Selectively Bred Diabetes Models: GK Rats, NSY Mice, and ON Mice

  • Mototsugu NagaoEmail author
  • Jonathan Lou S. Esguerra
  • Anna Wendt
  • Akira Asai
  • Hitoshi Sugihara
  • Shinichi Oikawa
  • Lena EliassonEmail author
Part of the Methods in Molecular Biology book series (MIMB, volume 2128)


The polygenic background of selectively bred diabetes models mimics the etiology of type 2 diabetes. So far, three different rodent models (Goto-Kakizaki rats, Nagoya-Shibata-Yasuda mice, and Oikawa-Nagao mice) have been established in the diabetes research field by continuous selective breeding for glucose tolerance from outbred rodent stocks. The origin of hyperglycemia in these rodents is mainly insulin secretion deficiency from the pancreatic β-cells and mild insulin resistance in insulin target organs. In this chapter, we summarize backgrounds and phenotypes of these rodent models to highlight their importance in diabetes research. Then, we introduce experimental methodologies to evaluate β-cell exocytosis as a putative common defect observed in these rodent models.

Key words

Goto-Kakizaki rats Nagoya-Shibata-Yasuda mice Oikawa-Nagao mice Islets β-Cells Insulin secretion Exocytosis Capacitance measurement 



All animal experiments were performed in accordance to ethical permits issued by the Malmö/Lund Ethical Committee of Animal Research (Malmö and Lund, Sweden) or the Nippon Medical School Animal Policy and Welfare Committee (Tokyo, Japan).

We thank Britt-Marie Nilsson, Anna-Maria Veljanovska Ramsay, and Neelanjan Vishnu (Lund University) for technical assistance of GK/LU rat studies, Holger Luthman (Lund University) for valuable discussion regarding GK/LU rats, and Momoyo Kawahara (Nippon Medical School), Miki Onodera, and Ryoji Hokao (Institute for Animal Reproduction) for technical assistance of ON mice studies.

The work is financially supported by the Swedish Foundation for Strategic Research (IRC-LUDC), Swedish Research Council (SFO-EXODIAB; LE, 2016-02124), Region Skåne-ALF (LE), Swedish Diabetes Foundation (LE; DIA2016-130), Albert Påhlsson Foundation (LE and JLSE), Japan Society for the Promotion of Science (MN, JLSE, and AA), European Foundation for the Study of Diabetes, Japan Diabetes Society (MN), Uehara Memorial Foundation (MN), Scandinavia-Japan Sasakawa Foundation (MN), Sumitomo Life Welfare Foundation (MN), Diabetes Wellness Sverige (MN, 720-2964 JDWG), and Lotte Shigemitsu Prize (AA).


  1. 1.
    Goto Y, Kakizaki M, Masaki N (1975) Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc Jpn Acad 51(1):80–85CrossRefGoogle Scholar
  2. 2.
    Goto Y, Suzuki K, Sasaki M, Ono T, Abe S (1988) GK rats as a model of nonobese, noninsulin-dependent diabetes. Selective breeding over 35 generations. In: Shafrir E, Renold A (eds) Lessons from animal diabetes II. Libbey J, London, pp 490–492Google Scholar
  3. 3.
    Ostenson CG, Khan A, Abdel-Halim SM, Guenifi A, Suzuki K, Goto Y, Efendic S (1993) Abnormal insulin secretion and glucose metabolism in pancreatic islets from the spontaneously diabetic GK rat. Diabetologia 36(1):3–8CrossRefGoogle Scholar
  4. 4.
    Portha B, Serradas P, Bailbe D, Suzuki K, Goto Y, Giroix MH (1991) Beta-cell insensitivity to glucose in the GK rat, a spontaneous nonobese model for type II diabetes. Diabetes 40(4):486–491CrossRefGoogle Scholar
  5. 5.
    Lewis BM, Ismail IS, Issa B, Peters JR, Scanlon MF (1996) Desensitisation of somatostatin, TRH and GHRH responses to glucose in the diabetic (Goto-Kakizaki) rat hypothalamus. J Endocrinol 151(1):13–17CrossRefGoogle Scholar
  6. 6.
