Large Animal Models of Diabetes

  • Barbara LudwigEmail author
  • Eckhard Wolf
  • Uwe Schönmann
  • Stefan Ludwig
Part of the Methods in Molecular Biology book series (MIMB, volume 2128)


Safe and reliable large animal diabetes models are a key prerequisite for advanced preclinical studies on diabetes. Chemical induction is the standard model of diabetes in rodents but is often critiqued in higher animals due to reduced efficacy, relevant side effects, and inadequate mortality rate. In this chapter, we aim to describe both pharmacological and surgical approaches for reproducible and safe diabetes models in minipigs and primates. In addition, genetically modified pig models for diabetes research are described.

Key words

Diabetes model Diabetes induction Pig model Primate model Streptozotocin Pancreatectomy 



Blood glucose


Body weight






Nonhuman primate






  1. 1.
    Graham ML, Schuurman HJ (2015) Validity of animal models of type 1 diabetes, and strategies to enhance their utility in translational research. Eur J Pharmacol 759:221–230. Scholar
  2. 2.
    Hering BJ, Cozzi E, Spizzo T, Cowan PJ, Rayat GR, Cooper DK, Denner J (2016) First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Executive summary. Xenotransplantation 23(1):3–13. Scholar
  3. 3.
    Swindle MM, Makin A, Herron AJ, Clubb FJ Jr, Frazier KS (2012) Swine as models in biomedical research and toxicology testing. Vet Pathol 49(2):344–356. Scholar
  4. 4.
    Swindle MM, Smith AC (1998) Comparative anatomy and physiology of the pig. Scand J Lab Anim Sci 25(Supplement 1):11–21Google Scholar
  5. 5.
    King AJ (2012) The use of animal models in diabetes research. Br J Pharmacol 166(3):877–894. Scholar
  6. 6.
    Grussner R, Nakhleh R, Grussner A, Tomadze G, Diem P, Sutherland D (1993) Streptozotocin-induced diabetes mellitus in pigs. Horm Metab Res 25(4):199–203CrossRefGoogle Scholar
  7. 7.
    Wilson JD, Dhall DP, Simeonovic CJ, Lafferty KJ (1986) Induction and management of diabetes mellitus in the pig. Aust J Exp Biol Med Sci 64(Pt 6):489–500CrossRefGoogle Scholar
  8. 8.
    Bottino R, Criscimanna A, Casu A, He J, Van der Windt DJ, Rudert WA, Giordano C, Trucco M (2009) Recovery of endogenous beta-cell function in nonhuman primates after chemical diabetes induction and islet transplantation. Diabetes 58(2):442–447. Scholar
  9. 9.
    de la Garza-Rodea AS, Knaan-Shanzer S, den Hartigh JD, Verhaegen AP, van Bekkum DW (2010) Anomer-equilibrated streptozotocin solution for the induction of experimental diabetes in mice (Mus musculus). J Am Assoc Lab Anim Sci 49(1):40–44PubMedPubMedCentralGoogle Scholar
  10. 10.
    Schmidt W, Humke R (1985) Ueber die Anwendung von Novalgin in der Schweinepraxis. Tierarztl Umsch 40:584–589Google Scholar
  11. 11.
    Renner S, Dobenecker B, Blutke A, Zols S, Wanke R, Ritzmann M, Wolf E (2016) Comparative aspects of rodent and nonrodent animal models for mechanistic and translational diabetes research. Theriogenology 86(1):406–421. Scholar
  12. 12.
    Whitelaw CB, Sheets TP, Lillico SG, Telugu BP (2016) Engineering large animal models of human disease. J Pathol 238(2):247–256. Scholar
  13. 13.
    Wolf E, Braun-Reichhart C, Streckel E, Renner S (2014) Genetically engineered pig models for diabetes research. Transgenic Res 23(1):27–38. Scholar
  14. 14.
