Skip to main content

Advertisement

SpringerLink
Log in

Type 1 diabetes in mice and men: gene expression profiling to investigate disease pathogenesis

  • IMMUNOLOGY AT STANFORD UNIVERSITY
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

Type 1 diabetes (T1D) is a complex polygenic disease that is triggered by various environmental factors in genetically susceptible individuals. The emphasis placed on genome-wide association studies to explain the genetics of T1D has failed to advance our understanding of T1D pathogenesis or identify biomarkers of disease progression or therapeutic targets. Using the nonobese diabetic (NOD) mouse model of T1D and the non-disease prone congenic NOD.B10 mice, our laboratory demonstrated striking tissue-specific and age-dependent changes in gene expression during disease progression. We established a “roadmap” of differential gene expression and used this to identify candidate genes in mice (and human orthologs) that play a role in disease pathology. Here, we describe two genes, Deformed epidermal autoregulatory factor 1 (Deaf1) and Adenosine A1 receptor (Adora1), that are differentially expressed and alternatively spliced in the pancreatic lymph nodes or islets of NOD mice and T1D patients to form dominant-negative non-functional isoforms. Loss of Deaf1 function leads to reduced peripheral tissue antigen expression in lymph node stromal cells and may contribute to a breakdown in peripheral tolerance, while reduced Adora1 function results in an early intrinsic alpha cell defect that may explain the hyperglucagonemia and resulting beta cell stress observed prior to the onset of diabetes. Remarkably, both genes were also alternatively spliced in the same tissues of auto-antibody positive prediabetic patients, and these splicing events resulted in similar downstream effects as those seen in NOD mice. These findings demonstrate the value of gene expression profiling in studying disease pathogenesis in T1D.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med. 2009;360:1646–54.

    Article  CAS  PubMed  Google Scholar 

  2. Noble JA, Erlich HA. Genetics of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2:a007732.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Pociot F, Akolkar B, Concannon P, Erlich HA, Julier C, Morahan G, et al. Genetics of type 1 diabetes: what’s next? Diabetes. 2010;59:1561–71.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Leiter EH. Nonobese diabetic mice and the genetics of diabetes susceptibility. Curr Diabetes Rep. 2005;5:141–8.

    Article  CAS  Google Scholar 

  5. Suri A, Walters JJ, Gross ML, Unanue ER. Natural peptides selected by diabetogenic DQ8 and murine I-A(g7) molecules show common sequence specificity. J Clin Investig. 2005;115:2268–76.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Young EF, Hess PR, Arnold LW, Tisch R, Frelinger JA. Islet lymphocyte subsets in male and female NOD mice are qualitatively similar but quantitatively distinct. Autoimmunity. 2009;42:678–91.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Yaacob NS, Goh KS, Norazmi MN. Male and female NOD mice differentially express peroxisome proliferator-activated receptors and pathogenic cytokines. Exp Toxicol Pathol. 2012;64:127–31.

    Article  CAS  PubMed  Google Scholar 

  8. Enomoto A, Hasegawa M, Komine S. Spleen cells derived from male non-obese diabetic mice are capable of suppressing the autoantigen-specific production of interferon-gamma of female cells in vitro. Biosci Biotechnol Biochem. 2005;69:2312–8.

    Article  CAS  PubMed  Google Scholar 

  9. Bao M, Yang Y, Jun HS, Yoon JW. Molecular mechanisms for gender differences in susceptibility to T cell-mediated autoimmune diabetes in nonobese diabetic mice. J Immunol. 2002;168:5369–75.

    Article  CAS  PubMed  Google Scholar 

  10. Whitacre CC. Sex differences in autoimmune disease. Nat Immunol. 2001;2:777–80.

    Article  CAS  PubMed  Google Scholar 

  11. Ronningen KS. Type 1 diabetes: prospective cohort studies for identification of the environmental trigger. Arch Immunol Ther Exp (Warsz). 2013;61:459–68.

    Article  CAS  Google Scholar 

  12. Knip M, Simell O. Environmental triggers of type 1 diabetes. Cold Spring Harb Perspect Med. 2012;2:a007690.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Barbeau WE. What is the key environmental trigger in type 1 diabetes—is it viruses, or wheat gluten, or both? Autoimmun Rev. 2012;12:295–9.

