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Animal Models of Diabetes pp 55–67Cite as

A Review of Mouse Models of Monogenic Diabetes and ER Stress Signaling

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Part of the book series: Methods in Molecular Biology ((MIMB,volume 2128))

Abstract

Diabetes is a major public health problem: it is estimated that 420 million people are affected globally. Monogenic forms of diabetes are less common, but variants in monogenic diabetes genes have been shown to contribute to type 2 diabetes risk. In vitro and in vivo models of monogenic forms of diabetes related to the endoplasmic reticulum (ER) stress response provided compelling evidence on the role of ER stress and dysregulated ER stress signaling on β cell demise in type 1 and type 2 diabetes. In this chapter, we describe the genetics, background, and phenotype of ER stress-related monogenic diabetes mouse models, and we comment on their advantages and disadvantages. We conclude that these mouse models are very useful tools for monogenic diabetes molecular pathogenesis studies, although there is a variability on the methodology that is used. Regarding the use of these models for therapeutic testing of ER stress modulators, a specific consideration should be given to the fact that they recapitulate some, but not all, the phenotypic characteristics of the human disease.

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References

  1. IDF (2017) IDF diabetes atlas, 8th edn International Diabetes Federation, Brussels, Belgium

    Google Scholar 

  2. Flannick J, Johansson S, Njølstad PR (2016) Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nat Rev Endocrinol 12:394–406. https://doi.org/10.1038/nrendo.2016.50

    Article  CAS  PubMed  Google Scholar 

  3. Murphy R, Ellard S, Hattersley AT (2008) Clinical implications of a molecular genetic classification of monogenic β-cell diabetes. Nat Clin Pract Endocrinol Metab 4:200–213. https://doi.org/10.1038/ncpendmet0778

    Article  CAS  PubMed  Google Scholar 

  4. Ron D, Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol 8:519–529

    Article  CAS  Google Scholar 

  5. Asada R, Kanemoto S, Kondo S et al (2011) The signalling from endoplasmic reticulum-resident bZIP transcription factors involved in diverse cellular physiology. J Biochem 149:507–518. https://doi.org/10.1093/jb/mvr041

    Article  CAS  PubMed  Google Scholar 

  6. Cnop M, Foufelle F, Velloso LA (2012) Endoplasmic reticulum stress, obesity and diabetes. Trends Mol Med 18:59–68

    Article  CAS  Google Scholar 

  7. Cnop M, Toivonen S, Igoillo-Esteve M, Salpea P (2017) Endoplasmic reticulum stress and eIF2α phosphorylation: the Achilles heel of pancreatic β cells. Mol Metab 6:1024–1039

    Article  CAS  Google Scholar 

  8. Yoshioka M, Kayo T, Ikeda T, Koizumi A (1997) A novel locus, Mody4, distal to D7Mit189 on chromosome 7 determines early-onset NIDDM in nonobese C57BL/6 (Akita) mutant mice. Diabetes 46:887–894

    Article  CAS  Google Scholar 

  9. Stoy J, Edghill EL, Flanagan SE et al (2007) Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A 104:15040–15044. https://doi.org/10.1073/pnas.0707291104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Colombo C, Porzio O, Liu M et al (2008) Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest 118:2148–2156. https://doi.org/10.1172/JCI33777

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Polak M, Shield J (2004) Neonatal diabetes mellitus – genetic aspects 2004. Pediatr Endocrinol Rev 2:193–198

    PubMed  Google Scholar 

  12. Wang J, Takeuchi T, Tanaka S et al (1999) A mutation in the insulin 2 gene induces diabetes with severe pancreatic beta-cell dysfunction in the Mody mouse. J Clin Invest 103:27–37. https://doi.org/10.1172/JCI4431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kayo T, Koizumi A (1998) Mapping of murine diabetogenic gene mody on chromosome 7 at D7Mit258 and its involvement in pancreatic islet and beta cell development during the perinatal period. J Clin Invest 101:2112–2118. https://doi.org/10.1172/JCI1842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Barbetti F, Colombo C, Haataja L et al (2016) Hyperglucagonemia in an animal model of insulin- deficient diabetes: what therapy can improve it? Clin Diabetes Endocrinol 2:11. https://doi.org/10.1186/s40842-016-0029-5

    Article  PubMed  PubMed Central  Google Scholar 

  15. Oyadomari S, Koizumi A, Takeda K et al (2002) Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. J Clin Invest 109:525–532. https://doi.org/10.1172/JCI14550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stoy J, Steiner DF, Park S-Y et al (2010) Clinical and molecular genetics of neonatal diabetes due to mutations in the insulin gene. Rev Endocr Metab Disord 11:205–215. https://doi.org/10.1007/s11154-010-9151-3