    Kleinert M, Clemmensen C, Hofmann SM, Moore MC, Renner S, Woods SC, Huypens P, Beckers J, de Angelis MH, Schurmann A, Bakhti M, Klingenspor M, Heiman M, Cherrington AD, Ristow M, Lickert H, Wolf E, Havel PJ, Muller TD, Tschop MH (2018) Animal models of obesity and diabetes mellitus. Nat Rev Endocrinol 14(3):140–162. Scholar
  15. 15.
    Renner S, Fehlings C, Herbach N, Hofmann A, von Waldthausen DC, Kessler B, Ulrichs K, Chodnevskaja I, Moskalenko V, Amselgruber W, Goke B, Pfeifer A, Wanke R, Wolf E (2010) Glucose intolerance and reduced proliferation of pancreatic beta-cells in transgenic pigs with impaired glucose-dependent insulinotropic polypeptide function. Diabetes 59(5):1228–1238. Scholar
  16. 16.
    Renner S, Blutke A, Streckel E, Wanke R, Wolf E (2016) Incretin actions and consequences of incretin-based therapies: lessons from complementary animal models. J Pathol 238(2):345–358. Scholar
  17. 17.
    Renner S, Romisch-Margl W, Prehn C, Krebs S, Adamski J, Goke B, Blum H, Suhre K, Roscher AA, Wolf E (2012) Changing metabolic signatures of amino acids and lipids during the prediabetic period in a pig model with impaired incretin function and reduced beta-cell mass. Diabetes 61(8):2166–2175. Scholar
  18. 18.
    Streckel E, Braun-Reichhart C, Herbach N, Dahlhoff M, Kessler B, Blutke A, Bahr A, Ubel N, Eddicks M, Ritzmann M, Krebs S, Goke B, Blum H, Wanke R, Wolf E, Renner S (2015) Effects of the glucagon-like peptide-1 receptor agonist liraglutide in juvenile transgenic pigs modeling a pre-diabetic condition. J Transl Med 13:73. Scholar
  19. 19.
    Renner S, Braun-Reichhart C, Blutke A, Herbach N, Emrich D, Streckel E, Wunsch A, Kessler B, Kurome M, Bahr A, Klymiuk N, Krebs S, Puk O, Nagashima H, Graw J, Blum H, Wanke R, Wolf E (2013) Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes 62(5):1505–1511. Scholar
  20. 20.
    Hinkel R, Howe A, Renner S, Ng J, Lee S, Klett K, Kaczmarek V, Moretti A, Laugwitz KL, Skroblin P, Mayr M, Milting H, Dendorfer A, Reichart B, Wolf E, Kupatt C (2017) Diabetes mellitus-induced microvascular destabilization in the myocardium. J Am Coll Cardiol 69(2):131–143. Scholar
  21. 21.
    Blutke A, Renner S, Flenkenthaler F, Backman M, Haesner S, Kemter E, Landstrom E, Braun-Reichhart C, Albl B, Streckel E, Rathkolb B, Prehn C, Palladini A, Grzybek M, Krebs S, Bauersachs S, Bahr A, Bruhschwein A, Deeg CA, De Monte E, Dmochewitz M, Eberle C, Emrich D, Fux R, Groth F, Gumbert S, Heitmann A, Hinrichs A, Kessler B, Kurome M, Leipig-Rudolph M, Matiasek K, Ozturk H, Otzdorff C, Reichenbach M, Reichenbach HD, Rieger A, Rieseberg B, Rosati M, Saucedo MN, Schleicher A, Schneider MR, Simmet K, Steinmetz J, Ubel N, Zehetmaier P, Jung A, Adamski J, Coskun U, Hrabe de Angelis M, Simmet C, Ritzmann M, Meyer-Lindenberg A, Blum H, Arnold GJ, Frohlich T, Wanke R, Wolf E (2017) The Munich MIDY Pig Biobank - A unique resource for studying organ crosstalk in diabetes. Mol Metab 6(8):931–940. Scholar
  22. 22.
    Abbott A (2015) Inside the first pig biobank. Nature 519(7544):397–398. Scholar
  23. 23.
    Kleinwort KJH, Amann B, Hauck SM, Hirmer S, Blutke A, Renner S, Uhl PB, Lutterberg K, Sekundo W, Wolf E, Deeg CA (2017) Retinopathy with central oedema in an INS (C94Y) transgenic pig model of long-term diabetes. Diabetologia 60(8):1541–1549. Scholar
  24. 24.
    Umeyama K, Watanabe M, Saito H, Kurome M, Tohi S, Matsunari H, Miki K, Nagashima H (2009) Dominant-negative mutant hepatocyte nuclear factor 1alpha induces diabetes in transgenic-cloned pigs. Transgenic Res 18(5):697–706. Scholar
  25. 25.
