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β-Cell death during progression to diabetes

Nature volume 414, pages 792–798 (2001)Cite this article

Abstract

The hallmark of type 1 diabetes is specific destruction of pancreatic islet β-cells. Apoptosis of β-cells may be crucial at several points during disease progression, initiating leukocyte invasion of the islets and terminating the production of insulin in islet cells. β-Cell apoptosis may also be involved in the occasional evolution of type 2 into type 1 diabetes.

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Figure 1: Proposed scheme for the initiation of type 1 diabetes.
Figure 2: Intracellular death signalling molecules.
Figure 3: Proposed cellular mechanisms of β-cell death.

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References

  1. Tisch, R. & McDevitt, H. Insulin-dependent diabetes mellitus. Cell 85, 291–297 (1996).

    Article  CAS  PubMed  Google Scholar 

  2. Bach, J. F. & Mathis, D. 70th forum in immunology: the NOD mouse. Res. Immunol. 148, 281–370 (1997).

    Google Scholar 

  3. Hoglund, P. et al. Initiation of autoimmune diabetes by developmentally regulated presentation of islet cell antigens in the pancreatic lymph nodes. J. Exp. Med. 189, 331–339 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Green, E. A., Eynon, E. E. & Flavell, R. A. Local expression of TNFα in neonatal NOD mice promotes diabetes by enhancing presentation of islet antigens. Immunity 9, 733–743 (1998).

    CAS  PubMed  Google Scholar 

  5. Katz, J. D., Benoist, C. & Mathis, D. T helper cell subsets in insulin-dependent diabetes. Science 268, 1185–1188 (1995).

    CAS  ADS  PubMed  Google Scholar 

  6. Gonzalez, A. et al. Genetic control of diabetes progression. Immunity 7, 873–883 (1997).

    CAS  PubMed  Google Scholar 

  7. Finegood, D. T., Scaglia, L. & Bonner-Weir, S. Dynamics of β-cell mass in the growing rat pancreas. Diabetes 44, 249–256 (1995).

    CAS  PubMed  Google Scholar 

  8. Scaglia, L., Cahill, C. J., Finegood, D. T. & Bonner-Weir, S. Apoptosis participates in the remodeling of the endocrine pancreas in the neonatal rat. Endocrinology 138, 1736–1741 (1997).

    CAS  PubMed  Google Scholar 

  9. Petrik, J., Arany, E., McDonald, T. J. & Hill, D. J. Apoptosis in the pancreatic islet cells of the neonatal rat is associated with a reduced expression of insulin-like growth factor II that may act as a survival factor. Endocrinology 139, 2994–3004 (1998).

    CAS  PubMed  Google Scholar 

  10. Trudeau, J. D. et al. Neonatal β-cell apoptosis: a trigger for autoimmune diabetes? Diabetes 49, 1–7 (2000).

    CAS  PubMed  Google Scholar 

  11. Kassem, S. A., Ariel, I., Thornton, P. S., Scheimberg, I. & Glaser, B. β-cell proliferation and apoptosis in the developing normal human pancreas and in hyperinsulinism of infancy. Diabetes 49, 1325–1333 (2000).

    CAS  PubMed  Google Scholar 

  12. Steinman, R. M., Turley, S., Mellman, I. & Inaba, K. The induction of tolerance by dendritic cells that have captured apoptotic cells. J. Exp. Med. 191, 411–416 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bellone, M. et al. Processing of engulfed apoptotic bodies yields T cell epitopes. J. Immunol. 159, 5391–5399 (1997).

    CAS  PubMed  Google Scholar 

  14. Pittoni, V. & Isenberg, D. Apoptosis and antiphospholipid antibodies. Semin. Arthritis Rheum. 28, 163–178 (1998).

    CAS  PubMed  Google Scholar 

  15. Coles, H. S. R., Burne, J. F. & Raff, M. C. Large-scale normal cell death in the developing rat kidney and its reduction by epidermal growth factor. Development 118, 777–784 (1993).

