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Elucidation of genetic factors in diabetes based on studies of animal models

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Abstract

Although genetic factors are involved in the development of both type 1 (T1D) and type 2 (T2D) diabetes, a complete picture of those factors remains to be elucidated. T1D is an autoimmune disease in which the major histocompatibility complex (MHC) serves as a major genetic factor. By genetic analysis of an animal model of T1D, the Komeda diabetes-prone (KDP) rat, we identified the casitas B-lineage lymphoma b (Cblb) gene as another major genetic factor in this model. The Cblb mutation and MHC u haplotype determine autoimmune reaction and tissue specificity to pancreatic β cells, respectively. By mutation screening of the CBLB gene in Japanese patients with T1D, six missense mutations were found, among which Phe328Leu showed impaired suppression of T-cell activation. T2D is a metabolic disorder associated with insulin resistance and/or impaired insulin secretion. By genetic analysis of the spontaneously diabetic Torii (SDT) rat, an animal model of nonobese T2D, we identified several quantitative trait loci, among which a major locus, designated Dmsdt1, was involved in islet inflammation and fibrosis. Identification of the genes responsible should provide insight into the pathogenesis of diabetes. We recently established a novel model of obese T2D, the Zucker fatty diabetes mellitus (ZFDM) rat. In addition to severe insulin resistance and diminished insulin response to incretin, intrinsic fragility of islets in ZFDM rats is involved in the development of T2D. The ZFDM strain should be useful for studying the pathogenesis and pathophysiology of T2D, especially the mechanisms of incretin-induced insulin secretion and islet fragility.

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References

  1. Makino S, Kunimoto K, Muraoka Y, Mizushima Y, Katagiri K, Tochino Y. Breeding of a non-obese, diabetic strain of mice. Exp Anim (Jikken Dobutsu). 1980;29:1–13.

    CAS  Google Scholar 

  2. Like AA, Butler L, Williams RM, Appel MC, Weringer EJ, Rossini AA. Spontaneous autoimmune diabetes mellitus in the BB rat. Diabetes. 1982;31:S7–13.

    Article  Google Scholar 

  3. Chappel CI, Chappel WR. The discovery and development of the BB rat colony: an animal model of spontaneous diabetes mellitus. Metabolism. 1983;32:S8–10.

    Article  Google Scholar 

  4. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. New inbred strain of Long-Evans Tokushima lean rats with IDDM without lymphopenia. Diabetes. 1991;40:1375–81.

    Article  CAS  PubMed  Google Scholar 

  5. Komeda K, Noda M, Terao K, Kuzuya N, Kanazawa M, Kanazawa Y. Establishment of two substrains, diabetes-prone and non-diabetic, from Long-Evans Tokushima Lean (LETL) rats. Endocr J. 1998;45:737–44.

    Article  CAS  PubMed  Google Scholar 

  6. Yokoi N, Namae M, Fuse M, Wang HY, Hirata T, Seino S, Komeda K. Establishment and characterization of the Komeda diabetes-prone rat as a segregating inbred strain. Exp Anim. 2003;52:295–301.

    Article  CAS  PubMed  Google Scholar 

  7. Lenzen S, Tiedge M, Elsner M, Lortz S, Weiss H, Jorns A, Kloppel G, Wedekind D, Prokop CM, Hedrich HJ. The LEW.1AR1/Ztm-iddm rat: a new model of spontaneous insulin-dependent diabetes mellitus. Diabetologia. 2001;44:1189–96.

    Article  CAS  PubMed  Google Scholar 

  8. Goto Y, Kakizaki M, Masaki N. Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc Jpn Acad. 1975;51:80–5.

    Google Scholar 

  9. Kawano K, Hirashima T, Mori S, Saitoh Y, Kurosumi M, Natori T. Spontaneous long-term hyperglycemic rat with diabetic complications. Otsuka Long-Evans Tokushima Fatty (OLETF) strain. Diabetes. 1992;41:1422–8.

    Article  CAS  PubMed  Google Scholar 

  10. Shinohara M, Masuyama T, Shoda T, Takahashi T, Katsuda Y, Komeda K, Kuroki M, Kakehashi A, Kanazawa Y. A new spontaneously diabetic non-obese Torii rat strain with severe ocular complications. Int J Exp Diabetes Res. 2000;1:89–100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Masuyama T, Katsuda Y, Shinohara M. A novel model of obesity-related diabetes: introgression of the Lepr(fa) allele of the Zucker fatty rat into nonobese Spontaneously Diabetic Torii (SDT) rats. Exp Anim. 2005;54:13–20.

