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Rat Models of Human Type 1 Diabetes

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Book cover Animal Models of Diabetes

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2128))

Abstract

Rat models of human type 1 diabetes have been shown to be of great importance for the elucidation of the mechanisms underlying the development of autoimmune diabetes. The three major well-established spontaneous rat models are the BioBreeding (BB) diabetes-prone rat, the Komeda diabetes-prone (KDP) rat, and the IDDM (LEW.1AR1-iddm) rat. Their distinctive features are described with special reference to their pathology, immunology, and genetics and compared with the situation in patients with type 1 diabetes mellitus. For all three established rat models, a distinctive genetic mutation has been identified that is responsible for the manifestation of the diabetic syndrome in these rat strains.

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References

  1. Yanagisawa M, Hara Y, Satoh K et al (1986) Spontaneous autoimmune thyroiditis in Bio Breeding/Worcester (BB/W) rat. Endocrinol Jpn 33:851–861

    Article  CAS  PubMed  Google Scholar 

  2. Mordes JP, Poussier P, Rossini AA, Blankenhorn EP, Greiner DL (2007) Rat models of type 1 diabetes: genetics, environment, and autoimmunity. In: Shafrir E (ed) Animal models of diabetes. CRC Press, Boca Raton, FL

    Google Scholar 

  3. Yokoi N, Hayashi C, Fujiwara Y, Wang HY, Seino S (2007) Genetic reconstitution of autoimmune type 1 diabetes with two major susceptibility genes in the rat. Diabetes 56:506–512

    Article  CAS  PubMed  Google Scholar 

  4. Rajatanavin R, Appel MC, Reinhardt W, Alex S, Yang YN, Braverman LE (1991) Variable prevalence of lymphocytic thyroiditis among diabetes-prone sublines of BB/W or rats. Endocrinology 128:153–157

    Article  CAS  PubMed  Google Scholar 

  5. Jörns A, Kubat B, Tiedge M et al (2004) Pathology of the pancreas and other organs in the diabetic LEW.1AR1/Ztm- iddm rat, a new model of spontaneous insulin-dependent diabetes mellitus. Virchows Arch 444:183–189

    Article  PubMed  Google Scholar 

  6. Scott FW (1996) Food-induced type 1 diabetes in the BB rat. Diabetes Metab Rev 12:341–359

    Article  CAS  PubMed  Google Scholar 

  7. Komeda K, Noda M, Terao K, Kuzuya N, Kanazawa M, Kanazawa Y (1998) Establishment of two substrains, diabetes-prone and non-diabetic, from Long-Evans Tokushima Lean (LETL) rats. Endocr J 45:737–744

    Article  CAS  PubMed  Google Scholar 

  8. Lenzen S, Tiedge M, Elsner M et al (2001) The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia 44:1189–1196

    Article  CAS  PubMed  Google Scholar 

  9. Guberski DL, Thomas VA, Shek WR et al (1991) Induction of type I diabetes by Kilham's rat virus in diabetes-resistant BB/Wor rats. Science 254:1010–1013

    Article  CAS  PubMed  Google Scholar 

  10. Yoon JW, Jun HS (2006) Viruses cause type 1 diabetes in animals. Ann N Y Acad Sci 1079:138–146

    Article  PubMed  Google Scholar 

  11. Markholst H, Klaff LJ, Klöppel G, Lernmark A, Mordes JP, Palmer J (1990) Lack of systematically found insulin autoantibodies in spontaneously diabetic BB rats. Diabetes 39:720–727

    Article  CAS  PubMed  Google Scholar 

  12. Nakhooda AF, Like AA, Chappel CI, Murray FT, Marliss EB (1977) The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes 26:100–112

    Article  CAS  PubMed  Google Scholar 

  13. Mordes JP, Desemone J, Rossini AA (1987) The BB rat. Diabetes Metab Rev 3:725–750

    Article  CAS  PubMed  Google Scholar 

  14. Scott J (1990) The spontaneously diabetic BB rat: sites of the defects leading to autoimmunity and diabetes mellitus. A review. Curr Top Microbiol Immunol 156:1–14

    CAS  PubMed  Google Scholar 

  15. Mordes JP, Guberski DL, Leif JH et al (2005) LEW.1WR1 rats develop autoimmune diabetes spontaneously and in response to environmental perturbation. Diabetes 54:2727–2733