    CAS  PubMed  Google Scholar 

  16. Meier, P., Finch, A. & Evan, G. Apoptosis in development. Nature 407, 796–801 (2001).

    ADS  Google Scholar 

  17. Chautan, M., Chazal, G., Cecconi, F., Gruss, P. & Golstein, P. Interdigital cell death can occur through a necrotic and caspase-independent pathway. Curr. Biol. 9, 967–970 (1999).

    CAS  PubMed  Google Scholar 

  18. Jacobson, M. D., Weil, M. & Raff, M. C. Programmed cell death in animal development. Cell 88, 347–354 (1997).

    CAS  PubMed  Google Scholar 

  19. Mayor, F. & Cuezva, J. M. Hormonal and metabolic changes in the perinatal period. Biol. Neonate 48, 185–196 (1985).

    CAS  PubMed  Google Scholar 

  20. Parham, P. Intolerable secretion in tolerant transgenice mice. Nature 333, 500–503 (1988).

    CAS  PubMed  ADS  Google Scholar 

  21. Li, K. et al. Cytochrome c deficiency causes embryonic lethality and attenuates stress-induced apoptosis. Cell 101, 389–399 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Cecconi, F., Alvarez-Bolado, G., Meyer, B. I., Roth, K. A. & Gruss, P. Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94, 727–737 (1998).

    CAS  PubMed  Google Scholar 

  23. Yoshida, H. et al. Apaf1 is required for mitochondrial pathways of apoptosis and brain development. Cell 94, 739–750 (1998).

    CAS  PubMed  Google Scholar 

  24. Hakem, R. et al. Differential requirement for caspase 9 in apoptotic pathways in vivo. Cell 94, 339–352 (1998).

    CAS  PubMed  Google Scholar 

  25. Kuida, K. et al. Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94, 325–337 (1998).

    CAS  PubMed  Google Scholar 

  26. Nakagawa, T. et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-β. Nature 403, 98–103 (2000).

    CAS  ADS  PubMed  Google Scholar 

  27. Rao, R. V. et al. Coupling endoplasmic reticulum stress to the cell death program: mechanism of caspase activation. J. Biol. Chem. (in the press).

  28. Nakagawa, T. & Yuan, J. Cross-talk between two cysteine protease families. Activation of caspase 12 by calpain in apoptosis. J. Cell Biol. 150, 887–894 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Yoneda, T. et al. Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor recepto-associated factor 2-dependent mechanism in response to the ER stress. J. Biol. Chem. 276, 13935–13940 (2001).

    CAS  PubMed  Google Scholar 

  30. Wegmann, D. R. The immune response to islets in experimental diabetes and insulin-dependent diabetes mellitus. Curr. Opin. Immunol. 8, 860–864 (1996).

    CAS  PubMed  Google Scholar 

  31. Benoist, C. & Mathis, D. Autoimmunity provoked by infection: how good is the case for T cell epitope mimicry? Nature Immunol. 2, 797–801 (2001).

    CAS  Google Scholar 

  32. Huang, F.-P. et al. A discrete subpopulation of dendritic cells transports apoptotic intestinal epithelial cells to T cell areas of mesenteric lymph nodes. J. Exp. Med. 191, 435–443 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Wong, F. S., Visintin, I., Wen, L., Flavell, R. A. & Janeway, C. A. 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 (1996).

    CAS  PubMed  Google Scholar 

  34. Graser, R. T. et al. 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, 3913–3918 (2000).

    CAS  PubMed  Google Scholar 

  35. Itoh, N. et al. Mononuclear cell infiltration and its relation to the expression of major histocompatibility complex antigens and adhesion moleucles in pancreas biospy speciments from newly diagnosed insulin-dependent diabetes mellitus patients. J. Clin. Invest. 92, 2313–2322 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kurrer, M. O., Pakala, S. V., Hanson, H. L. & Katz, J. D. β cell apoptosis in T cell-mediated autoimmune diabetes. Proc. Natl Acad. Sci. USA 94, 213–218 (1997).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  37. Serreze, D. V. et al. Initiation of autoimmune diabetes in NOD/Lt mice is MHC class I-dependent. J. Immunol. 158, 3978–3986 (1997).