    Hughes SJ, Suzuki K, Goto Y (1994) The role of islet secretory function in the development of diabetes in the GK Wistar rat. Diabetologia 37(9):863–870CrossRefGoogle Scholar
  7. 7.
    Lagerholm S, Park HB, Luthman H, Nilsson M, McGuigan F, Swanberg M, Akesson K (2010) Genetic loci for bone architecture determined by three-dimensional CT in crosses with the diabetic GK rat. Bone 47(6):1039–1047. Scholar
  8. 8.
    Bihoreau MT, Dumas ME, Lathrop M, Gauguier D (2017) Genomic regulation of type 2 diabetes endophenotypes: contribution from genetic studies in the Goto-Kakizaki rat. Biochimie 143:56–65. Scholar
  9. 9.
    Östenson C (2007) The Goto-Kakizaki rat. In: Shafrir E (ed) Animal models of diabetes, Frontiers in research, 2nd edn. CRC Press, New York, pp 119–138CrossRefGoogle Scholar
  10. 10.
    Goto Y (1991) Foundation of the GK rat. J Jpn Diabetes Soc 34(11):939–941Google Scholar
  11. 11.
    Kimura K, Toyota T, Kakizaki M, Kudo M, Takebe K, Goto Y (1982) Impaired insulin secretion in the spontaneous diabetes rats. Tohoku J Exp Med 137(4):453–459CrossRefGoogle Scholar
  12. 12.
    Suzuki K, Goto Y, Toyoda T (1993) Spontaneously diabetic GK (Goto-Kakizaki) rats. In: Shafrir E (ed) Lessons from animal diabetes IV. Smith-Gordon, London, pp 107–116Google Scholar
  13. 13.
    Portha B, Giroix MH, Tourrel-Cuzin C, Le-Stunff H, Movassat J (2012) The GK rat: a prototype for the study of non-overweight type 2 diabetes. Methods Mol Biol 933:125–159. Scholar
  14. 14.
    Ostenson CG, Efendic S (2007) Islet gene expression and function in type 2 diabetes; studies in the Goto-Kakizaki rat and humans. Diabetes Obes Metab 9(Suppl 2):180–186. Scholar
  15. 15.
    Bisbis S, Bailbe D, Tormo MA, Picarel-Blanchot F, Derouet M, Simon J, Portha B (1993) Insulin resistance in the GK rat: decreased receptor number but normal kinase activity in liver. Am J Physiol 265(5 Pt 1):E807–E813. Scholar
  16. 16.
    Tourrel C, Bailbe D, Lacorne M, Meile MJ, Kergoat M, Portha B (2002) Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 51(5):1443–1452CrossRefGoogle Scholar
  17. 17.
    Movassat J, Calderari S, Fernandez E, Martin MA, Escriva F, Plachot C, Gangnerau MN, Serradas P, Alvarez C, Portha B (2007) Type 2 diabetes - a matter of failing beta-cell neogenesis? Clues from the GK rat model. Diabetes Obes Metab 9(Suppl 2):187–195. Scholar
  18. 18.
    Movassat J, Saulnier C, Serradas P, Portha B (1997) Impaired development of pancreatic beta-cell mass is a primary event during the progression to diabetes in the GK rat. Diabetologia 40(8):916–925. Scholar
  19. 19.
    Guenifi A, Abdel-Halim SM, Hoog A, Falkmer S, Ostenson CG (1995) Preserved beta-cell density in the endocrine pancreas of young, spontaneously diabetic Goto-Kakizaki (GK) rats. Pancreas 10(2):148–153CrossRefGoogle Scholar
  20. 20.
    Momose K, Nunomiya S, Nakata M, Yada T, Kikuchi M, Yashiro T (2006) Immunohistochemical and electron-microscopic observation of beta-cells in pancreatic islets of spontaneously diabetic Goto-Kakizaki rats. Med Mol Morphol 39(3):146–153. Scholar
  21. 21.