    Article  CAS  PubMed  Google Scholar 

  16. Jackson R, Rassi N, Crump T, Haynes B, Eisenbarth GS (1981) The BB diabetic rat. Profound T-cell lymphocytopenia. Diabetes 30:887–889

    Article  CAS  PubMed  Google Scholar 

  17. Elder ME, Maclaren NK (1983) Identification of profound peripheral T lymphocyte immunodeficiencies in the spontaneously diabetic BB rat. J Immunol 130:1723–1731

    CAS  PubMed  Google Scholar 

  18. MacMurray AJ, Moralejo DH, Kwitek AE et al (2002) Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene. Genome Res 12:1029–1039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ramanathan S, Poussier P (2001) BB rat lyp mutation and type 1 diabetes. Immunol Rev 184:161–171

    Article  CAS  PubMed  Google Scholar 

  20. Yale JF, Grose M, Marliss EB (1985) Time course of the lymphopenia in BB rats. Relation to the onset of diabetes. Diabetes 34:955–959

    Article  CAS  PubMed  Google Scholar 

  21. Nakamura N, Tsutsumi Y, Kimata S et al (1991) Induction of diabetes by poly I:C and anti-RT6.1 antibody treatment in DR-BB rats. Endocrinol Jpn 38:523–526

    Article  CAS  PubMed  Google Scholar 

  22. Bortel R, Waite DJ, Whalen BJ et al (2001) Levels of Art2+ cells but not soluble Art2 protein correlate with expression of autoimmune diabetes in the BB rat. Autoimmunity 33:199–211

    Article  CAS  PubMed  Google Scholar 

  23. Joseph S, Diamond AG, Smith W, Baird JD, Butcher GW (1993) BB-DR/Edinburgh: a lymphopenic, non-diabetic subline of BB rats. Immunology 78:318–328

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Like AA, Guberski DL, Butler L (1986) Diabetic BioBreeding/Worcester (BB/Wor) rats need not be lymphopenic. J Immunol 136:3254–3258

    CAS  PubMed  Google Scholar 

  25. Awata T, Guberski DL, Like AA (1995) Genetics of the BB rat: association of autoimmune disorders (diabetes, insulitis, and thyroiditis) with lymphopenia and major histocompatibility complex class II. Endocrinology 136:5731–5735

    Article  CAS  PubMed  Google Scholar 

  26. Hawkins T, Fuller J, Olson K, Speros S, Lernmark A (2005) DR.lyp/lyp bone marrow maintains lymphopenia and promotes diabetes in lyp/lyp but not in +/+ recipient DR.lyp BB rats. J Autoimmun 25:251–257

    Article  CAS  PubMed  Google Scholar 

  27. Medina A, Parween S, Ullsten S et al (2017) Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats. Diabetologia 61:896–905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Arndt T, Jörns A, Weiss H et al (2013) A variable CD3(+) T-cell frequency in peripheral blood lymphocytes associated with type 1 diabetes mellitus development in the LEW.1AR1-iddm rat. PLoS One 8:e64305

    Article  PubMed  PubMed Central  Google Scholar 

  29. Wilcox NS, Rui J, Hebrok M, Herold KC (2016) Life and death of beta cells in type 1 diabetes: a comprehensive review. J Autoimmun 71:51–58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Arndt T, Jörns A, Hedrich HJ, Lenzen S, Wedekind D (2014) Variable immune cell frequencies in peripheral blood of LEW.1AR1-iddm rats over time compared to other congenic LEW strains. Clin Exp Immunol 177:168–178

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T (1991) New inbred strain of Long-Evans Tokushima lean rats with IDDM without lymphopenia. Diabetes 40:1375–1381

    Article  CAS  PubMed  Google Scholar 

  32. Yokoi N, Namae M, Fuse M et al (2003) Establishment and characterization of the Komeda diabetes-prone rat as a segregating inbred strain. Exp Anim 52:295–301

    Article  CAS  PubMed  Google Scholar 

  33. McKeever U, Mordes JP, Greiner DL et al (1990) Adoptive transfer of autoimmune diabetes and thyroiditis to athymic rats. Proc Natl Acad Sci U S A 87:7618–7622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Whalen BJ, Greiner DL, Mordes JP, Rossini AA (1994) Adoptive transfer of autoimmune diabetes mellitus to athymic rats: synergy of CD4+ and CD8+ T cells and prevention by RT6+ T cells. J Autoimmun 7:819–831