    Article  PubMed  Google Scholar 

  14. Larsson PG, Lakshmikanth T, Svedin E, King C, Flodstrom-Tullberg M. Previous maternal infection protects offspring from enterovirus infection and prevents experimental diabetes development in mice. Diabetologia. 2013;56:867–74.

    Article  CAS  PubMed  Google Scholar 

  15. Hyoty H. Enterovirus infections and type 1 diabetes. Ann Med. 2002;34:138–47.

    Article  PubMed  Google Scholar 

  16. Myers MA, Hettiarachchi KD, Ludeman JP, Wilson AJ, Wilson CR, Zimmet PZ. Dietary microbial toxins and type 1 diabetes. Ann N Y Acad Sci. 2003;1005:418–22.

    Article  CAS  PubMed  Google Scholar 

  17. Furuse M, Kimura C, Takahashi H, Okumura J. Influence of dietary sorbose on diabetes in nonobese diabetic mice. Comp Biochem Physiol Comp Physiol. 1994;108:123–7.

    Article  CAS  PubMed  Google Scholar 

  18. Hermitte L, Atlan-Gepner C, Payan MJ, Mehelleb M, Vialettes B. Dietary protection against diabetes in NOD mice: lack of a major change in the immune system. Diabete Metab. 1995;21:261–8.

    CAS  PubMed  Google Scholar 

  19. Marietta EV, Gomez AM, Yeoman C, Tilahun AY, Clark CR, Luckey DH, et al. Low incidence of spontaneous type 1 diabetes in non-obese diabetic mice raised on gluten-free diets is associated with changes in the intestinal microbiome. PLoS One. 2013;8:e78687.

    Article  PubMed Central  PubMed  Google Scholar 

  20. Funda DP, Kaas A, Tlaskalova-Hogenova H, Buschard K. Gluten-free but also gluten-enriched (gluten+) diet prevent diabetes in NOD mice; the gluten enigma in type 1 diabetes. Diabetes Metab Res Rev. 2008;24:59–63.

    Article  CAS  PubMed  Google Scholar 

  21. MacFarlane AJ, Strom A, Scott FW. Epigenetics: deciphering how environmental factors may modify autoimmune type 1 diabetes. Mamm Genome. 2009;20:624–32.

    Article  CAS  PubMed  Google Scholar 

  22. Luo FL, Yuan F, Peng Z, Zhou W, Fang L, Cai JF. Regulation different network analysis of rheumatoid arthritis (RA) and osteoarthritis (OA). Eur Rev Med Pharmacol Sci. 2013;17:2504–11.

    PubMed  Google Scholar 

  23. Armananzas R, Calvo B, Inza I, Lopez-Hoyos M, Martinez-Taboada V, Ucar E, et al. Microarray analysis of autoimmune diseases by machine learning procedures. IEEE Trans Inf Technol Biomed. 2009;13:341–50.

    Article  PubMed  Google Scholar 

  24. Dutta R. Gene expression changes underlying cortical pathology: clues to understanding neurological disability in multiple sclerosis. Mult Scler J. 2013;19:1249–54.

    Article  CAS  Google Scholar 

  25. Yip L, Taylor C, Whiting CC, Fathman CG. Diminished adenosine A1 receptor expression in pancreatic alpha cells may contribute to the pathology of type 1 diabetes. Diabetes. 2013;62:4208–19.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kodama K, Butte AJ, Creusot RJ, Su L, Sheng D, Hartnett M, et al. Tissue- and age-specific changes in gene expression during disease induction and progression in NOD mice. Clin Immunol. 2008;129:195–201.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattari P, et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005;37:1317–9.

    Article  CAS  PubMed  Google Scholar 

  28. Long A, Buckner JH. Intersection between genetic polymorphisms and immune deviation in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2013;20:285–91.