    Hoog A, Sandberg-Nordqvist AC, Abdel-Halim SM, Carlsson-Skwirut C, Guenifi A, Tally M, Ostenson CG, Falkmer S, Sara VR, Efendic S, Schalling M, Grimelius L (1996) Increased amounts of a high molecular weight insulin-like growth factor II (IGF-II) peptide and IGF-II messenger ribonucleic acid in pancreatic islets of diabetic Goto-Kakizaki rats. Endocrinology 137(6):2415–2423. Scholar
  22. 22.
    Homo-Delarche F, Calderari S, Irminger JC, Gangnerau MN, Coulaud J, Rickenbach K, Dolz M, Halban P, Portha B, Serradas P (2006) Islet inflammation and fibrosis in a spontaneous model of type 2 diabetes, the GK rat. Diabetes 55(6):1625–1633. Scholar
  23. 23.
    Salehi A, Henningsson R, Mosen H, Ostenson CG, Efendic S, Lundquist I (1999) Dysfunction of the islet lysosomal system conveys impairment of glucose-induced insulin release in the diabetic GK rat. Endocrinology 140(7):3045–3053. Scholar
  24. 24.
    Frese T, Bazwinsky I, Muhlbauer E, Peschke E (2007) Circadian and age-dependent expression patterns of GLUT2 and glucokinase in the pancreatic beta-cell of diabetic and nondiabetic rats. Horm Metab Res 39(8):567–574. Scholar
  25. 25.
    Ohneda M, Johnson JH, Inman LR, Chen L, Suzuki K, Goto Y, Alam T, Ravazzola M, Orci L, Unger RH (1993) GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion. Diabetes 42(7):1065–1072CrossRefGoogle Scholar
  26. 26.
    Ling ZC, Efendic S, Wibom R, Abdel-Halim SM, Ostenson CG, Landau BR, Khan A (1998) Glucose metabolism in Goto-Kakizaki rat islets. Endocrinology 139(6):2670–2675. Scholar
  27. 27.
    Hughes SJ, Faehling M, Thorneley CW, Proks P, Ashcroft FM, Smith PA (1998) Electrophysiological and metabolic characterization of single beta-cells and islets from diabetic GK rats. Diabetes 47(1):73–81CrossRefGoogle Scholar
  28. 28.
    Fabregat ME, Novials A, Giroix MH, Sener A, Gomis R, Malaisse WJ (1996) Pancreatic islet mitochondrial glycerophosphate dehydrogenase deficiency in two animal models of non-insulin-dependent diabetes mellitus. Biochem Biophys Res Commun 220(3):1020–1023. Scholar
  29. 29.
    Matsuoka T, Kajimoto Y, Watada H, Umayahara Y, Kubota M, Kawamori R, Yamasaki Y, Kamada T (1995) Expression of CD38 gene, but not of mitochondrial glycerol-3-phosphate dehydrogenase gene, is impaired in pancreatic islets of GK rats. Biochem Biophys Res Commun 214(1):239–246CrossRefGoogle Scholar
  30. 30.
    Ostenson CG, Abdel-Halim SM, Rasschaert J, Malaisse-Lagae F, Meuris S, Sener A, Efendic S, Malaisse WJ (1993) Deficient activity of FAD-linked glycerophosphate dehydrogenase in islets of GK rats. Diabetologia 36(8):722–726CrossRefGoogle Scholar
  31. 31.
    Tsuura Y, Ishida H, Okamoto Y, Kato S, Horie M, Ikeda H, Seino Y (1994) Reduced sensitivity of dihydroxyacetone on ATP-sensitive K+ channels of pancreatic beta cells in GK rats. Diabetologia 37(11):1082–1087CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Rasschaert J, Giroix MH, Conget I, Mercan D, Leclercq-Meyer V, Sener A, Portha B, Malaisse WJ (1994) Pancreatic islet response to dicarboxylic acid esters in rats with type 2 diabetes: enzymatic, metabolic and secretory aspects. J Mol Endocrinol 13(2):209–217CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Metz SA, Meredith M, Vadakekalam J, Rabaglia ME, Kowluru A (1999) A defect late in stimulus-secretion coupling impairs insulin secretion in Goto-Kakizaki diabetic rats. Diabetes 48(9):1754–1762CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Tsuura Y, Ishida H, Okamoto Y, Kato S, Sakamoto K, Horie M, Ikeda H, Okada Y, Seino Y (1993) Glucose sensitivity of ATP-sensitive K+ channels is impaired in beta-cells of the GK rat. A new genetic model of NIDDM. Diabetes 42(10):1446–1453CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Marie JC, Bailbe D, Gylfe E, Portha B (2001) Defective glucose-dependent cytosolic Ca2+ handling in islets of GK and nSTZ rat models of type 2 diabetes. J Endocrinol 169(1):169–176CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Zaitsev S, Efanova I, Ostenson CG, Efendic S, Berggren PO (1997) Delayed Ca2+ response to glucose in diabetic GK rat. Biochem Biophys Res Commun 239(1):129–133. Scholar
  37. 37.