    Article  PubMed  PubMed Central  Google Scholar 

  17. Herbach N, Rathkolb B, Kemter E et al (2007) Dominant-negative effects of a novel mutated Ins2 allele causes early-onset diabetes and severe beta-cell loss in Munich Ins2C95S mutant mice. Diabetes 56:1268–1276. https://doi.org/10.2337/db06-0658

    Article  CAS  PubMed  Google Scholar 

  18. Scheuner D, Song B, McEwen E et al (2001) Translational control is required for the unfolded protein response and in vivo glucose homeostasis. Mol Cell 7:1165–1176. https://doi.org/10.1016/S1097-2765(01)00265-9

    Article  CAS  PubMed  Google Scholar 

  19. Scheuner D, Vander Mierde D, Song B et al (2005) Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nat Med 11:757–764. https://doi.org/10.1038/nm1259

    Article  CAS  PubMed  Google Scholar 

  20. Boyce M, Bryant KF, Jousse C et al (2005) A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science 307:935–939. https://doi.org/10.1126/science.1101902

    Article  CAS  PubMed  Google Scholar 

  21. Tsaytler P, Harding HP, Ron D, Bertolotti A (2011) Selective inhibition of a regulatory subunit of protein phosphatase 1 restores proteostasis. Science 332:91–94. https://doi.org/10.1126/science.1201396

    Article  CAS  PubMed  Google Scholar 

  22. Cnop M, Ladriere L, Hekerman P et al (2007) Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. J Biol Chem 282:3989–3997. https://doi.org/10.1074/jbc.M607627200

    Article  CAS  PubMed  Google Scholar 

  23. Abdulkarim B, Hernangomez M, Igoillo-Esteve M et al (2017) Guanabenz sensitizes pancreatic beta cells to lipotoxic endoplasmic reticulum stress and apoptosis. Endocrinology 158:1659–1670. https://doi.org/10.1210/en.2016-1773

    Article  CAS  PubMed  Google Scholar 

  24. Ladriere L, Igoillo-Esteve M, Cunha DA et al (2010) Enhanced signaling downstream of ribonucleic acid-activated protein kinase-like endoplasmic reticulum kinase potentiates lipotoxic endoplasmic reticulum stress in human islets. J Clin Endocrinol Metab 95:1442–1449. https://doi.org/10.1210/jc.2009-2322

    Article  CAS  PubMed  Google Scholar 

  25. Borck G, Shin B-S, Stiller B et al (2012) eIF2gamma mutation that disrupts eIF2 complex integrity links intellectual disability to impaired translation initiation. Mol Cell 48:641–646. https://doi.org/10.1016/j.molcel.2012.09.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Moortgat S, Desir J, Benoit V et al (2016) Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy. Am J Med Genet A 170:2927–2933. https://doi.org/10.1002/ajmg.a.37792

    Article  CAS  PubMed  Google Scholar 

  27. Skopkova M, Hennig F, Shin B-S et al (2017) EIF2S3 mutations associated with severe X-linked intellectual disability syndrome MEHMO. Hum Mutat 38:409–425. https://doi.org/10.1002/humu.23170

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hansen GM, Markesich DC, Burnett MB et al (2008) Large-scale gene trapping in C57BL/6N mouse embryonic stem cells. Genome Res 18:1670–1679. https://doi.org/10.1101/gr.078352.108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Delépine M, Nicolino M, Barrett T et al (2000) EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nat Genet 25:406–409. https://doi.org/10.1038/78085

    Article  PubMed  Google Scholar 

  30. Julier C, Nicolino M (2010) Wolcott-Rallison syndrome. Orphanet J Rare Dis 5:29

    Article  Google Scholar 

  31. Harding HP, Zeng H, Zhang Y et al (2001) Diabetes mellitus and exocrine pancreatic dysfunction in Perk−/− mice reveals a role for translational control in secretory cell survival. Mol Cell 7:1153–1163. https://doi.org/10.1016/S1097-2765(01)00264-7

    Article  CAS  PubMed  Google Scholar 

  32. Zhang P, McGrath B, Li S et al (2002) The PERK eukaryotic initiation factor 2 alpha kinase is required for the development of the skeletal system, postnatal growth, and the function and viability of the pancreas. Mol Cell Biol 22:3864–3874. https://doi.org/10.1128/MCB.22.11.3864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wei J, Sheng X, Feng D et al (2008) PERK is essential for neonatal skeletal development to regulate osteoblast proliferation and differentiation. J Cell Physiol 217:693–707. https://doi.org/10.1002/jcp.21543

