholar
  161. 161.
    Korsgren O, Nilsson B, Berne C et al (2005) Current status of clinical islet transplantation. Transplantation 79:1289–1293. doi:10.1097/01.TP.0000157273.60147.7C PubMedCrossRefGoogle Scholar
  162. 162.
    Johansson H, Lukinius A, Moberg L et al (2005) Tissue factor produced by the endocrine cells of the islets of langerhans is associated with a negative outcome of clinical islet transplantation. Diabetes 54:1755–1762. doi:10.2337/diabetes.54.6.1755 PubMedCrossRefGoogle Scholar
  163. 163.
    Moberg L, Johansson H, Lukinius A et al (2002) Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet 360:2039–2045. doi:10.1016/S0140-6736(02)12020-4 PubMedCrossRefGoogle Scholar
  164. 164.
    Bottino R, Balamurugan AN, Tse H et al (2004) Response of human islets to isolation stress and the effect of antioxidant treatment. Diabetes 53:2559–2568. doi:10.2337/diabetes.53.10.2559 PubMedCrossRefGoogle Scholar
  165. 165.
    Piemonti L, Leone BE, Nano R et al (2002) Human pancreatic islets produce and secrete MCP-1/CCL2: relevance in human islet transplantation. Diabetes 51:55–65. doi:10.2337/diabetes.51.1.55 PubMedCrossRefGoogle Scholar
  166. 166.
    Marzorati S, Antonioli B, Nano R et al (2006) Culture medium modulates proinflammatory conditions of human pancreatic islets before transplantation. Am J Transplant 6:2791–2795. doi:10.1111/j.1600-6143.2006.01512.x PubMedCrossRefGoogle Scholar
  167. 167.
    Pileggi A, Molano RD, Berney T et al (2001) Heme oxygenase-1 induction in islet cells results in protection from apoptosis and improved in vivo function after transplantation. Diabetes 50:1983–1991. doi:10.2337/diabetes.50.9.1983 PubMedCrossRefGoogle Scholar
  168. 168.
    Riachy R, Vandewalle B, Belaich S et al (2001) Beneficial effect of 1, 25 dihydroxyvitamin D3 on cytokine-treated human pancreatic islets. J Endocrinol 169:161–168. doi:10.1677/joe.0.1690161 PubMedCrossRefGoogle Scholar
  169. 169.
    Yang Z, Chen M, Ellett JD et al (2005) Inflammatory blockade improves human pancreatic islet function and viability. Am J Transplant 5:475–483. doi:10.1111/j.1600-6143.2005.00707.x PubMedCrossRefGoogle Scholar
  170. 170.
    Wang H, Lee SS, Gao W et al (2005) Donor treatment with carbon monoxide can yield islet allograft survival and tolerance. Diabetes 54:1400–1406. doi:10.2337/diabetes.54.5.1400 PubMedCrossRefGoogle Scholar
  171. 171.
    Lewis EC, Shapiro L, Bowers OJ et al (2005) Alpha1-antitrypsin monotherapy prolongs islet allograft survival in mice. Proc Natl Acad Sci USA 102:12153–12158. doi:10.1073/pnas.0505579102 PubMedCrossRefGoogle Scholar
  172. 172.
    Langlois A, Bietiger W, Mandes K et al (2008) Overexpression of vascular endothelial growth factor in vitro using deferoxamine: a new drug to increase islet vascularization during transplantation. Transplant Proc 40:473–476. doi:10.1016/j.transproceed.2008.01.003 PubMedCrossRefGoogle Scholar
  173. 173.
    Hui H, Khoury N, Zhao X et al (2005) Adenovirus-mediated XIAP gene transfer reverses the negative effects of immunosuppressive drugs on insulin secretion and cell viability of isolated human islets. Diabetes 54:424–433. doi:10.2337/diabetes.54.2.424 PubMedCrossRefGoogle Scholar
  174. 174.
    Emamaullee JA, Stanton L, Schur C et al (2007) Caspase inhibitor therapy enhances marginal mass islet graft survival and preserves long-term function in islet transplantation. Diabetes 56:1289–1298. doi:10.2337/db06-1653 PubMedCrossRefGoogle Scholar
  175. 175.
    Sutton VR, Estella E, Li C et al (2006) A critical role for granzyme B, in addition to perforin and TNFalpha, in alloreactive CTL-induced mouse pancreatic beta cell death. Transplantation 81:146–154. doi:10.1097/01.tp.0000191939.68451.d9 PubMedCrossRefGoogle Scholar
  176. 176.
