, Volume 57, Issue 3, pp 512–521 | Cite as

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

  • Anne Jörns
  • Tanja Arndt
  • Andreas Meyer zu Vilsendorf
  • Jürgen Klempnauer
  • Dirk Wedekind
  • Hans-Jürgen Hedrich
  • Lorella Marselli
  • Piero Marchetti
  • Nagakatsu Harada
  • Yutaka Nakaya
  • Gen-Sheng Wang
  • Fraser W. Scott
  • Conny Gysemans
  • Chantal Mathieu
  • Sigurd LenzenEmail author



Research on the pathogenesis of type 1 diabetes relies heavily on good animal models. The aim of this work was to study the translational value of animal models of type 1 diabetes to the human situation.


We compared the four major animal models of spontaneous type 1 diabetes, namely the NOD mouse, BioBreeding (BB) rat, Komeda rat and LEW.1AR1-iddm rat, by examining the immunohistochemistry and in situ RT-PCR of immune cell infiltrate and cytokine pattern in pancreatic islets, and by comparing findings with human data.


After type 1 diabetes manifestation CD8+ T cells, CD68+ macrophages and CD4+ T cells were observed as the main immune cell types with declining frequency, in infiltrated islets of all diabetic pancreases. IL-1β and TNF-α were the main proinflammatory cytokines in the immune cell infiltrate in NOD mice, BB rats and LEW.1AR1-iddm rats, as well as in humans. The Komeda rat was the exception, with IFN-γ and TNF-α being the main cytokines. In addition, IL-17 and IL-6 and the anti-inflammatory cytokines IL-4, IL-10 and IL-13 were found in some infiltrating immune cells. Apoptotic as well as proliferating beta cells were observed in infiltrated islets. In healthy pancreases no proinflammatory cytokine expression was observed.


With the exception of the Komeda rat, the animal models mirror very well the situation in humans with type 1 diabetes. Thus animal models of type 1 diabetes can provide meaningful information on the disease processes in the pancreas of patients with type 1 diabetes.


Animal models Cytokines Human Immune cells Pancreatic islets Type 1 diabetes 







Forkhead box P3


Inducible nitric oxide synthase


Nuclear factor κB


Transforming growth factor β1



We thank D. Lischke and U. Sommerfeld (both from the Institute of Clinical Biochemistry, Hannover Medical School) for skilful technical assistance.


This work was supported by grants from the Deutsche Forschungsgemeinschaft (JO 395/2-1), from the European Union (Collaborative Project NAIMIT in the 7th Framework Programme, Contract No. 241447) to PM, CM and SL and from the Canadian Institutes of Health Research and the Canadian Diabetes Association and Cure Diabetes to FWS. CM is a clinical researcher at the FWO-Vlaanderen.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

AJ designed and performed experiments, analysed data, and wrote manuscript. TA, AMV, JK, DW, H-JH, LM, PM, NH, YN, G-SW FWS, CG and CM contributed to acquisition of data and revised the manuscript according to the discussion section. G-SW and CM drafted the article and revised it critically for important intellectual content. SL designed experiments, contributed to the discussion and wrote the manuscript. All authors revised and approved the final version to be published.