    Article  CAS  PubMed  Google Scholar 

  12. Ikeda H, Shino A, Matsuo T, Iwatsuka H, Suzuoki Z. A new genetically obese-hyperglycemic rat (Wistar fatty). Diabetes. 1981;30:1045–50.

    Article  CAS  PubMed  Google Scholar 

  13. Peterson RG, Shaw WN, Neel MA, Little LA, Eichberg J. Zucker diabetic fatty rat as a model for non-insulindependent diabetes mellitus. ILAR News. 1990;32:16–9.

    Article  Google Scholar 

  14. Hummel KP, Dickie MM, Coleman DL. Diabetes, a new mutation in the mouse. Science. 1966;153:1127–8.

    Article  CAS  PubMed  Google Scholar 

  15. Nishimura M. Breeding of mice strains for diabetes mellitus. Jikken Dobutsu (Exp Anim). 1969;18:147–57.

    Google Scholar 

  16. Shibata M, Yasuda B. New experimental congenital diabetic mice (N.S.Y. mice). Tohoku J Exp Med. 1980;130:139–42.

    Article  CAS  PubMed  Google Scholar 

  17. Bielschowsky M, Goodall CM. Origin of inbred NZ mouse strains. Cancer Res. 1970;30:834–6.

    CAS  PubMed  Google Scholar 

  18. Kim JH, Sen S, Avery CS, Simpson E, Chandler P, Nishina PM, Churchill GA, Naggert JK. Genetic analysis of a new mouse model for non-insulin-dependent diabetes. Genomics. 2001;74:273–86.

    Article  CAS  PubMed  Google Scholar 

  19. Suzuki W, Iizuka S, Tabuchi M, Funo S, Yanagisawa T, Kimura M, Sato T, Endo T, Kawamura H. A new mouse model of spontaneous diabetes derived from ddY strain. Exp Anim. 1999;48:181–9.

    Article  CAS  PubMed  Google Scholar 

  20. Yokoi N, Kanazawa M, Kitada K, Tanaka A, Kanazawa Y, Suda S, Ito H, Serikawa T, Komeda K. A non-MHC locus essential for autoimmune type I diabetes in the Komeda Diabetes-Prone rat. J Clin Invest. 1997;100:2015–21.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Yokoi N, Komeda K, Wang HY, Yano H, Kitada K, Saitoh Y, Seino Y, Yasuda K, Serikawa T, Seino S. Cblb is a major susceptibility gene for rat type 1 diabetes mellitus. Nat Genet. 2002;31:391–4.

    CAS  PubMed  Google Scholar 

  22. Keane MM, Rivero-Lezcano OM, Mitchell JA, Robbins KC, Lipkowitz S. Cloning and characterization of cbl-b: a SH3 binding protein with homology to the c-cbl proto-oncogene. Oncogene. 1995;10:2367–77.

    CAS  PubMed  Google Scholar 

  23. Bachmaier K, Krawczyk C, Kozieradzki I, Kong YY, Sasaki T, Oliveira-dos-Santos A, Mariathasan S, Bouchard D, Wakeham A, Itie A, Le J, Ohashi PS, Sarosi I, Nishina H, Lipkowitz S, Penninger JM. Negative regulation of lymphocyte activation and autoimmunity by the molecular adaptor Cbl-b. Nature. 2000;403:211–6.

    Article  CAS  PubMed  Google Scholar 

  24. Chiang YJ, Kole HK, Brown K, Naramura M, Fukuhara S, Hu RJ, Jang IK, Gutkind JS, Shevach E, Gu H. Cbl-b regulates the CD28 dependence of T-cell activation. Nature. 2000;403:216–20.

    Article  CAS  PubMed  Google Scholar 

  25. Yokoi N. Identification of a major gene responsible for type 1 diabetes in the Komeda diabetes-prone rat. Exp Anim. 2005;54:111–5.

    Article  CAS  PubMed  Google Scholar 

  26. Yokoi N, Hayashi C, Fujiwara Y, Wang HY, Seino S. Genetic reconstitution of autoimmune type 1 diabetes with two major susceptibility genes in the rat. Diabetes. 2007;56:506–12.

    Article  CAS  PubMed  Google Scholar 

  27. Awata T, Kuzuya T, Matsuda A, Iwamoto Y, Kanazawa Y. Genetic analysis of HLA class II alleles and susceptibility to type 1 (insulin-dependent) diabetes mellitus in Japanese subjects. Diabetologia. 1992;35:419–24.

