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
Yanagisawa M, Hara Y, Satoh K et al (1986) Spontaneous autoimmune thyroiditis in Bio Breeding/Worcester (BB/W) rat. Endocrinol Jpn 33:851–861
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
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
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
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
Scott FW (1996) Food-induced type 1 diabetes in the BB rat. Diabetes Metab Rev 12:341–359
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
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
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
Yoon JW, Jun HS (2006) Viruses cause type 1 diabetes in animals. Ann N Y Acad Sci 1079:138–146
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
Nakhooda AF, Like AA, Chappel CI, Murray FT, Marliss EB (1977) The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes 26:100–112
Mordes JP, Desemone J, Rossini AA (1987) The BB rat. Diabetes Metab Rev 3:725–750
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
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
Jackson R, Rassi N, Crump T, Haynes B, Eisenbarth GS (1981) The BB diabetic rat. Profound T-cell lymphocytopenia. Diabetes 30:887–889
Elder ME, Maclaren NK (1983) Identification of profound peripheral T lymphocyte immunodeficiencies in the spontaneously diabetic BB rat. J Immunol 130:1723–1731
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
Ramanathan S, Poussier P (2001) BB rat lyp mutation and type 1 diabetes. Immunol Rev 184:161–171
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
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
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
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
Like AA, Guberski DL, Butler L (1986) Diabetic BioBreeding/Worcester (BB/Wor) rats need not be lymphopenic. J Immunol 136:3254–3258
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Lally FJ, Ratcliff H, Bone AJ (2001) Apoptosis and disease progression in the spontaneously diabetic BB/S rat. Diabetologia 44:320–324
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
Oschilewski U, Kiesel U, Kolb H (1985) Administration of silica prevents diabetes in BB-rats. Diabetes 34:197–199
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Hara N, Alkanani AK, Ir D et al (2013) The role of the intestinal microbiota in type 1 diabetes. Clin Immunol 146:112–119
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
Knip M, Honkanen J (2017) Modulation of type 1 diabetes risk by the intestinal microbiome. Curr Diab Rep 17:105
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
Colle E (1990) Genetic susceptibility to the development of spontaneous insulin-dependent diabetes mellitus in the rat. Clin Immunol Immunopathol 57:1–9
Ellerman KE, Like AA (2000) Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia 43:890–898
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
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
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
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
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
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
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
Smits K, Iannucci V, Stove V et al (2010) Rho GTPase Cdc42 is essential for human T-cell development. Haematologica 95:367–375
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
Yokoi N (2005) Identification of a major gene responsible for type 1 diabetes in the Komeda diabetes-prone rat. Exp Anim 54:111–115
Wallis RH, Wang K, Marandi L et al (2009) Type 1 diabetes in the BB rat: a polygenic disease. Diabetes 58:1007–1017
Su HC, Jing H, Zhang Q (2011) DOCK8 deficiency. Ann N Y Acad Sci 1246:26–33
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
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
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
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
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
Lenzen S (2008) The mechanisms of alloxan- and streptozotocin-induced diabetes. Diabetologia 51:216–226
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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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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