    CAS  PubMed  Google Scholar 

  38. Sarukhan, A., Lechner, O. & von Boehmer, H. Autoimmune insulitis and diabetes in the absence of antigen-specific contact between T cells and islet β-cells. Eur. J. Immunol. 29, 3410–3416 (1999).

    CAS  PubMed  Google Scholar 

  39. Thomas, H. E. & Kay, T. W. H. Beta cell destruction in the development of autoimmune diabetes in the non-obese diabetic (NOD) mouse. Diabetes Metab. Res. Rev. 16, 251–261 (2000).

    CAS  PubMed  Google Scholar 

  40. O'Brien, B. A., Harmon, B. V., Cameron, D. P. & Allan, D. J. Apoptosis is the mode of beta-cell death responsible for the development of IDDM in the nonobese diabetic (NOD) mouse. Diabetes 46, 750–757 (1997).

    CAS  PubMed  Google Scholar 

  41. Kagi, D. et al. Reduced incidence and delayed onset of diabetes in perforin-deficient nonobese diabetic mice. J. Exp. Med. 186, 989–997 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Amrani, A. et al. Perforin-independent β-cell destruction by diabetogenic CD8+ T lymphocytes in transgenic nonobese diabetic mice. J. Clin. Invest. 103, 1201–1209 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Kagi, D., Odermatt, B., Ohashi, P. S., Zinkernagel, R. M. & Hengartner, H. Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity. J. Exp. Med. 183, 2143–2152 (1996).

    CAS  PubMed  Google Scholar 

  44. Seewaldt, S. et al. Virus-induced autoimmune diabetes: most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes 49, 1801–1809 (2000).

    CAS  PubMed  Google Scholar 

  45. Kreuwel, H. T. et al. 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, 4335–4341 (1999).

    CAS  PubMed  Google Scholar 

  46. Badovinac, V. P., Tvinnereim, A. R. & Harty, J. T. Regulation of antigen-specific CD8+ T cell homeostasis by perforin and interferon-gamma. Science 290, 1354–1358 (2000).

    CAS  PubMed  ADS  Google Scholar 

  47. Krammer, P. H. CD95's deadly mission in the immune system. Nature 407, 789–795 (2000).

    CAS  PubMed  ADS  Google Scholar 

  48. Chervonsky, A. V. et al. The role of Fas in autoimmune diabetes. Cell 89, 17–24 (1997).

    CAS  PubMed  Google Scholar 

  49. Thomas, H. E., Darwiche, R., Corbett, J. A. & Kay, T. W. H. Evidence that β cell death in the nonobese diabetic mouse is Fas independent. J. Immunol. 163, 1562–1569 (1999).

    CAS  PubMed  Google Scholar 

  50. Loweth, A. C., Williams, G. T., James, R. F. L., Scarpello, J. H. B. & Morgan, N. G. Human islets of Langerhans express Fas ligand and undergo apoptosis in response to interleukin-1β and Fas ligation. Diabetes 47, 727–732 (1998).

    CAS  PubMed  Google Scholar 

  51. Itoh, N. et al. Requirement of Fas for the development of autoimmune diabetes in nonobese diabetic mice. J. Exp. Med. 186, 613–618 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Allison, J. & Strasser, A. Mechanisms of beta cell death in diabetes: a minor role for CD95. Proc. Natl Acad. Sci. USA 95, 13818–13822 (1998).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  53. Kim, Y. H. et al. Apoptosis of pancreatic beta-cells detected in accelerated diabetes of NOD mice: no role of Fas-Fas ligand interaction in autoimmune diabetes. Eur. J. Immunol. 29, 455–465 (1999).

    CAS  PubMed  Google Scholar 

  54. Watanabe, D., Suda, T., Hashimoto, H. & Nagata, S. Constitutive activation of the Fas ligand gene in mouse lymphoproliferative disorders. EMBO J. 14, 12–18 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Kim, S. et al. Inhibition of autoimmune diabetes by Fas ligand: the paradox is solved. J. Immunol. 164, 2931–2936 (2000).