    Rose T, Efendic S, Rupnik M (2007) Ca2+-secretion coupling is impaired in diabetic Goto Kakizaki rats. J Gen Physiol 129(6):493–508. Scholar
  38. 38.
    Ohara-Imaizumi M, Nishiwaki C, Kikuta T, Nagai S, Nakamichi Y, Nagamatsu S (2004) TIRF imaging of docking and fusion of single insulin granule motion in primary rat pancreatic beta-cells: different behaviour of granule motion between normal and Goto-Kakizaki diabetic rat beta-cells. Biochem J 381(Pt 1):13–18. Scholar
  39. 39.
    Eliasson L, Abdulkader F, Braun M, Galvanovskis J, Hoppa MB, Rorsman P (2008) Novel aspects of the molecular mechanisms controlling insulin secretion. J Physiol 586(14):3313–3324. Scholar
  40. 40.
    Gaisano HY, Ostenson CG, Sheu L, Wheeler MB, Efendic S (2002) Abnormal expression of pancreatic islet exocytotic soluble N-ethylmaleimide-sensitive factor attachment protein receptors in Goto-Kakizaki rats is partially restored by phlorizin treatment and accentuated by high glucose treatment. Endocrinology 143(11):4218–4226. Scholar
  41. 41.
    Zhang W, Khan A, Ostenson CG, Berggren PO, Efendic S, Meister B (2002) Down-regulated expression of exocytotic proteins in pancreatic islets of diabetic GK rats. Biochem Biophys Res Commun 291(4):1038–1044. Scholar
  42. 42.
    Ohara-Imaizumi M, Nishiwaki C, Nakamichi Y, Kikuta T, Nagai S, Nagamatsu S (2004) Correlation of syntaxin-1 and SNAP-25 clusters with docking and fusion of insulin granules analysed by total internal reflection fluorescence microscopy. Diabetologia 47(12):2200–2207. Scholar
  43. 43.
    Qin T, Liang T, Zhu D, Kang Y, Xie L, Dolai S, Sugita S, Takahashi N, Ostenson CG, Banks K, Gaisano HY (2017) Munc18b increases insulin granule fusion, restoring deficient insulin secretion in Type-2 diabetes human and Goto-Kakizaki rat islets with improvement in glucose homeostasis. EBioMedicine 16:262–274. Scholar
  44. 44.
    Seino S, Shibasaki T (2005) PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev 85(4):1303–1342. Scholar
  45. 45.
    Abdel-Halim SM, Guenifi A, He B, Yang B, Mustafa M, Hojeberg B, Hillert J, Bakhiet M, Efendic S (1998) Mutations in the promoter of adenylyl cyclase (AC)-III gene, overexpression of AC-III mRNA, and enhanced cAMP generation in islets from the spontaneously diabetic GK rat model of type 2 diabetes. Diabetes 47(3):498–504CrossRefGoogle Scholar
  46. 46.
    Portela-Gomes GM, Abdel-Halim SM (2002) Overexpression of Gs proteins and adenylyl cyclase in normal and diabetic islets. Pancreas 25(2):176–181CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Wierup N, Bjorkqvist M, Kuhar MJ, Mulder H, Sundler F (2006) CART regulates islet hormone secretion and is expressed in the beta-cells of type 2 diabetic rats. Diabetes 55(2):305–311CrossRefGoogle Scholar
  48. 48.