Supplementary material

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  1. 1.
    Imagawa A, Hanafusa T, Itoh N et al (1996) Islet-infiltrating T lymphocytes in insulin-dependent diabetic patients express CD80 (B7-1) and CD86 (B7-2). J Autoimmun 9:391–396PubMedCrossRefGoogle Scholar
  2. 2.
    Imagawa A, Hanafusa T, Tamura S et al (2001) Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes: close correlation between serological markers and histological evidence of cellular autoimmunity. Diabetes 50:1269–1273PubMedCrossRefGoogle Scholar
  3. 3.
    Uno S, Imagawa A, Okita K et al (2007) Macrophages and dendritic cells infiltrating islets with or without beta cells produce tumour necrosis factor-alpha in patients with recent-onset type 1 diabetes. Diabetologia 50:596–601PubMedCrossRefGoogle Scholar
  4. 4.
    Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y (1980) Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu 29:1–13PubMedGoogle Scholar
  5. 5.
    Anderson MS, Bluestone JA (2005) The NOD mouse: a model of immune dysregulation. Annu Rev Immunol 23:447–485PubMedCrossRefGoogle Scholar
  6. 6.
    Gysemans C, Callewaert H, Moore F et al (2009) Interferon regulatory factor-1 is a key transcription factor in murine beta cells under immune attack. Diabetologia 52:2374–2384PubMedCrossRefGoogle Scholar
  7. 7.
    Koulmanda M, Bhasin M, Awdeh Z et al (2012) The role of TNF-alpha in mice with type 1- and 2- diabetes. PLoS One 7:e33254PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Nakhooda AF, Like AA, Chappel CI, Murray FT, Marliss EB (1977) The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes 26:100–112PubMedCrossRefGoogle Scholar
  9. 9.
    Mordes JP, Bortell R, Blankenhorn EP, Rossini AA, Greiner DL (2004) Rat models of type 1 diabetes: genetics, environment, and autoimmunity. ILAR J 45:278–291PubMedCrossRefGoogle Scholar
  10. 10.
    Wang GS, Kauri LM, Patrick C, Bareggi M, Rosenberg L, Scott FW (2010) Enhanced islet expansion by beta-cell proliferation in young diabetes-prone rats fed a protective diet. J Cell Physiol 224:501–508PubMedCrossRefGoogle Scholar
  11. 11.
    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 40:1375–1381PubMedCrossRefGoogle Scholar
  12. 12.
    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 45:737–744PubMedCrossRefGoogle Scholar
  13. 13.
    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 44:1189–1196PubMedCrossRefGoogle Scholar
  14. 14.
    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 54:2041–2052PubMedCrossRefGoogle Scholar
  15. 15.
    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:e64305PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    King AJ (2012) The use of animal models in diabetes research. Br J Pharmacol 166:877–894PubMedCrossRefGoogle Scholar
  17. 17.
    Buschard K (2011) What causes type 1 diabetes? Lessons from animal models. APMIS, Suppl 132:1–19CrossRefGoogle Scholar
  18. 18.
    Roep BO, Atkinson M, von Herrath M (2004) Satisfaction (not) guaranteed: re-evaluating the use of animal models of type 1 diabetes. Nat Rev Immunol 4:989–997PubMedCrossRefGoogle Scholar
  19. 19.
    Roep BO, Buckner J, Sawcer S, Toes R, Zipp F (2012) The problems and promises of research into human immunology and autoimmune disease. Nat Med 18:48–53PubMedCrossRefGoogle Scholar
  20. 20.
    Pearson T, Greiner DL, Shultz LD (2008) Creation of “humanized” mice to study human immunity. Curr Protoc Immunol Chapter 15:Unit 15.21Google Scholar
  21. 21.
    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 151:3555–3565PubMedCrossRefGoogle Scholar
  22. 22.