    Article  CAS  PubMed  Google Scholar 

  28. Ikegami H, Kawaguchi Y, Yamato E, Kuwata S, Tokunaga K, Noma Y, Shima K, Ogihara T. Analysis by the polymerase chain reaction of histocompatibility leucocyte antigen-DR9-linked susceptibility to insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1992;75:1381–5.

    CAS  PubMed  Google Scholar 

  29. Yasunaga S, Kimura A, Hamaguchi K, Ronningen KS, Sasazuki T. Different contribution of HLA-DR and -DQ genes in susceptibility and resistance to insulin-dependent diabetes mellitus (IDDM). Tissue Antigens. 1996;47:37–48.

    Article  CAS  PubMed  Google Scholar 

  30. Kawabata Y, Ikegami H, Kawaguchi Y, Fujisawa T, Shintani M, Ono M, Nishino M, Uchigata Y, Lee I, Ogihara T. Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes. Diabetes. 2002;51:545–51.

    Article  CAS  PubMed  Google Scholar 

  31. Ellerman KE, Like AA. Susceptibility to diabetes is widely distributed in normal class IIu haplotype rats. Diabetologia. 2000;43:890–8.

    Article  CAS  PubMed  Google Scholar 

  32. Yokoi N, Hidaka S, Tanabe S, Ohya M, Ishima M, Takagi Y, Masui N, Seino S. Role of major histocompatibility complex class II in the development of autoimmune type 1 diabetes and thyroiditis in rats. Genes Immun. 2012;13:139–45.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Masuyama T, Komeda K, Hara A, Noda M, Shinohara M, Oikawa T, Kanazawa Y, Taniguchi K. Chronological characterization of diabetes development in male Spontaneously Diabetic Torii rats. Biochem Biophys Res Commun. 2004;314:870–7.

    Article  CAS  PubMed  Google Scholar 

  34. Kakehashi A, Saito Y, Mori K, Sugi N, Ono R, Yamagami H, Shinohara M, Tamemoto H, Ishikawa SE, Kawakami M, Kanazawa Y. Characteristics of diabetic retinopathy in SDT rats. Diabetes Metab Res Rev. 2006;22:455–61.

    Article  PubMed  Google Scholar 

  35. Shinohara M, Masuyama T, Kakehashi A. The Spontaneously Diabetic Torii (SDT) rat with retinopathy lesions resembling those of humans. In: Shafrir E, editor. Animal Models of Diabetes: Frontiers in Research. 2nd ed. New York: Taylor and Francis Group; 2006. p. 311–21.

    Google Scholar 

  36. Masuyama T, Fuse M, Yokoi N, Shinohara M, Tsujii H, Kanazawa M, Kanazawa Y, Komeda K, Taniguchi K. Genetic analysis for diabetes in a new rat model of nonobese type 2 diabetes, Spontaneously Diabetic Torii rat. Biochem Biophys Res Commun. 2003;304:196–206.

    Article  CAS  PubMed  Google Scholar 

  37. Fuse M, Yokoi N, Shinohara M, Masuyama T, Kitazawa R, Kitazawa S, Seino S. Identification of a major locus for islet inflammation and fibrosis in the spontaneously diabetic Torii rat. Physiol Genomics. 2008;35:96–105.

    Article  CAS  PubMed  Google Scholar 

  38. Zucker LM, Zucker TF. Fatty, a new mutation in the rat. J Hered. 1961;52:275–8.

    Google Scholar 

  39. Iida M, Murakami T, Ishida K, Mizuno A, Kuwajima M, Shima K. Phenotype-linked amino acid alteration in leptin receptor cDNA from Zucker fatty (fa/fa) rat. Biochem Biophys Res Commun. 1996;222:19–26.

    Article  CAS  PubMed  Google Scholar 

  40. Yokoi N, Hoshino M, Hidaka S, Yoshida E, Beppu M, Hoshikawa R, Sudo K, Kawada A, Takagi S, Seino S. A novel rat model of type 2 diabetes: the Zucker fatty diabetes mellitus ZFDM rat. J Diabetes Res. 2013;2013:103731.

    Article  PubMed Central  PubMed  Google Scholar 

  41. Gheni G, Yokoi N, Beppu M, Yamaguchi T, Hidaka S, Kawabata A, Hoshino Y, Hoshino M, Seino S. Characterization of the prediabetic state in a novel rat model of type 2 diabetes, the ZFDM rat. J Diabetes Res. 2015;2015:261418.