    CAS  PubMed  Google Scholar 

  56. Su, X. et al. Signficant role for Fas in the pathogenesis of autoimmune diabetes. J. Immunol. 164, 2523–2532 (2000).

    CAS  PubMed  Google Scholar 

  57. Herrera, P. L., Harlan, D. M. & Vassalli, P. A mouse CD8 T cell-mediated acute autoimmune diabetes independent of the perforin and Fas cytotoxic pathways: possible role of membrane TNF. Proc. Natl Acad. Sci. USA 97, 279–284 (2000).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  58. Walter, U. et al. Monitoring gene expressino of TNFR family members by β-cells during development of autoimmune diabetes. Eur. J. Immunol. 30, 1224–1232 (2000).

    CAS  PubMed  Google Scholar 

  59. Beutler, B. A. The role of tumor necrosis factor in health and disease. J. Rheumatol. 57, 16–21 (1999).

    CAS  Google Scholar 

  60. Mueller, C., Held, W., Imboden, M. A. & Carnaud, C. Accelerated β-cell destruction in adoptively transferred autoimmune diabetes correlates with an increased expression of the genes coding for TNF-α and granzyme A in the intra-islet infiltrates. Diabetes 44, 112–117 (1995).

    CAS  PubMed  Google Scholar 

  61. Kaneto, H. et al. Apoptotic cell death triggered by nitric oxide in pancreatic β-cells. Diabetes 44, 733–738 (1995).

    CAS  PubMed  Google Scholar 

  62. Mandrup-Poulsen, T., Bendtzen, K., Dinarello, C. A. & Nerup, J. Human tumor necrosis factor potentiates human interleukin 1-mediated rat pancreatic beta-cell cytotoxicity. J. Immunol. 139, 4077–4082 (1987).

    CAS  PubMed  Google Scholar 

  63. Yang, X.-D. et al. Effect of tumor necrosis factor α on insulin-dependent diabetes mellitus in NOD mice. I. The early development of autoimmunity and the diabetogenic process. J. Exp. Med. 180, 995–1004 (1994).

    CAS  PubMed  Google Scholar 

  64. Kagi, D. et al. TNF receptor 1-dependent β cell toxicity as an effector pathway in autoimmune diabetes. J. Immunol. 162, 4598–4605 (1999).

    CAS  PubMed  Google Scholar 

  65. Pakala, S. V., Chivetta, M., Kelly, C. B. & Katz, J. D. In autoimmune diabetes the transition from benign to pernicious insulitis requires an islet cell response to tumor necrosis factor α. J. Exp. Med. 189, 1053–1062 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Corbett, J. A. & McDaniel, M. L. Intraislet release of interleukin 1 inhibits β cell function by inducing β cell expression of inducible nitric oxide synthase. J. Exp. Med. 181, 559–568 (1995).

    CAS  PubMed  Google Scholar 

  67. Kroncke, K. D., Funda, J., Berschick, B., Kolb, H. & Kolb-Bachofen, V. Macrophage cytotoxicity towards isolated rat islet cells: neither lysis nor its protection by nicotinamide are beta-cell specific. Diabetologia 34, 232–238 (1991).

    CAS  PubMed  Google Scholar 

  68. Corbett, J. A., Lancaster, J. R. Jr, weetland, M. A. & McDaniel, M. L. Interleukin-1β-induced formation of EPR-detectable iron-nitrosyl complexes in islets of Langerhans. J. Biol. Chem. 266, 21351–21354 (1991).

    CAS  PubMed  Google Scholar 

  69. Corbett, J. A. et al. Nitric oxide production in islets from nonobese diabetic mice: aminoguanidine-sensitive and -resistant stages in the immunological diabetic process. Proc. Natl Acad. Sci. USA 90, 8992–8995 (1993).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  70. Rothe, H., Burkart, V., Faust, A. & Kolb, H. Interleukin-12 gene expression is associated with rapid development of diabetes mellitus in non-obese diabetic mice. Diabetologia 39, 119–122 (1996).