    Rosengren AH, Jokubka R, Tojjar D, Granhall C, Hansson O, Li DQ, Nagaraj V, Reinbothe TM, Tuncel J, Eliasson L, Groop L, Rorsman P, Salehi A, Lyssenko V, Luthman H, Renstrom E (2010) Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 327(5962):217–220. Scholar
  49. 49.
    Abdel-Halim SM, Guenifi A, Khan A, Larsson O, Berggren PO, Ostenson CG, Efendic S (1996) Impaired coupling of glucose signal to the exocytotic machinery in diabetic GK rats: a defect ameliorated by cAMP. Diabetes 45(7):934–940CrossRefGoogle Scholar
  50. 50.
    Dolz M, Bailbe D, Giroix MH, Calderari S, Gangnerau MN, Serradas P, Rickenbach K, Irminger JC, Portha B (2005) Restitution of defective glucose-stimulated insulin secretion in diabetic GK rat by acetylcholine uncovers paradoxical stimulatory effect of beta-cell muscarinic receptor activation on cAMP production. Diabetes 54(11):3229–3237CrossRefGoogle Scholar
  51. 51.
    Gauguier D, Froguel P, Parent V, Bernard C, Bihoreau MT, Portha B, James MR, Penicaud L, Lathrop M, Ktorza A (1996) Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet 12(1):38–43. Scholar
  52. 52.
    Nobrega MA, Solberg Woods LC, Fleming S, Jacob HJ (2009) Distinct genetic regulation of progression of diabetes and renal disease in the Goto-Kakizaki rat. Physiol Genomics 39(1):38–46. Scholar
  53. 53.
    Galli J, Li LS, Glaser A, Ostenson CG, Jiao H, Fakhrai-Rad H, Jacob HJ, Lander ES, Luthman H (1996) Genetic analysis of non-insulin dependent diabetes mellitus in the GK rat. Nat Genet 12(1):31–37. Scholar
  54. 54.
    Wallace KJ, Wallis RH, Collins SC, Argoud K, Kaisaki PJ, Ktorza A, Woon PY, Bihoreau MT, Gauguier D (2004) Quantitative trait locus dissection in congenic strains of the Goto-Kakizaki rat identifies a region conserved with diabetes loci in human chromosome 1q. Physiol Genomics 19(1):1–10. Scholar
  55. 55.
    Atanur SS, Diaz AG, Maratou K, Sarkis A, Rotival M, Game L, Tschannen MR, Kaisaki PJ, Otto GW, Ma MC, Keane TM, Hummel O, Saar K, Chen W, Guryev V, Gopalakrishnan K, Garrett MR, Joe B, Citterio L, Bianchi G, McBride M, Dominiczak A, Adams DJ, Serikawa T, Flicek P, Cuppen E, Hubner N, Petretto E, Gauguier D, Kwitek A, Jacob H, Aitman TJ (2013) Genome sequencing reveals loci under artificial selection that underlie disease phenotypes in the laboratory rat. Cell 154(3):691–703. Scholar
  56. 56.
    Granhall C, Rosengren AH, Renstrom E, Luthman H (2006) Separately inherited defects in insulin exocytosis and beta-cell glucose metabolism contribute to type 2 diabetes. Diabetes 55(12):3494–3500. Scholar
  57. 57.
    Esguerra JL, Bolmeson C, Cilio CM, Eliasson L (2011) Differential glucose-regulation of microRNAs in pancreatic islets of non-obese type 2 diabetes model Goto-Kakizaki rat. PLoS One 6(4):e18613. Scholar
  58. 58.
    Salunkhe VA, Ofori JK, Gandasi NR, Salo SA, Hansson S, Andersson ME, Wendt A, Barg S, Esguerra JLS, Eliasson L (2017) MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesicles. Physiol Rep 5(21).
  59. 59.
    Ofori JK, Salunkhe VA, Bagge A, Vishnu N, Nagao M, Mulder H, Wollheim CB, Eliasson L, Esguerra JL (2017) Elevated miR-130a/miR130b/miR-152 expression reduces intracellular ATP levels in the pancreatic beta cell. Sci Rep 7:44986. Scholar
  60. 60.