    Article  CAS  PubMed  Google Scholar 

  34. Harding HP, Zhang Y, Bertolotti A et al (2000) Perk is essential for translational regulation and cell survival during the unfolded protein response. Mol Cell 5:897–904. S1097-2765(00)80330-5 [pii]

    Article  CAS  Google Scholar 

  35. Zhang W, Feng D, Li Y et al (2006) PERK EIF2AK3 control of pancreatic β cell differentiation and proliferation is required for postnatal glucose homeostasis. Cell Metab 4:491–497. https://doi.org/10.1016/j.cmet.2006.11.002

    Article  CAS  PubMed  Google Scholar 

  36. Gupta S, McGrath B, Cavener DR (2010) PERK (EIF2AK3) regulates proinsulin trafficking and quality control in the secretory pathway. Diabetes 59:1937–1947. https://doi.org/10.2337/db09-1064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Synofzik M, Haack TB, Kopajtich R et al (2014) Absence of BiP Co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet 95:689–697. https://doi.org/10.1016/j.ajhg.2014.10.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ladiges WC, Knoblaugh SE, Morton JF et al (2005) Pancreatic ??-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54:1074–1081. https://doi.org/10.2337/diabetes.54.4.1074

    Article  CAS  PubMed  Google Scholar 

  39. Barrett TG, Bundey SE, Macleod AF (1995) Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet 346:1458–1463. https://doi.org/10.1016/S0140-6736(95)92473-6

    Article  CAS  PubMed  Google Scholar 

  40. Kinsley BT, Swift M, Dumont RH, Swift RG (1995) Morbidity and mortality in the Wolfram syndrome. Diabetes Care 18:1566–1570. 5p

    Article  CAS  Google Scholar 

  41. Ishihara H, Takeda S, Tamura A et al (2004) Disruption of the WFS1 gene in mice causes progressive β-cell loss and impaired stimulus - Secretion coupling in insulin secretion. Hum Mol Genet 13:1159–1170. https://doi.org/10.1093/hmg/ddh125

    Article  CAS  PubMed  Google Scholar 

  42. Riggs AC, Bernal-Mizrachi E, Ohsugi M et al (2005) Mice conditionally lacking the Wolfram gene in pancreatic islet beta cells exhibit diabetes as a result of enhanced endoplasmic reticulum stress and apoptosis. Diabetologia 48:2313–2321. https://doi.org/10.1007/s00125-005-1947-4

    Article  CAS  PubMed  Google Scholar 

  43. Kõks S, Soomets U, Paya-Cano JL et al (2009) Wfs1 gene deletion causes growth retardation in mice and interferes with the growth hormone pathway. Physiol Genomics 37:249–259. https://doi.org/10.1152/physiolgenomics.90407.2008

    Article  CAS  PubMed  Google Scholar 

  44. Noormets K, Kõks S, Muldmaa M et al (2011) Sex differences in the development of diabetes in mice with deleted wolframin (Wfs1) gene. Exp Clin Endocrinol Diabetes 119:271–275. https://doi.org/10.1055/s-0030-1265163

    Article  CAS  PubMed  Google Scholar 

  45. Luuk H, Plaas M, Raud S et al (2009) Wfs1-deficient mice display impaired behavioural adaptation in stressful environment. Behav Brain Res 198:334–345. https://doi.org/10.1016/j.bbr.2008.11.007

    Article  CAS  PubMed  Google Scholar 

  46. Rigoli L, Di Bella C (2012) Wolfram syndrome 1 and Wolfram syndrome 2. Curr Opin Pediatr 24:512–517

    CAS  PubMed  Google Scholar 

  47. Chen YF, Kao CH, Chen YT et al (2009) Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev 23:1183–1194. https://doi.org/10.1101/gad.1779509

    Article  PubMed  PubMed Central  Google Scholar 

  48. Alquier T, Poitout V (2018) Considerations and guidelines for mouse metabolic phenotyping in diabetes research. Diabetologia 61:526–538

    Article  Google Scholar 

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Authors and Affiliations

  1. Université Libre de Bruxelles, Bruxelles, Belgium

    Paraskevi Salpea, Cristina Cosentino & Mariana Igoillo-Esteve

Authors
  1. Paraskevi Salpea
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  2. Cristina Cosentino
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  3. Mariana Igoillo-Esteve
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Editors and Affiliations

  1. Department of Diabetes, School of Life Course Sciences, King’s College London, London, UK

    Aileen J. F. King

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Salpea, P., Cosentino, C., Igoillo-Esteve, M. (2020). A Review of Mouse Models of Monogenic Diabetes and ER Stress Signaling. 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_4

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  • DOI: https://doi.org/10.1007/978-1-0716-0385-7_4

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0384-0

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