    CAS  PubMed  Google Scholar 

  29. Maine CJ, Hamilton-Williams EE, Cheung J, Stanford SM, Bottini N, Wicker LS, et al. PTPN22 alters the development of regulatory T cells in the thymus. J Immunol. 2012;188:5267–75.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Vang T, Liu WH, Delacroix L, Wu S, Vasile S, Dahl R, et al. LYP inhibits T-cell activation when dissociated from CSK. Nat Chem Biol. 2012;8:437–46.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Welch JS, Escoubet-Lozach L, Sykes DB, Liddiard K, Greaves DR, Glass CK. TH2 cytokines and allergic challenge induce Ym1 expression in macrophages by a STAT6-dependent mechanism. J Biol Chem. 2002;277:42821–9.

    Article  CAS  PubMed  Google Scholar 

  32. Arora M, Chen L, Paglia M, Gallagher I, Allen JE, Vyas YM, et al. Simvastatin promotes Th2-type responses through the induction of the chitinase family member Ym1 in dendritic cells. Proc Natl Acad Sci USA. 2006;103:7777–82.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Yoshida Y. F-box proteins that contain sugar-binding domains. Biosci Biotechnol Biochem. 2007;71:2623–31.

    Article  CAS  PubMed  Google Scholar 

  34. Gagnerault MC, Luan JJ, Lotton C, Lepault F. Pancreatic lymph nodes are required for priming of beta cell reactive T cells in NOD mice. J Exp Med. 2002;196:369–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Kuttenkeuler D, Pelte N, Ragab A, Gesellchen V, Schneider L, Blass C, et al. A large-scale RNAi screen identifies Deaf1 as a regulator of innate immune responses in Drosophila. J Innate Immun. 2010;2:181–94.

    Article  CAS  PubMed  Google Scholar 

  36. Reed DE, Huang XM, Wohlschlegel JA, Levine MS, Senger K. DEAF-1 regulates immunity gene expression in Drosophila. Proc Natl Acad Sci USA. 2008;105:8351–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Huggenvik JI, Michelson RJ, Collard MW, Ziemba AJ, Gurley P, Mowen KA. Characterization of a nuclear deformed epidermal autoregulatory factor-1 (DEAF-1)-related (NUDR) transcriptional regulator protein. Mol Endocrinol. 1998;12:1619–39.

    Article  CAS  PubMed  Google Scholar 

  38. Wojciak JM, Clubb RT. Finding the function buried in SAND. Nat Struct Biol. 2001;8:568–70.

    Article  CAS  PubMed  Google Scholar 

  39. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, et al. Projection of an immunological self shadow within the thymus by the aire protein. Science. 2002;298:1395–401.

    Article  CAS  PubMed  Google Scholar 

  40. Gavanescu I, Benoist C, Mathis D. B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: a therapeutic approach for APECED patients. Proc Natl Acad Sci USA. 2008;105:13009–14.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Lee JW, Epardaud M, Sun J, Becker JE, Cheng AC, Yonekura AR, et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol. 2007;8:181–90.

    Article  CAS  PubMed  Google Scholar 

  42. Yip L, Su L, Sheng D, Chang P, Atkinson M, Czesak M, et al. Deaf1 isoforms control the expression of genes encoding peripheral tissue antigens in the pancreatic lymph nodes during type 1 diabetes. Nat Immunol. 2009;10:1026–33.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  43. Yip L, Creusot RJ, Pager CT, Sarnow P, Fathman CG. Reduced DEAF1 function during type 1 diabetes inhibits translation in lymph node stromal cells by suppressing Eif4g3. J Mol Cell Biol. 2013;5:99–110.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Gradi A, Imataka H, Svitkin YV, Rom E, Raught B, Morino S, et al. A novel functional human eukaryotic translation initiation factor 4G. Mol Cell Biol. 1998;18:334–42.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Marissen WE, Gradi A, Sonenberg N, Lloyd RE. Cleavage of eukaryotic translation initiation factor 4GII correlates with translation inhibition during apoptosis. Cell Death Differ. 2000;7:1234–43.

    Article  CAS  PubMed  Google Scholar 

  46. Larsen SL, Pedersen LO, Buus S, Stryhn A. T cell responses affected by aminopeptidase N (CD13)-mediated trimming of major histocompatibility complex class II-bound peptides. J Exp Med. 1996;184:183–9.