    Malm HA, Mollet IG, Berggreen C, Orho-Melander M, Esguerra JL, Goransson O, Eliasson L (2016) Transcriptional regulation of the miR-212/miR-132 cluster in insulin-secreting beta-cells by cAMP-regulated transcriptional co-activator 1 and salt-inducible kinases. Mol Cell Endocrinol 424:23–33. Scholar
  61. 61.
    Chavey A, Ah Kioon MD, Bailbe D, Movassat J, Portha B (2014) Maternal diabetes, programming of beta-cell disorders and intergenerational risk of type 2 diabetes. Diabetes Metab 40(5):323–330. Scholar
  62. 62.
    Dayeh T, Volkov P, Salo S, Hall E, Nilsson E, Olsson AH, Kirkpatrick CL, Wollheim CB, Eliasson L, Ronn T, Bacos K, Ling C (2014) Genome-wide DNA methylation analysis of human pancreatic islets from type 2 diabetic and non-diabetic donors identifies candidate genes that influence insulin secretion. PLoS Genet 10(3):e1004160. Scholar
  63. 63.
    El-Omar MM, Yang ZK, Phillips AO, Shah AM (2004) Cardiac dysfunction in the Goto-Kakizaki rat. A model of type II diabetes mellitus. Basic Res Cardiol 99(2):133–141. Scholar
  64. 64.
    Devanathan S, Nemanich ST, Kovacs A, Fettig N, Gropler RJ, Shoghi KI (2013) Genomic and metabolic disposition of non-obese type 2 diabetic rats to increased myocardial fatty acid metabolism. PLoS One 8(10):e78477. Scholar
  65. 65.
    Korkmaz-Icoz S, Lehner A, Li S, Vater A, Radovits T, Brune M, Ruppert M, Sun X, Brlecic P, Zorn M, Karck M, Szabo G (2016) Left ventricular pressure-volume measurements and myocardial gene expression profile in type 2 diabetic Goto-Kakizaki rats. Am J Physiol Heart Circ Physiol 311(4):H958–H971. Scholar
  66. 66.
    Nagao M, Asai A, Oikawa S (2013) FoxO1 breaks diabetic heart. J Diabetes Investig 4(1):37–38. Scholar
  67. 67.
    Yagihashi S, Goto Y, Kakizaki M, Kaseda N (1978) Thickening of glomerular basement membrane in spontaneously diabetic rats. Diabetologia 15(4):309–312CrossRefGoogle Scholar
  68. 68.
    Yagihashi S, Kaseda N, Kakizaki M, Goto Y (1979) Evolution of glomerular lesions in rats with spontaneous diabetes. Tohoku J Exp Med 127(4):359–367CrossRefGoogle Scholar
  69. 69.
    Oikawa S, Kakizaki M, Goto Y (1982) Inhibitory effect of pancreatic elastase on thickening of the renal glomerular basement membrane in the spontaneously diabetic rat. Tohoku J Exp Med 138(1):103–109CrossRefGoogle Scholar
  70. 70.
    Yagihashi S, Tonosaki A, Yamada K, Kakizaki M, Goto Y (1982) Peripheral neuropathy in selectively-inbred spontaneously diabetic rats: electrophysiological, morphometrical and freeze-replica studies. Tohoku J Exp Med 138(1):39–48CrossRefGoogle Scholar
  71. 71.
    Goto Y (2009) Our diabetes studies over 50 years. Soshinsya, TokyoGoogle Scholar
  72. 72.
    Tang Y, Axelsson AS, Spegel P, Andersson LE, Mulder H, Groop LC, Renstrom E, Rosengren AH (2014) Genotype-based treatment of type 2 diabetes with an alpha2A-adrenergic receptor antagonist. Sci Transl Med 6(257):257ra139. Scholar
  73. 73.
    Shibata M, Yasuda B (1980) New experimental congenital diabetic mice (N.S.Y. mice). Tohoku J Exp Med 130(2):139–142CrossRefGoogle Scholar
  74. 74.
    Ueda H, Ikegami H, Yamato E, Fu J, Fukuda M, Shen G, Kawaguchi Y, Takekawa K, Fujioka Y, Fujisawa T et al (1995) The NSY mouse: a new animal model of spontaneous NIDDM with moderate obesity. Diabetologia 38(5):503–508CrossRefGoogle Scholar
  75. 75.