    Article  PubMed Central  PubMed  Google Scholar 

  42. Jones HB, Nugent D, Jenkins R. Variation in characteristics of islets of Langerhans in insulin-resistant, diabetic and non-diabetic-rat strains. Int J Exp Pathol. 2010;91:288–301.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Kosoy R, Yokoi N, Seino S, Concannon P. Polymorphic variation in the CBLB gene in human type 1 diabetes. Genes Immun. 2004;5:232–5.

    Article  CAS  PubMed  Google Scholar 

  44. Bergholdt R, Taxvig C, Eising S, Nerup J, Pociot F. CBLB variants in type 1 diabetes and their genetic interaction with CTLA4. J Leukoc Biol. 2005;77:579–85.

    Article  CAS  PubMed  Google Scholar 

  45. Payne F, Cooper JD, Walker NM, Lam AC, Smink LJ, Nutland S, Stevens HE, Hutchings J, Todd JA. Interaction analysis of the CBLB and CTLA4 genes in type 1 diabetes. J Leukoc Biol. 2007;81:581–3.

    Article  CAS  PubMed  Google Scholar 

  46. Yokoi N, Fujiwara Y, Wang HY, Kitao M, Hayashi C, Someya T, Kanamori M, Oiso Y, Tajima N, Yamada Y, Seino Y, Ikegami H, Seino S. Identification and functional analysis of CBLB mutations in type 1 diabetes. Biochem Biophys Res Commun. 2008;368:37–42.

    Article  CAS  PubMed  Google Scholar 

  47. Fukushima M, Suzuki H, Seino Y. Insulin secretion capacity in the development from normal glucose tolerance to type 2 diabetes. Diabetes Res Clin Pract. 2004;66:S37–43.

    Article  CAS  PubMed  Google Scholar 

  48. Fukushima M, Usami M, Ikeda M, Nakai Y, Taniguchi A, Matsuura T, Suzuki H, Kurose T, Yamada Y, Seino Y. Insulin secretion and insulin sensitivity at different stages of glucose tolerance: a cross-sectional study of Japanese type 2 diabetes. Metabolism. 2004;53:831–5.

    Article  CAS  PubMed  Google Scholar 

  49. Mitsui R, Fukushima M, Nishi Y, Ueda N, Suzuki H, Taniguchi A, Nakai Y, Kawakita T, Kurose T, Yamada Y, Inagaki N, Seino Y. Factors responsible for deteriorating glucose tolerance in newly diagnosed type 2 diabetes in Japanese men. Metabolism. 2006;55:53–8.

    Article  CAS  PubMed  Google Scholar 

  50. Yokoi N, Kanamori M, Horikawa Y, Takeda J, Sanke T, Furuta H, Nanjo K, Mori H, Kasuga M, Hara K, Kadowaki T, Tanizawa Y, Oka Y, Iwami Y, Ohgawara H, Yamada Y, Seino Y, Yano H, Cox NJ, Seino S. Association studies of variants in the genes involved in pancreatic beta-cell function in type 2 diabetes in Japanese subjects. Diabetes. 2006;55:2379–86.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Parts of this review were presented as the Lilly Award Lecture at the Japan Diabetes Society 2015, Shimonoseki, Japan. The author thanks late Professor Kajuro Komeda and Professors Susumu Seino, Yutaka Seino, and Tadao Serikawa for their instruction and generous support. The author also thanks colleagues and collaborators, especially Drs. Kohtaro Minami, Tadao Shibasaki, Harumi Takahashi, Toshiya Matsubara, and Daisuke Yabe, for their significant contribution. The studies in this review were supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, Japan, and grants from the Takeda Science Foundation, the Ichiro Kanehara Foundation, the Kanae Foundation for the Promotion of Medical Science, the Astellas Foundation for Research on Metabolic Disorders, and the Suzuken Memorial Foundation.

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  1. Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan

    Norihide Yokoi

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Correspondence to Norihide Yokoi.

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All institutional and national guidelines for the care and use of laboratory animals were followed.

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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Declaration of Helsinki of 1964 and later versions. Informed consent or substitute for it was obtained from all patients for being included in the study.

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Yokoi, N. Elucidation of genetic factors in diabetes based on studies of animal models. Diabetol Int 6, 255–260 (2015). https://doi.org/10.1007/s13340-015-0228-9

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