    Article  CAS  PubMed  Google Scholar 

  35. Wedekind D, Weiss H, Jörns A, Lenzen S, Tiedge M, Hedrich HJ (2005) Effects of polyinosinic-polycytidylic acid and adoptive transfer of immune cells in the Lew.1AR1-iddm rat and in its coisogenic LEW.1AR1 background strain. Autoimmunity 38:265–275

    Article  CAS  PubMed  Google Scholar 

  36. Arndt T, Wedekind D, Weiss H et al (2009) Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes. Diabetologia 52:1381–1390

    Article  CAS  PubMed  Google Scholar 

  37. Metroz-Dayer MD, Mouland A, Brideau C, Duhamel D, Poussier P (1990) Adoptive transfer of diabetes in BB rats induced by CD4 T lymphocytes. Diabetes 39:928–932

    Article  CAS  PubMed  Google Scholar 

  38. Logothetopoulos J, Valiquette N, Madura E, Cvet D (1984) The onset and progression of pancreatic insulitis in the overt, spontaneously diabetic, young adult BB rat studied by pancreatic biopsy. Diabetes 33:33–36

    Article  CAS  PubMed  Google Scholar 

  39. Lally FJ, Ratcliff H, Bone AJ (2001) Apoptosis and disease progression in the spontaneously diabetic BB/S rat. Diabetologia 44:320–324

    Article  CAS  PubMed  Google Scholar 

  40. Jörns A, Günther A, Hedrich HJ, Wedekind D, Tiedge M, Lenzen S (2005) Immune cell infiltration, cytokine expression, and beta-cell apoptosis during the development of type 1 diabetes in the spontaneously diabetic LEW.1AR1/Ztm-iddm rat. Diabetes 54:2041–2052

    Article  PubMed  Google Scholar 

  41. Oschilewski U, Kiesel U, Kolb H (1985) Administration of silica prevents diabetes in BB-rats. Diabetes 34:197–199

    Article  CAS  PubMed  Google Scholar 

  42. Walker R, Bone AJ, Cooke A, Baird JD (1988) Distinct macrophage subpopulations in pancreas of prediabetic BB/E rats. Possible role for macrophages in pathogenesis of IDDM. Diabetes 37:1301–1304

    Article  CAS  PubMed  Google Scholar 

  43. Voorbij HA, Jeucken PH, Kabel PJ, De Haan M, Drexhage HA (1989) Dendritic cells and scavenger macrophages in pancreatic islets of prediabetic BB rats. Diabetes 38:1623–1629

    Article  CAS  PubMed  Google Scholar 

  44. Hanenberg H, Kolb-Bachofen V, Kantwerk-Funke G, Kolb H (1989) Macrophage infiltration precedes and is a prerequisite for lymphocytic insulitis in pancreatic islets of pre-diabetic BB rats. Diabetologia 32:126–134

    Article  CAS  PubMed  Google Scholar 

  45. Sobel DO, Azumi N, Creswell K et al (1995) The role of NK cell activity in the pathogenesis of poly I:C accelerated and spontaneous diabetes in the diabetes prone BB rat. J Autoimmun 8:843–857

    Article  CAS  PubMed  Google Scholar 

  46. Iwakoshi NN, Greiner DL, Rossini AA, Mordes JP (1999) Diabetes prone BB rats are severely deficient in natural killer T cells. Autoimmunity 31:1–14

    Article  CAS  PubMed  Google Scholar 

  47. Todd DJ, Forsberg EM, Greiner DL, Mordes JP, Rossini AA, Bortell R (2004) Deficiencies in gut NK cell number and function precede diabetes onset in BB rats. J Immunol 172:5356–5362

    Article  CAS  PubMed  Google Scholar 

  48. Jörns A, Arndt T, Meyer zu Vilsendorf A et al (2014) Islet infiltration, cytokine expression and beta cell death in the NOD mouse, BB rat, Komeda rat, LEW.1AR1-iddm rat and humans with type 1 diabetes. Diabetologia 57:512–521

    Article  CAS  PubMed  Google Scholar 

  49. Kolb H, Worz-Pagenstert U, Kleemann R, Rothe H, Rowsell P, Scott FW (1996) Cytokine gene expression in the BB rat pancreas: natural course and impact of bacterial vaccines. Diabetologia 39:1448–1454