    Fushimi H, Shibata M, Tarui S (1980) Glycosidase activities in the liver and kidney of hereditary diabetic mice. J Biochem 87(3):941–949CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Kaku K, Fiedorek FT Jr, Province M, Permutt MA (1988) Genetic analysis of glucose tolerance in inbred mouse strains. Evidence for polygenic control. Diabetes 37(6):707–713CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Nojima K, Babaya N, Yamada K, Shibata M, Yamato E, Ogihara T (2000) Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse. Diabetologia 43(7):932–938. Scholar
  78. 78.
    Hamada Y, Ikegami H, Ueda H, Kawaguchi Y, Yamato E, Nojima K, Yamada K, Babaya N, Shibata M, Ogihara T (2001) Insulin secretion to glucose as well as nonglucose stimuli is impaired in spontaneously diabetic Nagoya-Shibata-Yasuda mice. Metabolism 50(11):1282–1285. Scholar
  79. 79.
    Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Yamato E, Shibata M, Ogihara T (1999) Genetic analysis of late-onset type 2 diabetes in a mouse model of human complex trait. Diabetes 48(5):1168–1174CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Babaya N, Ikegami H, Fujisawa T, Nojima K, Itoi-Babaya M, Inoue K, Ohno T, Shibata M, Ogihara T (2005) Susceptibility to streptozotocin-induced diabetes is mapped to mouse chromosome 11. Biochem Biophys Res Commun 328(1):158–164. Scholar
  81. 81.
    Ueda H, Ikegami H, Kawaguchi Y, Fujisawa T, Nojima K, Babaya N, Yamada K, Shibata M, Yamato E, Ogihara T (2001) Mapping and promoter sequencing of HNF-1beta gene in diabetes-prone and -resistant mice. Diabetes Res Clin Pract 53(2):67–71CrossRefGoogle Scholar
  82. 82.
    Gonzalez C, Cuvellier S, Hue-Beauvais C, Levi-Strauss M (2003) Genetic control of non obese diabetic mice susceptibility to high-dose streptozotocin-induced diabetes. Diabetologia 46(9):1291–1295. Scholar
  83. 83.
    Itoi-Babaya M, Ikegami H, Fujisawa T, Ueda H, Nojima K, Babaya N, Kobayashi M, Noso S, Kawaguchi Y, Yamaji K, Shibata M, Ogihara T (2007) Fatty liver and obesity: phenotypically correlated but genetically distinct traits in a mouse model of type 2 diabetes. Diabetologia 50(8):1641–1648. Scholar
  84. 84.
    Babaya N, Fujisawa T, Nojima K, Itoi-Babaya M, Yamaji K, Yamada K, Kobayashi M, Ueda H, Hiromine Y, Noso S, Ikegami H (2010) Direct evidence for susceptibility genes for type 2 diabetes on mouse chromosomes 11 and 14. Diabetologia 53(7):1362–1371. Scholar
  85. 85.
    Babaya N, Ueda H, Noso S, Hiromine Y, Itoi-Babaya M, Kobayashi M, Fujisawa T, Ikegami H (2014) Genetic dissection of susceptibility genes for diabetes and related phenotypes on mouse chromosome 14 by means of congenic strains. BMC Genet 15:93. Scholar
  86. 86.
    Shibata M, Kishi T, Yasuda B, Kuno T (1986) The inhibitory effect of lysozyme on the glomerular basement membrane thickening in spontaneous diabetic mice (NSY mice). Tohoku J Exp Med 149(1):39–46CrossRefGoogle Scholar
  87. 87.
    Shimizu K, Morita H, Niwa T, Maeda K, Shibata M, Higuchi K, Takeda T (1993) Spontaneous amyloidosis in senile NSY mice. Acta Pathol Jpn 43(5):215–221PubMedGoogle Scholar
  88. 88.