    Article  CAS  PubMed  Google Scholar 

  47. Eizirik DL, Sammeth M, Bouckenooghe T, Bottu G, Sisino G, Igoillo-Esteve M, et al. The human pancreatic islet transcriptome: expression of candidate genes for type 1 diabetes and the impact of pro-inflammatory cytokines. PLoS Genet. 2012;8:e1002552.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. van Lummel M, Zaldumbide A, Roep BO. Changing faces, unmasking the beta-cell: post-translational modification of antigens in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2013;20:299–306.

    Article  PubMed  Google Scholar 

  49. Cheng JT, Chi TC, Liu IM. Activation of adenosine A1 receptors by drugs to lower plasma glucose in streptozotocin-induced diabetic rats. Auton Neurosci. 2000;83:127–33.

    Article  CAS  PubMed  Google Scholar 

  50. Johansson SM, Salehi A, Sandstrom ME, Westerblad H, Lundquist I, Carlsson PO, et al. A1 receptor deficiency causes increased insulin and glucagon secretion in mice. Biochem Pharmacol. 2007;74:1628–35.

    Article  CAS  PubMed  Google Scholar 

  51. Ohneda A, Kobayashi T, Nihei J, Nishikawa K. Glucagon in spontaneously diabetic KK mice. Horm Metab Res. 1981;13:207–11.

    Article  CAS  PubMed  Google Scholar 

  52. Ohneda A, Kobayashi T, Nihei J, Tochino Y, Kanaya H, Makino S. Secretion of glucagon in spontaneously diabetic NOD mice. J Jpn Diabet Soc. 1981;24:202.

    Google Scholar 

  53. Ohneda A, Kobayashi T, Nihei J, Tochino Y, Kanaya H, Makino S. Insulin and glucagon in spontaneously diabetic non-obese mice. Diabetologia. 1984;27:460–3.

    Article  CAS  PubMed  Google Scholar 

  54. Yang GK, Fredholm BB, Kieffer TJ, Kwok YN. Improved blood glucose disposal and altered insulin secretion patterns in adenosine A(1) receptor knockout mice. Am J Physiol Endocrinol Metab. 2012;303:E180–90.

    Article  CAS  PubMed  Google Scholar 

  55. Salehi A, Parandeh F, Fredholm BB, Grapengiesser E, Hellman B. Absence of adenosine A1 receptors unmasks pulses of insulin release and prolongs those of glucagon and somatostatin. Life Sci. 2009;85:470–6.

    Article  CAS  PubMed  Google Scholar 

  56. Burton AR, Vincent E, Arnold PY, Lennon GP, Smeltzer M, Li CS, et al. On the pathogenicity of autoantigen-specific T-cell receptors. Diabetes. 2008;57:1321–30.

    Article  CAS  PubMed  Google Scholar 

  57. Leiter EH, Coleman DL, Eppig JJ. Endocrine pancreatic cells of postnatal “diabetes” (db) mice in cell culture. In Vitro. 1979;15:507–21.

    Article  CAS  PubMed  Google Scholar 

  58. Coulaud J, Durant S, Homo-Delarche F. Glucose homeostasis in pre-diabetic NOD and lymphocyte-deficient NOD/SCID mice during gestation. Rev Diabet Stud. 2010;7:36–46.

    Article  PubMed Central  PubMed  Google Scholar 

  59. Amrani A, Durant S, Throsby M, Coulaud J, Dardenne M, Homo-Delarche F. Glucose homeostasis in the nonobese diabetic mouse at the prediabetic stage. Endocrinology. 1998;139:1115–24.

    CAS  PubMed  Google Scholar 

  60. Aaen K, Rygaard J, Josefsen K, Petersen H, Brogren CH, Horn T, et al. Dependence of antigen expression on functional state of beta-cells. Diabetes. 1990;39:697–701.

    Article  CAS  PubMed  Google Scholar 

  61. Buschard K. The functional state of the beta cells in the pathogenesis of insulin-dependent diabetes mellitus. Autoimmunity. 1991;10:65–9.