    CAS  PubMed  Google Scholar 

  71. Rabinovitch, A. et al. Human pancreatic islet beta-cell destruction by cytokines is independent of nitric oxide production. J. Clin. Endocrinol. Metab. 79, 1058–1062 (1994).

    CAS  PubMed  Google Scholar 

  72. Stassi, G. et al. Nitric oxide primes pancreatic beta cells for Fas-mediated destruction in insulin-dependent diabetes mellitus. J. Exp. Med. 186, 1193–1200 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Delaney, C. A. et al. Sensitivity of human pancreatic islets to peroxynitrite-induced cell dysfunction and death. FEBS Lett. 394, 300–306 (1996).

    CAS  PubMed  Google Scholar 

  74. Rabinovitch, A., Suarez, W. L., Thomas, P. D., Strynadka, K. & Simpson, I. Cytotoxic effects of cytokines on rat islets: evidence for involvement of free radicals and lipid peroxidation. Diabetologia 35, 409–413 (1992).

    CAS  PubMed  Google Scholar 

  75. Lortz, S. et al. Protection of insulin-producing RINm5F cells against cytokine-mediated toxicity through overexpression of antioxidant enzymes. Diabetes 49, 1123–1130 (2000).

    CAS  PubMed  Google Scholar 

  76. Hohmeier, H. E., Thigpen, A., Tran, W., Davis, R. & Newgard, C. B. Stable expression of manganese superoxide dismutase (MnSOD) in insulinoma cells prevents IL-1β-induced cytotoxicity and reduces nitric oxide production. J. Clin. Invest. 101, 1811–1820 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Hotta, M. et al. Pancreatic β cell-specific expression of thioredoxin, an antioxidative and antiapoptotic protein, prevents autoimmune and streptozotocin-induced diabetes. J. Exp. Med. 188, 1445–1451 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Mathews, C. E., Graser, R. T., Savinov, A., Serreze, D. V. & Leither, E. H. Unusual resistance of ALR/Lt mouse beta cells to autoimmune destruction: role for beta cell-expressed resistance determinants. Proc. Natl Acad. Sci. USA 98, 235–240 (2001).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  79. Allison, J. et al. Transgenic overexpression of human Bcl-2 in islet β cells inhibits apoptosis but does not prevent autoimmune destruction. Int. Immunol. 12, 9–17 (2000).

    CAS  PubMed  Google Scholar 

  80. Eizirik, D. L. et al. Major species differences between humans and rodents in the susceptibility to pancreatic β-cell injury. Proc. Natl Acad. Sci. USA 91, 9253–9256 (1994).

    CAS  ADS  PubMed  PubMed Central  Google Scholar 

  81. Klaus, G. G., Pepys, M. B., Kitajima, K. & Askonas, B. A. Activation of mouse complement by different classes of mouse antibody. Immunology 38, 687–695 (1979).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Bach, J. F. Insulin-dependent diabetes mellitus as an autoimmune disease. Endocr. Rev. 15, 516–542 (1994).

    CAS  PubMed  Google Scholar 

  83. Taylor, S. I. Deconstructing type 2 diabetes. Cell 97, 9–12 (1999).

    CAS  PubMed  Google Scholar 

  84. Shimabukuro, M., Ohneda, M., Lee, Y. & Unger, R. H. Islet amyloid, increased A-cells, reduced B-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes. Diabetes Res. 9, 151–159 (1988).

    Google Scholar 

  85. Sempoux, C., Guiot, Y., Dubois, D., Moulin, P. & Rahier, J. Human type 2 diabetes: morphological evidence for abnormal β-cell function. Diabetes 50, S172–S177 (2001).

  86. Guiot, Y., Sempoux, C., Moulin, P. & Rahier, J. No decrease of the β-cell mass in type 2 diabetic patients. Diabetes 50, S188 (2001).

  87. Federici, M. et al. High glucose causes apoptosis in cultured human pancreatic islets of Langerhans. Diabetes 50, 1290–1301 (2001).