    Emamaullee JA, Shapiro AM (2006) Interventional strategies to prevent beta-cell apoptosis in islet transplantation. Diabetes 55:1907–1914. doi:10.2337/db05-1254 PubMedCrossRefGoogle Scholar
  177. 177.
    Contreras JL, Bilbao G, Smyth C et al (2001) Gene transfer of the Bcl-2 gene confers cytoprotection to isolated adult porcine pancreatic islets exposed to xenoreactive antibodies and complement. Surgery 130:166–174. doi:10.1067/msy.2001.115828 PubMedCrossRefGoogle Scholar
  178. 178.
    Grey ST, Arvelo MB, Hasenkamp WM et al (1999) Adenovirus-mediated gene transfer of the anti-apoptotic protein A20 in rodent islets inhibits IL-1 beta-induced NO release. Transplant Proc 31:789. doi:10.1016/S0041-1345(98)01769-2 PubMedCrossRefGoogle Scholar
  179. 179.
    Prentki M, Nolan CJ (2006) Islet beta cell failure in type 2 diabetes. J Clin Invest 116:1802–1812. doi:10.1172/JCI29103 PubMedCrossRefGoogle Scholar
  180. 180.
    Donath MY, Gross DJ, Cerasi E et al (1999) Hyperglycemia-induced beta-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes. Diabetes 48:738–744. doi:10.2337/diabetes.48.4.738 PubMedCrossRefGoogle Scholar
  181. 181.
    Pick A, Clark J, Kubstrup C et al (1998) Role of apoptosis in failure of beta-cell mass compensation for insulin resistance and beta-cell defects in the male Zucker diabetic fatty rat. Diabetes 47:358–364. doi:10.2337/diabetes.47.3.358 PubMedCrossRefGoogle Scholar
  182. 182.
    Zini E, Osto M, Franchini M et al (2009) Hyperglycaemia but not hyperlipidaemia causes beta cell dysfunction and beta cell loss in the domestic cat. Diabetologia 52:336–346. doi:10.1007/s00125-008-1201-y PubMedCrossRefGoogle Scholar
  183. 183.
    Federici M, Hribal M, Perego L et al (2001) High glucose causes apoptosis in cultured human pancreatic islets of langerhans: a potential role for regulation of specific Bcl family genes toward an apoptotic cell death program. Diabetes 50:1290–1301. doi:10.2337/diabetes.50.6.1290 PubMedCrossRefGoogle Scholar
  184. 184.
    Danial NN, Walensky LD, Zhang CY et al (2008) Dual role of proapoptotic BAD in insulin secretion and beta cell survival. Nat Med 14:144–153. doi:10.1038/nm1717 PubMedCrossRefGoogle Scholar
  185. 185.
    Tanaka Y, Tran PO, Harmon J et al (2002) A role for glutathione peroxidase in protecting pancreatic beta cells against oxidative stress in a model of glucose toxicity. Proc Natl Acad Sci USA 99:12363–12368. doi:10.1073/pnas.192445199 PubMedCrossRefGoogle Scholar
  186. 186.
    Chen J, Saxena G, Mungrue IN et al (2008) Thioredoxin-interacting protein: a critical link between glucose toxicity and beta-cell apoptosis. Diabetes 57:938–944. doi:10.2337/db07-0715 PubMedCrossRefGoogle Scholar
  187. 187.
    Nakayama M, Inoguchi T, Sonta T et al (2005) Increased expression of NAD(P)H oxidase in islets of animal models of type 2 diabetes and its improvement by an AT1 receptor antagonist. Biochem Biophys Res Commun 332:927–933. doi:10.1016/j.bbrc.2005.05.065 PubMedCrossRefGoogle Scholar
  188. 188.
    Ehses JA, Perren A, Eppler E et al (2007) Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56:2356–2370. doi:10.2337/db06-1650 PubMedCrossRefGoogle Scholar
  189. 189.
    Maedler K, Sergeev P, Ris F et al (2002) Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 110:851–860PubMedGoogle Scholar
  190. 190.
    Maedler K, Spinas GA, Lehmann R et al (2001) Glucose induces beta-cell apoptosis via upregulation of the Fas receptor in human islets. Diabetes 50:1683–1690. doi:10.2337/diabetes.50.8.1683 PubMedCrossRefGoogle Scholar
  191. 191.