    Hara S, Umeyama K, Yokoo T, Nagashima H, Nagata M (2014) Diffuse glomerular nodular lesions in diabetic pigs carrying a dominant-negative mutant hepatocyte nuclear factor 1-alpha, an inheritant diabetic gene in humans. PLoS One 9(3):e92219. Scholar
  26. 26.
    Kemter E, Cohrs CM, Schafer M, Schuster M, Steinmeyer K, Wolf-van Buerck L, Wolf A, Wuensch A, Kurome M, Kessler B, Zakhartchenko V, Loehn M, Ivashchenko Y, Seissler J, Schulte AM, Speier S, Wolf E (2017) INS-eGFP transgenic pigs: a novel reporter system for studying maturation, growth and vascularisation of neonatal islet-like cell clusters. Diabetologia 60(6):1152–1156. Scholar
  27. 27.
    Kobayashi T, Yamaguchi T, Hamanaka S, Kato-Itoh M, Yamazaki Y, Ibata M, Sato H, Lee YS, Usui J, Knisely AS, Hirabayashi M, Nakauchi H (2010) Generation of rat pancreas in mouse by interspecific blastocyst injection of pluripotent stem cells. Cell 142(5):787–799. Scholar
  28. 28.
    Matsunari H, Nagashima H, Watanabe M, Umeyama K, Nakano K, Nagaya M, Kobayashi T, Yamaguchi T, Sumazaki R, Herzenberg LA, Nakauchi H (2013) Blastocyst complementation generates exogenic pancreas in vivo in apancreatic cloned pigs. Proc Natl Acad Sci U S A 110(12):4557–4562. Scholar
  29. 29.
    Wu J, Platero-Luengo A, Sakurai M, Sugawara A, Gil MA, Yamauchi T, Suzuki K, Bogliotti YS, Cuello C, Morales Valencia M, Okumura D, Luo J, Vilarino M, Parrilla I, Soto DA, Martinez CA, Hishida T, Sanchez-Bautista S, Martinez-Martinez ML, Wang H, Nohalez A, Aizawa E, Martinez-Redondo P, Ocampo A, Reddy P, Roca J, Maga EA, Esteban CR, Berggren WT, Nunez Delicado E, Lajara J, Guillen I, Guillen P, Campistol JM, Martinez EA, Ross PJ, Izpisua Belmonte JC (2017) Interspecies chimerism with mammalian pluripotent stem cells. Cell 168(3):473–486.e415. Scholar
  30. 30.
    Klymiuk N, van Buerck L, Bahr A, Offers M, Kessler B, Wuensch A, Kurome M, Thormann M, Lochner K, Nagashima H, Herbach N, Wanke R, Seissler J, Wolf E (2012) Xenografted islet cell clusters from INSLEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes 61(6):1527–1532. Scholar
  31. 31.
    Klymiuk N, Ludwig B, Seissler J, Reichart B, Wolf E (2016) Current concepts of using pigs as a source for beta-cell replacement therapy of type 1 diabetes. Curr Mol Bio Rep 2(2):73–82. Scholar
  32. 32.
    Heinke S, Ludwig B, Schubert U, Schmid J, Kiss T, Steffen A, Bornstein S, Ludwig S (2016) Diabetes induction by total pancreatectomy in minipigs with simultaneous splenectomy: a feasible approach for advanced diabetes research. Xenotransplantation 23(5):405–413. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Barbara Ludwig
    • 1
    • 2
    • 3
    • 4
    Email author
  • Eckhard Wolf
    • 5
  • Uwe Schönmann
    • 6
  • Stefan Ludwig
    • 7
  1. 1.Department of Medicine IIIUniversity Hospital Carl Gustav CarusDresdenGermany
  2. 2.Paul Langerhans Institute Dresden (PLID) of the Helmholtz Center Munich at the University Hospital Carl Gustav Carus and Faculty of Medicine of the TU DresdenDresdenGermany
  3. 3.DFG-Center for Regenerative Therapies Dresden, Technische Universität DresdenDresdenGermany
  4. 4.Department of Endocrinology and DiabetologyUniversity Hospital ZurichZurichSwitzerland
  5. 5.Department of Molecular Animal Breeding and BiotechnologyLudwig Maximilian UniversityMunichGermany
  6. 6.German Primate CenterLeibniz-Institute for Primate ResearchGöttingenGermany
  7. 7.Department of Visceral, Thoracic and Vascular SurgeryUniversity Hospital Carl Gustav CarusDresdenGermany

Personalised recommendations