    CAS  PubMed  Google Scholar 

  88. Bar-On, H., Ben-Sasson, R., Ziv, E., Arar, N. & Shafrir, E. Irreversibility of nutritionally induced NIDDM in Psammomys obesus is related to beta-cell apoptosis. Pancreas 18, 259–265 (1999).

    CAS  PubMed  Google Scholar 

  89. Donath, M. Y., Gorss, D. J., Cerasi, E. & Kaiser, N. Hyperglycemia-induced β-cell apoptosis in pancreatic islets of psammomys obesus during development of diabetes. Diabetes 48, 738–744 (1999).

    CAS  PubMed  Google Scholar 

  90. Leibowitz, G. et al. β-cell glucotoxicity in the psammomys obesus model of type 2 diabetes. Diabetes 50, S113–S117 (2001).

    CAS  PubMed  Google Scholar 

  91. Shimabukuro, M., Zhou, Y. T., Levi, M. & Unger, R. H. Fatty acid-induced beta cell apoptosis: a link between obesity and diabetes. Proc. Natl Acad. Sci. USA 95, 2498–2502 (1998).

    CAS  PubMed  ADS  PubMed Central  Google Scholar 

  92. Efanova, I. B. et al. Glucose and tolbutamide induce apoptosis in pancreatic beta-cells: a process dependent on intracellular Ca2+ concentration. J. Biol. Chem. 273, 33501–33507 (1998).

    CAS  PubMed  Google Scholar 

  93. Withers, D. J. et al. Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling. Nature Genet. 23, 32–40 (1999).

    CAS  PubMed  Google Scholar 

  94. Harding, H. P. et al. Diabetes mellitus and exocrine pancreatic dysfunction in perk−/− mice reveals a role for translational control in secretory cell survival. Mol. Cell 7, 1153–1163 (2001).

    CAS  PubMed  Google Scholar 

  95. Gilligan, M. et al. Glucose stimulates the activity of the guanine nucleotide-exchange factor eIF-2B in isolated rat islets of Langerhans. J. Biol. Chem. 271, 2121–2125 (1996).

    CAS  PubMed  Google Scholar 

  96. Delepine, M. et al. EIF2AK3, encoding translation initiation factor 2-α kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nature Genet. 25, 406–409 (2000).

    CAS  PubMed  Google Scholar 

  97. Guerder, S., Eynon, E. E. & Flavell, R. A. Autoimmunity without diabetes in transgenic mice expressing β cell-specific CD86, but not CD80: parameters that trigger progression to diabetes. J. Immunol. 161, 2128–2140 (1998).

    CAS  PubMed  Google Scholar 

  98. Katz, J. D., Wang, B., Haskins, K., Benoist, C. & Mathis, D. Following a diabetogenic T cell from genesis through pathogenesis. Cell 74, 1089–1100 (1993).

    CAS  PubMed  Google Scholar 

  99. Ohashi, P. S. et al. Ablation of “tolerance” and induction of diabetes by virus infection in viral antigen transgenic mice. Cell 65, 305–317 (1991).

    CAS  PubMed  Google Scholar 

  100. Sarvetnick, N., Liggitt, D., Pitts, S. L., Hansen, S. E. & Stewart, T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell 52, 773–782 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We apologize to the many investigators whose work we could not cite due to a limit on the number of references. We thank C. R. Kahn for his insights into type 2 diabetes. Our work on β-cell death is funded by a research grant from the Juvenile Diabetes Research Foundation.

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Authors and Affiliations

  1. Section on Immunology and Immunogenetics, Joslin Diabetes Centre, One Joslin Place, Boston, 02215, Massachusetts, USA

    Diane Mathis

  2. Department of Medicine, Brigham and Women's Hospital, One Joslin Place, Boston, 02215, Massachusetts, USA

    Luis Vence

  3. Harvard Medical School, One Joslin Place, Boston, 02215, Massachusetts, USA

    Christophe Benoist

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Correspondence to Christophe Benoist.

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Mathis, D., Vence, L. & Benoist, C. β-Cell death during progression to diabetes. Nature 414, 792–798 (2001). https://doi.org/10.1038/414792a

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