    Article  CAS  PubMed  Google Scholar 

  50. Kacheva S, Lenzen S, Gurgul-Convey E (2011) Differential effects of proinflammatory cytokines on cell death and ER stress in insulin-secreting INS1E cells and the involvement of nitric oxide. Cytokine 55:195–201

    Article  CAS  PubMed  Google Scholar 

  51. Jörns A, Rath KJ, Terbish T et al (2010) Diabetes prevention by immunomodulatory FTY720 treatment in the LEW.1AR1-iddm rat despite immune cell activation. Endocrinology 151:3555–3565

    Article  CAS  PubMed  Google Scholar 

  52. Jörns A, Ertekin UG, Arndt T, Terbish T, Wedekind D, Lenzen S (2015) TNF-alpha antibody therapy in combination with the T-cell-cpecific antibody anti-TCR reverses the diabetic metabolic state in the LEW.1AR1-iddm rat. Diabetes 64:2880–2891

    Article  CAS  PubMed  Google Scholar 

  53. Ferraro A, Socci C, Stabilini A et al (2011) Expansion of Th17 cells and functional defects in T regulatory cells are key features of the pancreatic lymph nodes in patients with type 1 diabetes. Diabetes 60:2903–2913

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Scott FW, Mongeau R, Kardish M, Hatina G, Trick KD, Wojcinski Z (1985) Diet can prevent diabetes in the BB rat. Diabetes 34:1059–1062

    Article  CAS  PubMed  Google Scholar 

  55. Graham S, Courtois P, Malaisse WJ, Rozing J, Scott FW, Mowat AM (2004) Enteropathy precedes type 1 diabetes in the BB rat. Gut 53:1437–1444

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Scott FW, Pound LD, Patrick C, Eberhard CE, Crookshank JA (2017) Where genes meet environment-integrating the role of gut luminal contents, immunity and pancreas in type 1 diabetes. Transl Res 179:183–198

    Article  CAS  PubMed  Google Scholar 

  57. Hara N, Alkanani AK, Ir D et al (2013) The role of the intestinal microbiota in type 1 diabetes. Clin Immunol 146:112–119

    Article  CAS  PubMed  Google Scholar 

  58. Crookshank JA, Patrick C, Wang GS, Noel JA, Scott FW (2015) Gut immune deficits in LEW.1AR1-iddm rats partially overcome by feeding a diabetes-protective diet. Immunology 145:417–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Knip M, Honkanen J (2017) Modulation of type 1 diabetes risk by the intestinal microbiome. Curr Diab Rep 17:105

    Article  CAS  PubMed  Google Scholar 

  60. Chao NJ, Timmerman L, McDevitt HO, Jacob CO (1989) Molecular characterization of MHC class II antigens (beta 1 domain) in the BB diabetes-prone and -resistant rat. Immunogenetics 29:231–234

    Article  CAS  PubMed  Google Scholar 

  61. Colle E (1990) Genetic susceptibility to the development of spontaneous insulin-dependent diabetes mellitus in the rat. Clin Immunol Immunopathol 57:1–9

    Article  CAS  PubMed  Google Scholar 

  62. Ellerman KE, Like AA (2000) Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia 43:890–898

    Article  CAS  PubMed  Google Scholar 

  63. Mordes JP, Bortell R, Blankenhorn EP, Rossini AA, Greiner DL (2004) Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J 45:278–291

    Article  CAS  PubMed  Google Scholar 

  64. Yokoi N, Komeda K, Wang HY et al (2002) Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 31:391–394

    Article  CAS  PubMed  Google Scholar 

  65. Mordes JP, Bortell R, Doukas J et al (1996) The BB/Wor rat and the balance hypothesis of autoimmunity. Diabetes Metab Rev 12:103–109

    Article  CAS  PubMed  Google Scholar 

  66. Hornum L, Rømer J, Markholst H (2002) The diabetes-prone BB rat carries a frameshift mutation in Ian4, a positional candidate of Iddm1. Diabetes 51:1972–1979

    Article  CAS  PubMed  Google Scholar 

  67. Arndt T, Wedekind D, Jörns A et al (2015) A novel Dock8 gene mutation confers diabetogenic susceptibility in the LEW.1AR1/Ztm-iddm rat, an animal model of human type 1 diabetes. Diabetologia 58:2800–2809