    Welsh N, Cnop M, Kharroubi I et al (2005) Is there a role for locally produced interleukin-1 in the deleterious effects of high glucose or the type 2 diabetes milieu to human pancreatic islets? Diabetes 54:3238–3244. doi:10.2337/diabetes.54.11.3238 PubMedCrossRefGoogle Scholar
  192. 192.
    Elouil H, Cardozo AK, Eizirik DL et al (2005) High glucose and hydrogen peroxide increase c-Myc and haeme-oxygenase 1 mRNA levels in rat pancreatic islets without activating NFkappaB. Diabetologia 48:496–505. doi:10.1007/s00125-004-1664-4 PubMedCrossRefGoogle Scholar
  193. 193.
    Eizirik DL, Cardozo AK, Cnop M (2008) The role for endoplasmic reticulum stress in diabetes mellitus. Endocr Rev 29:42–61. doi:10.1210/er.2007-0015 PubMedCrossRefGoogle Scholar
  194. 194.
    Laybutt DR, Preston AM, Akerfeldt MC et al (2007) Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia 50:752–763. doi:10.1007/s00125-006-0590-z PubMedCrossRefGoogle Scholar
  195. 195.
    Huang CJ, Lin CY, Haataja L et al (2007) High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes 56:2016–2027. doi:10.2337/db07-0197 PubMedCrossRefGoogle Scholar
  196. 196.
    Zraika S, Hull RL, Udayasankar J et al (2009) Oxidative stress is induced by islet amyloid formation and time-dependently mediates amyloid-induced beta cell apoptosis. Diabetologia 52:626–635. doi:10.1007/s00125-008-1255-x PubMedCrossRefGoogle Scholar
  197. 197.
    Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529. doi:10.1038/nrm2199 PubMedCrossRefGoogle Scholar
  198. 198.
    Puthalakath H, O’Reilly LA, Gunn P et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129:1337–1349. doi:10.1016/j.cell.2007.04.027 PubMedCrossRefGoogle Scholar
  199. 199.
    Zinszner H, Kuroda M, Wang X et al (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995. doi:10.1101/gad.12.7.982 PubMedCrossRefGoogle Scholar
  200. 200.
    Wei MC, Zong WX, Cheng EH et al (2001) Proapoptotic BAX and BAK: a requisite gateway to mitochondrial dysfunction and death. Science 292:727–730. doi:10.1126/science.1059108 PubMedCrossRefGoogle Scholar
  201. 201.
    Zhou YP, Pena JC, Roe MW et al (2000) Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion. Am J Physiol Endocrinol Metab 278:E340–E351PubMedGoogle Scholar
  202. 202.
    Scheuner D, Kaufman RJ (2008) The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes. Endocr Rev 29:317–333. doi:10.1210/er.2007-0039 PubMedCrossRefGoogle Scholar
  203. 203.
    Haynes CM, Titus EA, Cooper AA (2004) Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death. Mol Cell 15:767–776. doi:10.1016/j.molcel.2004.08.025 PubMedCrossRefGoogle Scholar
  204. 204.
    Oyadomari S, Koizumi A, Takeda K et al (2002) Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest 109:525–532PubMedGoogle Scholar
  205. 205.
    Harding HP, Zeng H, Zhang Y et al (2001) Diabetes mellitus and exocrine pancreatic dysfunction in perk-/- mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163. doi:10.1016/S1097-2765(01)00264-7 PubMedCrossRefGoogle Scholar
  206. 206.
    Osman AA, Saito M, Makepeace C et al (2003) Wolframin expression induces novel ion channel activity in endoplasmic reticulum membranes and increases intracellular calcium. J Biol Chem 278:52755–52762. doi:10.1074/jbc.M310331200 PubMedCrossRefGoogle Scholar
  207. 207.
    Delepine M, Nicolino M, Barrett T et al (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat Genet 25:406–409. doi:10.1038/78085 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Helen E. Thomas
    • 1
    • 2
  • Mark D. McKenzie
    • 1
    • 2
  • Eveline Angstetra
    • 1
    • 2
  • Peter D. Campbell
    • 1
    • 2
  • Thomas W. Kay
    • 1
    • 2
  1. 1.St. Vincent’s Institute of Medical ResearchFitzroyAustralia
  2. 2.Department of Medicine, St. Vincent’s HospitalThe University of MelbourneFitzroy, MelbourneAustralia

Personalised recommendations