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

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Animal Models of Diabetes

Abstract

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.

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References

  1. Goto Y, Kakizaki M, Masaki N (1975) Spontaneous diabetes produced by selective breeding of normal Wistar rats. Proc Jpn Acad 51(1):80–85

    Article  Google Scholar 

  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 490–492

    Google Scholar 

  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):3–8

    Article  CAS  PubMed  Google Scholar 

  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):486–491

    Article  CAS  PubMed  Google Scholar 

  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):13–17

    Article  CAS  PubMed  Google Scholar 

  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):863–870

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.bone.2010.08.003

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.biochi.2017.08.012

    Article  CAS  PubMed  Google Scholar 

  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 119–138

    Chapter  Google Scholar 

  10. Goto Y (1991) Foundation of the GK rat. J Jpn Diabetes Soc 34(11):939–941

    Google Scholar 

  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):453–459

    Article  CAS  PubMed  Google Scholar 

  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 107–116

    Google Scholar 

  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. https://doi.org/10.1007/978-1-62703-068-7_9

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1463-1326.2007.00787.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1152/ajpendo.1993.265.5.E807

    Article  CAS  PubMed  Google Scholar 

  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):1443–1452

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.1463-1326.2007.00786.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s001250050768

    Article  CAS  PubMed  Google Scholar 

  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):148–153

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00795-006-0324-9

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1210/endo.137.6.8641194

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2337/db05-1526

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/endo.140.7.6862

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1055/s-2007-984471

    Article  CAS  PubMed  Google Scholar 

  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):1065–1072

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1210/endo.139.6.6053

    Article  CAS  PubMed  Google Scholar 

  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):73–81

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/bbrc.1996.0525

    Article  CAS  PubMed  Google Scholar 

  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):239–246

    Article  CAS  PubMed  Google Scholar 

  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):722–726

    Article  CAS  PubMed  Google Scholar 

  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):1082–1087

    Article  CAS  PubMed  Google Scholar 

  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):209–217

    Article  CAS  PubMed  Google Scholar 

  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):1754–1762

    Article  CAS  PubMed  Google Scholar 

  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):1446–1453

    Article  CAS  PubMed  Google Scholar 

  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):169–176

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/bbrc.1997.7441

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1085/jgp.200609604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1042/BJ20040434

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1113/jphysiol.2008.155317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1210/en.2002-220237

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1006/bbrc.2002.6555

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00125-004-1579-0

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.ebiom.2017.01.030

    Article  PubMed  PubMed Central  Google Scholar 

  44. Seino S, Shibasaki T (2005) PKA-dependent and PKA-independent pathways for cAMP-regulated exocytosis. Physiol Rev 85(4):1303–1342. https://doi.org/10.1152/physrev.00001.2005

    Article  CAS  PubMed  Google Scholar 

  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):498–504

    Article  CAS  PubMed  Google Scholar 

  46. Portela-Gomes GM, Abdel-Halim SM (2002) Overexpression of Gs proteins and adenylyl cyclase in normal and diabetic islets. Pancreas 25(2):176–181

    Article  PubMed  Google Scholar 

  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):305–311

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1126/science.1176827

    Article  CAS  PubMed  Google Scholar 

  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):934–940

    Article  PubMed  Google Scholar 

  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):3229–3237

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/ng0196-38

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1152/physiolgenomics.90389.2008

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/ng0196-31

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1152/physiolgenomics.00114.2004

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.cell.2013.06.040

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.2337/db06-0796

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0018613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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). https://doi.org/10.14814/phy2.13493

  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. https://doi.org/10.1038/srep44986

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1016/j.mce.2016.01.010

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.diabet.2014.02.003

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pgen.1004160

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s00395-004-0440-4

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0078477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1152/ajpheart.00956.2015

    Article  PubMed  Google Scholar 

  66. Nagao M, Asai A, Oikawa S (2013) FoxO1 breaks diabetic heart. J Diabetes Investig 4(1):37–38. https://doi.org/10.1111/jdi.12022

    Article  CAS  PubMed  Google Scholar 

  67. Yagihashi S, Goto Y, Kakizaki M, Kaseda N (1978) Thickening of glomerular basement membrane in spontaneously diabetic rats. Diabetologia 15(4):309–312

    Article  CAS  PubMed  Google Scholar 

  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):359–367

    Article  CAS  PubMed  Google Scholar 

  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):103–109

    Article  CAS  PubMed  Google Scholar 

  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):39–48

    Article  CAS  PubMed  Google Scholar 

  71. Goto Y (2009) Our diabetes studies over 50 years. Soshinsya, Tokyo

    Google Scholar 

  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. https://doi.org/10.1126/scitranslmed.3009934

    Article  CAS  PubMed  Google Scholar 

  73. Shibata M, Yasuda B (1980) New experimental congenital diabetic mice (N.S.Y. mice). Tohoku J Exp Med 130(2):139–142

    Article  CAS  PubMed  Google Scholar 

  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):503–508

    Article  CAS  PubMed  Google Scholar 

  75. Fushimi H, Shibata M, Tarui S (1980) Glycosidase activities in the liver and kidney of hereditary diabetic mice. J Biochem 87(3):941–949

    Article  CAS  PubMed  Google Scholar 

  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):707–713

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s001250051472

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1053/meta.2001.27198

    Article  CAS  PubMed  Google Scholar 

  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):1168–1174

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.bbrc.2004.12.149

    Article  CAS  PubMed  Google Scholar 

  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):67–71

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00125-003-1168-7

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00125-007-0700-6

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s00125-010-1737-5

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1186/s12863-014-0093-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):39–46

    Article  CAS  PubMed  Google Scholar 

  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):215–221

    CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1111/j.2040-1124.2011.00175.x

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1371/journal.pone.0084725

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1507/endocrj.EJ14-0241

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1507/endocrj.EJ15-0055

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1016/j.atherosclerosis.2013.10.009

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2337/dc14-0396

    Article  PubMed  PubMed Central  Google Scholar 

  94. Groop L, Pociot F (2014) Genetics of diabetes – are we missing the genes or the disease? Mol Cell Endocrinol 382(1):726–739. https://doi.org/10.1016/j.mce.2013.04.002

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.2337/db11-1516

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):617–639

    Article  CAS  PubMed  Google Scholar 

  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):717–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

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).

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Nagao, M. et al. (2020). Selectively Bred Diabetes Models: GK Rats, NSY Mice, and ON Mice. 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_3

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