    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 12:1029–1039PubMedCrossRefGoogle Scholar
  23. 23.
    Sommandas V, Rutledge EA, van Yserloo B, Fuller J, Lernmark A, Drexhage HA (2007) Low-density cells isolated from the rat thymus resemble branched cortical macrophages and have a reduced capability of rescuing double-positive thymocytes from apoptosis in the BB-DP rat. J Leukoc Biol 82:869–876PubMedCrossRefGoogle Scholar
  24. 24.
    Atkinson MA, Bluestone JA, Eisenbarth GS et al (2011) How does type 1 diabetes develop? the notion of homicide or beta-cell suicide revisited. Diabetes 60:1370–1379PubMedCrossRefGoogle Scholar
  25. 25.
    Reddy S, Chai RC, Rodrigues JA, Hsu TH, Robinson E (2008) Presence of residual beta cells and co-existing islet autoimmunity in the NOD mouse during longstanding diabetes: a combined histochemical and immunohistochemical study. J Mol Histol 39:25–36PubMedCrossRefGoogle Scholar
  26. 26.
    Coppieters KT, Dotta F, Amirian N et al (2012) Demonstration of islet-autoreactive CD8 T cells in insulitic lesions from recent onset and long-term type 1 diabetes patients. J Exp Med 209:51–60PubMedCentralPubMedCrossRefGoogle Scholar
  27. 27.
    Lally FJ, Ratcliff H, Bone AJ (2001) Apoptosis and disease progression in the spontaneously diabetic BB/S rat. Diabetologia 44:320–324PubMedCrossRefGoogle Scholar
  28. 28.
    Mordes JP, Desemone J, Rossini AA (1987) The BB rat. Diabetes Metab Rev 3:725–750PubMedCrossRefGoogle Scholar
  29. 29.
    Richardson SJ, Willcox A, Bone AJ, Morgan NG, Foulis AK (2011) Immunopathology of the human pancreas in type-I diabetes. Semin Immunopathol 33:9–21PubMedCrossRefGoogle Scholar
  30. 30.
    Rowe PA, Campbell-Thompson ML, Schatz DA, Atkinson MA (2011) The pancreas in human type 1 diabetes. Semin Immunopathol 33:29–43PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Carrero JA, Calderon B, Towfic F, Artyomov MN, Unanue ER (2013) Defining the transcriptional and cellular landscape of type 1 diabetes in the NOD mouse. PLoS One 8:e59701PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    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 38:1623–1629PubMedCrossRefGoogle Scholar
  33. 33.
    Akirav EM, Baquero MT, Opare-Addo LW et al (2011) Glucose and inflammation control islet vascular density and beta-cell function in NOD mice: control of islet vasculature and vascular endothelial growth factor by glucose. Diabetes 60:876–883PubMedCrossRefGoogle Scholar
  34. 34.
    Kleemann R, Scott FW, Worz-Pagenstert U, Nimal Ratnayake WM, Kolb H (1998) Impact of dietary fat on Th1/Th2 cytokine gene expression in the pancreas and gut of diabetes-prone BB rats. J Autoimmun 11:97–103PubMedCrossRefGoogle Scholar
  35. 35.
    Mastrandrea L, Yu J, Behrens T et al (2009) Etanercept treatment in children with new-onset type 1 diabetes: pilot randomized, placebo-controlled, double-blind study. Diabetes Care 32:1244–1249PubMedCrossRefGoogle Scholar
  36. 36.
    Arif S, Cox P, Afzali B et al (2010) Anti-TNFalpha therapy–killing two birds with one stone? Lancet 375:2278PubMedCrossRefGoogle Scholar
  37. 37.
    Kalden JR (2011) Anti-TNF therapy: what have we learned in 12 years? Arthritis Res Ther 13(Suppl. 1): S1Google Scholar
  38. 38.
    Wang F, Smith N, Maier L et al (2012) Etanercept suppresses regenerative hyperplasia in psoriasis by acutely downregulating epidermal expression of IL-19, IL-20 and IL-24. Br J Dermatol 167:92–102PubMedCrossRefGoogle Scholar
  39. 39.