    Article  CAS  PubMed  Google Scholar 

  68. Weiss H, Bleich A, Hedrich HJ et al (2005) Genetic analysis of the LEW.1AR1-iddm rat: an animal model for spontaneous diabetes mellitus. Mamm Genome 16:432–441

    Article  CAS  PubMed  Google Scholar 

  69. Weiss H, Arndt T, Jörns A et al (2008) The mutation of the LEW.1AR1-iddm rat maps to the telomeric end of rat chromosome 1. Mamm Genome 19:292–297

    Article  CAS  PubMed  Google Scholar 

  70. Smits K, Iannucci V, Stove V et al (2010) Rho GTPase Cdc42 is essential for human T-cell development. Haematologica 95:367–375

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Payne F, Smyth DJ, Pask R et al (2004) Haplotype tag single nucleotide polymorphism analysis of the human orthologues of the rat type 1 diabetes genes Ian4 (Lyp/Iddm1) and Cblb. Diabetes 53:505–509

    Article  CAS  PubMed  Google Scholar 

  72. Yokoi N (2005) Identification of a major gene responsible for type 1 diabetes in the Komeda diabetes-prone rat. Exp Anim 54:111–115

    Article  CAS  PubMed  Google Scholar 

  73. Wallis RH, Wang K, Marandi L et al (2009) Type 1 diabetes in the BB rat: a polygenic disease. Diabetes 58:1007–1017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Su HC, Jing H, Zhang Q (2011) DOCK8 deficiency. Ann N Y Acad Sci 1246:26–33

    Article  CAS  PubMed  Google Scholar 

  75. Lenzen S (2017) Animal models of human type 1 diabetes for evaluating combination therapies and successful translation to the patient with type 1 diabetes. Diabetes Metab Res Rev 33. https://doi.org/10.1002/dmrr.2915

  76. Ben Nasr M, D'Addio F, Usuelli V, Tezza S, Abdi R, Fiorina P (2015) The rise, fall, and resurgence of immunotherapy in type 1 diabetes. Pharmacol Res 98:31–38

    Article  CAS  PubMed  Google Scholar 

  77. Jörns A, Akin M, Arndt T et al (2014) Anti-TCR therapy combined with fingolimod for reversal of diabetic hyperglycemia by beta cell regeneration in the LEW.1AR1-iddm rat model of type 1 diabetes. J Mol Med (Berl) 92:743–755

    Google Scholar 

  78. Popovic J, Kover KL, Moore WV (2004) The effect of immunomodulators on prevention of autoimmune diabetes is stage dependent: FTY720 prevents diabetes at three different stages in the diabetes-resistant biobreeding rat. Pediatr Diabetes 5:3–9

    Article  PubMed  Google Scholar 

  79. Satoh J, Seino H, Shintani S et al (1990) Inhibition of type 1 diabetes in BB rats with recombinant human tumor necrosis factor-alpha. J Immunol 145:1395–1399

    CAS  PubMed  Google Scholar 

  80. Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226

    Article  CAS  PubMed  Google Scholar 

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Acknowledgment

This book chapter is dedicated to the memory of my old friend, the distinguished biochemist and diabetologist Professor Eleazar Shafrir (1924–2016), Jerusalem.

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Authors and Affiliations

  1. Institute of Experimental Diabetes Research, Hannover Medical School, Hannover, Germany

    Sigurd Lenzen

  2. Institute of Clinical Biochemistry, Hannover Medical School, Hannover, Germany

    Sigurd Lenzen, Tanja Arndt, Matthias Elsner & Anne Jörns

  3. Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany

    Dirk Wedekind

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  1. Sigurd Lenzen
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  2. Tanja Arndt
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  3. Matthias Elsner
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  4. Dirk Wedekind
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  5. Anne Jörns
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Corresponding author

Correspondence to Sigurd Lenzen .

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Editors and Affiliations

  1. Department of Diabetes, School of Life Course Sciences, King’s College London, London, UK

    Aileen J. F. King

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Lenzen, S., Arndt, T., Elsner, M., Wedekind, D., Jörns, A. (2020). Rat Models of Human Type 1 Diabetes. In: King, A. (eds) Animal Models of Diabetes. Methods in Molecular Biology, vol 2128. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0385-7_5

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  • DOI: https://doi.org/10.1007/978-1-0716-0385-7_5

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