    Article  CAS  PubMed  Google Scholar 

  62. Greenbaum CJ, Prigeon RL, D’Alessio DA. Impaired beta-cell function, incretin effect, and glucagon suppression in patients with type 1 diabetes who have normal fasting glucose. Diabetes. 2002;51:951–7.

    Article  CAS  PubMed  Google Scholar 

  63. Unger RH, Aguilar-Parada E, Muller WA, Eisentraut AM. Studies of pancreatic alpha cell function in normal and diabetic subjects. J Clin Investig. 1970;49:837–48.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Dinneen S, Alzaid A, Turk D, Rizza R. Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia. 1995;38:337–43.

    Article  CAS  PubMed  Google Scholar 

  65. Hollander PH, Asplin CM, Kniaz D, Hansen JA, Palmer JP. Beta-cell dysfunction in nondiabetic HLA identical siblings of insulin-dependent diabetics. Diabetes. 1982;31:149–53.

    Article  CAS  PubMed  Google Scholar 

  66. Lopez-Bigas N, Audit B, Ouzounis C, Parra G, Guigo R. Are splicing mutations the most frequent cause of hereditary disease? FEBS Lett. 2005;579:1900–3.

    Article  CAS  PubMed  Google Scholar 

  67. Douglas AG, Wood MJ. RNA splicing: disease and therapy. Brief Funct Genomics. 2011;10:151–64.

    Article  CAS  PubMed  Google Scholar 

  68. Bauman J, Jearawiriyapaisarn N, Kole R. Therapeutic potential of splice-switching oligonucleotides. Oligonucleotides. 2009;19:1–13.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Mourich DV, Oda SK, Schnell FJ, Crumley SL, Hauck LL, Moentenich CA, et al. Alternative splice forms of CTLA-4 induced by antisense mediated splice-switching influences autoimmune diabetes susceptibility in NOD mice. Nucleic Acid Ther. 2014;24:114–26.

    Google Scholar 

  70. van Deutekom JC, Janson AA, Ginjaar IB, Frankhuizen WS, Aartsma-Rus A, Bremmer-Bout M, et al. Local dystrophin restoration with antisense oligonucleotide PRO051. N Engl J Med. 2007;357:2677–86.

    Article  PubMed  Google Scholar 

  71. Kinali M, Arechavala-Gomeza V, Feng L, Cirak S, Hunt D, Adkin C, et al. Local restoration of dystrophin expression with the morpholino oligomer AVI-4658 in Duchenne muscular dystrophy: a single-blind, placebo-controlled, dose-escalation, proof-of-concept study. Lancet Neurol. 2009;8:918–28.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  72. Luo YB, Mastaglia FL, Wilton SD. Normal and aberrant splicing of LMNA. J Med Genet. 2014;51:215–23.

    Google Scholar 

  73. Wan J, Bauman JA, Graziewicz MA, Sazani P, Kole R. Oligonucleotide therapeutics in cancer. Cancer Treat Res. 2013;158:213–33.

    Article  PubMed  Google Scholar 

  74. Yilmaz-Elis S, Aartsma-Rus A, Vroon A, van Deutekom J, de Kimpe S, t Hoen PA, et al. Antisense oligonucleotide mediated exon skipping as a potential strategy for the treatment of a variety of inflammatory diseases such as rheumatoid arthritis. Ann Rheum Dis. 2012;71(Suppl 2):i75–7.

    Article  CAS  PubMed  Google Scholar 

  75. Hua Y, Krainer AR. Antisense-mediated exon inclusion. Methods Mol Biol. 2012;867:307–23.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The work presented was funded by NIH grants DK-078123 and AI-083628 and performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org/for-partners/npod-partners. Linda Yip was supported by the JDRF Transition Award.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, 269 Campus Drive, CCSR Room 2225, Stanford, CA, 94305-5166, USA

    Linda Yip & C. Garrison Fathman

Authors
  1. Linda Yip
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C. Garrison Fathman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Garrison Fathman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yip, L., Fathman, C.G. Type 1 diabetes in mice and men: gene expression profiling to investigate disease pathogenesis. Immunol Res 58, 340–350 (2014). https://doi.org/10.1007/s12026-014-8501-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-014-8501-8

Keywords

Search

Navigation