    Nagao M, Asai A, Kawahara M, Nakajima Y, Sato Y, Tanimura K, Okajima F, Takaya M, Sudo M, Takemitsu S, Harada T, Sugihara H, Oikawa S (2012) Selective breeding of mice for different susceptibilities to high fat diet-induced glucose intolerance: development of two novel mouse lines, Selectively bred Diet-induced Glucose intolerance-Prone and -Resistant. J Diabetes Investig 3(3):245–251. Scholar
  89. 89.
    Nagao M, Asai A, Inaba W, Kawahara M, Shuto Y, Kobayashi S, Sanoyama D, Sugihara H, Yagihashi S, Oikawa S (2014) Characterization of pancreatic islets in two selectively bred mouse lines with different susceptibilities to high-fat diet-induced glucose intolerance. PLoS One 9(1):e84725. Scholar
  90. 90.
    Nagao M, Asai A, Sugihara H, Oikawa S (2015) Transgenerational changes of metabolic phenotypes in two selectively bred mouse colonies for different susceptibilities to diet-induced glucose intolerance. Endocr J 62(4):371–378. Scholar
  91. 91.
    Nagao M, Asai A, Sugihara H, Oikawa S (2015) Fat intake and the development of type 2 diabetes. Endocr J 62(7):561–572. Scholar
  92. 92.
    Asai A, Nagao M, Kawahara M, Shuto Y, Sugihara H, Oikawa S (2013) Effect of impaired glucose tolerance on atherosclerotic lesion formation: an evaluation in selectively bred mice with different susceptibilities to glucose intolerance. Atherosclerosis 231(2):421–426. Scholar
  93. 93.
    Halban PA, Polonsky KS, Bowden DW, Hawkins MA, Ling C, Mather KJ, Powers AC, Rhodes CJ, Sussel L, Weir GC (2014) Beta-cell failure in type 2 diabetes: postulated mechanisms and prospects for prevention and treatment. Diabetes Care 37(6):1751–1758. Scholar
  94. 94.
    Groop L, Pociot F (2014) Genetics of diabetes – are we missing the genes or the disease? Mol Cell Endocrinol 382(1):726–739. Scholar
  95. 95.
    Rosengren AH, Braun M, Mahdi T, Andersson SA, Travers ME, Shigeto M, Zhang E, Almgren P, Ladenvall C, Axelsson AS, Edlund A, Pedersen MG, Jonsson A, Ramracheya R, Tang Y, Walker JN, Barrett A, Johnson PR, Lyssenko V, McCarthy MI, Groop L, Salehi A, Gloyn AL, Renstrom E, Rorsman P, Eliasson L (2012) Reduced insulin exocytosis in human pancreatic beta-cells with gene variants linked to type 2 diabetes. Diabetes 61(7):1726–1733. Scholar
  96. 96.
    Hiriart M, Matteson DR (1988) Na channels and two types of Ca channels in rat pancreatic B cells identified with the reverse hemolytic plaque assay. J Gen Physiol 91(5):617–639CrossRefGoogle Scholar
  97. 97.
    Gopel S, Kanno T, Barg S, Galvanovskis J, Rorsman P (1999) Voltage-gated and resting membrane currents recorded from B-cells in intact mouse pancreatic islets. J Physiol 521(Pt 3):717–728CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Mototsugu Nagao
    • 1
    • 2
    • 3
    Email author
  • Jonathan Lou S. Esguerra
    • 1
    • 2
  • Anna Wendt
    • 1
    • 2
  • Akira Asai
    • 3
    • 4
  • Hitoshi Sugihara
    • 3
  • Shinichi Oikawa
    • 3
    • 5
  • Lena Eliasson
    • 1
    • 2
    Email author
  1. 1.Islet Cell Exocytosis, Lund University Diabetes Centre, Department of Clinical Sciences MalmöLund UniversityMalmöSweden
  2. 2.Clinical Research CentreSkåne University HospitalLund and MalmöSweden
  3. 3.Department of Endocrinology, Diabetes and Metabolism, Graduate School of MedicineNippon Medical SchoolTokyoJapan
  4. 4.Food and Health Science Research Unit, Graduate School of Agricultural ScienceTohoku UniversitySendaiJapan
  5. 5.Diabetes and Lifestyle-related Disease Center, Japan Anti-Tuberculosis AssociationFukujuji HospitalTokyoJapan

Personalised recommendations