    Goldbach-Mansky R (2012) Immunology in clinic review series; focus on autoinflammatory diseases: update on monogenic autoinflammatory diseases: the role of interleukin (IL)-1 and an emerging role for cytokines beyond IL-1. Clin Exp Immunol 167:391–404PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Ordas I, Mould DR, Feagan BG, Sandborn WJ (2012) Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clin Pharmacol Ther 91:635–646PubMedCrossRefGoogle Scholar
  41. 41.
    Yokoi N, Komeda K, Wang HY et al (2002) Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet 31:391–394PubMedGoogle Scholar
  42. 42.
    Bonner-Weir S, Li WC, Ouziel-Yahalom L, Guo L, Weir GC, Sharma A (2010) Beta-cell growth and regeneration: replication is only part of the story. Diabetes 59:2340–2348PubMedCrossRefGoogle Scholar
  43. 43.
    Salpeter SJ, Klein AM, Huangfu D, Grimsby J, Dor Y (2010) Glucose and aging control the quiescence period that follows pancreatic beta cell replication. Development 137:3205–3213PubMedCrossRefGoogle Scholar
  44. 44.
    Rabinovitch A, Suarez-Pinzon WL (1998) Cytokines and their roles in pancreatic islet beta-cell destruction and insulin-dependent diabetes mellitus. Biochem Pharmacol 55:1139–1149PubMedCrossRefGoogle Scholar
  45. 45.
    Bergmann L, Kröncke KD, Suschek C, Kolb H, Kolb-Bachofen V (1992) Cytotoxic action of IL-1 beta against pancreatic islets is mediated via nitric oxide formation and is inhibited by NG-monomethyl-L-arginine. FEBS Lett 299:103–106PubMedCrossRefGoogle Scholar
  46. 46.
    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 55:195–201PubMedCrossRefGoogle Scholar
  47. 47.
    Ortis F, Pirot P, Naamane N et al (2008) Induction of nuclear factor-kappaB and its downstream genes by TNF-alpha and IL-1beta has a pro-apoptotic role in pancreatic beta cells. Diabetologia 51:1213–1225PubMedCrossRefGoogle Scholar
  48. 48.
    Sleater M, Diamond AS, Gill RG (2007) Islet allograft rejection by contact-dependent CD8+ T cells: perforin and FasL play alternate but obligatory roles. Am J Transplant 7:1927–1933PubMedCrossRefGoogle Scholar
  49. 49.
    Barthson J, Germano CM, Moore F et al (2011) Cytokines tumor necrosis factor-alpha and interferon-gamma induce pancreatic beta-cell apoptosis through STAT1-mediated Bim protein activation. J Biol Chem 286:39632–39643PubMedCrossRefGoogle Scholar
  50. 50.
    Walz M, Overbergh L, Mathieu C, Kolb H, Martin S (2002) A murine interleukin-4-Ig fusion protein regulates the expression of Th1- and Th2-specific cytokines in the pancreas of NOD mice. Horm Metab Res 34:561–569PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Anne Jörns
    • 1
    • 2
  • Tanja Arndt
    • 1
  • Andreas Meyer zu Vilsendorf
    • 3
  • Jürgen Klempnauer
    • 3
  • Dirk Wedekind
    • 4
  • Hans-Jürgen Hedrich
    • 4
  • Lorella Marselli
    • 5
  • Piero Marchetti
    • 5
  • Nagakatsu Harada
    • 6
  • Yutaka Nakaya
    • 6
  • Gen-Sheng Wang
    • 7
  • Fraser W. Scott
    • 7
  • Conny Gysemans
    • 8
  • Chantal Mathieu
    • 8
  • Sigurd Lenzen
    • 1
    Email author
  1. 1.Institute of Clinical BiochemistryHannover Medical SchoolHannoverGermany
  2. 2.Centre of AnatomyHannover Medical SchoolHannoverGermany
  3. 3.Department of General, Visceral and Transplantation SurgeryHannover Medical SchoolHannoverGermany
  4. 4.Institute of Laboratory Animal ScienceHannover Medical SchoolHannoverGermany
  5. 5.Islet Cell Laboratory, Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
  6. 6.Institute of Health Biosciences, Department of Nutrition and MetabolismUniversity of Tokushima Graduate SchoolTokushimaJapan
  7. 7.Chronic Disease ProgramOttawa Hospital Research InstituteOttawaCanada
  8. 8.Clinical and Experimental EndocrinologyCatholic University of LeuvenLeuvenBelgium

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