Pathophysiology of Type 1 Diabetes

  • Rita A. Gómez-Díaz


This chapter reviews the etiopathogenesis of type 1 diabetes, which includes genetic (such as a strong association with HLA haplotypes, genetic linkage with immune system genes), immunological (such as specificity for beta cells and the presence of antigen-specific T cells), environmental factors (such as age at onset) and gut microbiota. Since type 1 diabetes onset is triggered by an inappropriate activation of both the innate and adaptive immune systems, which causes a cascade that results in pancreatic islet destruction, and invariant natural killer T (NKT) cells interact with both systems, we will also discuss their role in the physiopathology of this disease. It should be noted that there are many opportunities for further study in this area, in both pediatric and adult populations and in various ethnicities.


Type 1 diabetes Natural killer T cells HLA Antibodies against beta cells Microbiota Environmental factors 




Antibodies against glutamic acid decarboxylase




Class I-restricted T cell-associated molecule


Cytotoxic T-lymphocyte antigen


Cathepsin-L lysosomal protease


Insulinoma antigen 2


Inducible gene costimulatory molecule


Induced interferon with dominion 1 helicase C


Interferon gamma


Interleukin-2 receptor alpha chain


Interferon-stimulated genes


Major histocompatibility complex


Natural killer lymphocyte-type


Non-obese diabetic mouse models


Protein tyrosine phosphatase, non-receptor type 22


Type 1 diabetes


Receptor for T lymphocyte antigen


World Health Organization


Zinc cation transporter


  1. 1.
    Atkinson MA, Eisenbarth GS, Michels AW. Type 1 diabetes. Lancet. 2014;383(9911):69–82.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Todd JA, Bell JI, McDevitt HO. HLA-DQ gene contributes to susceptibility and resistance to IDDM. Nature. 1987;329:599–604.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Undlien DE, Lie BA, Thorsby E. HLA complex genes in type 1 diabetes and other autoimmune diseases. Which genes are involved? Trends Genet. 2001;17:93–100.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Caillat-Zucman S, Garchon HJ, Timsit J, et al. Age-dependent HLA genetic heterogeneity of type 1 insulin-dependent diabetes mellitus. J Clin Invest. 1992;90:2242–50.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Knip M, Siljander H. Autoimmune mechanisms in type 1 diabetes. Autoimmun Rev. 2008;7:550–7.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Lambert AP, Gillespie KM, Thomson G, et al. Absolute risk of childhood-onset type 1 diabetes defined by human leukocyte antigen class II genotype: a population-based study in the United Kingdom. J Clin Endocrinol Metab. 2004;89:4037–43.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Dorman JS, McCarthy B, McCanlies E, et al. Molecular IDDM epidemiology: international studies. WHO DiaMond Molecular Epidemiology Sub-Project Group. Diabetes Res Clin Pract. 1996;34 Suppl:S107–16.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Notkins AL. Immunologic and genetic factors in type 1 diabetes. J Biol Chem. 2002;277:43545–8.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Erlich HA, Zeidler A, Chang J, et al. HLA class II alleles and susceptibility and resistance to insulin dependent diabetes mellitus in Mexican-American families. Nat Genet. 1993;3:358–64.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Godoresky C, Olivares A, Debezo H, et al. MHC-dependent molecular mechanisms of susceptibility and protection in type 1 diabetes in Mexicans. Gac Med Mex. 1995;131:395–402.Google Scholar
  11. 11.
    Thorsby E, Gjertsen HA, Lundin KE, Rønningen KS. Insulin dependent diabetes mellitus susceptibility or protection may be determined by certain HLA-DQ molecules. Bailliere Clin Endocrinol Metab. 1991;5:361–73.CrossRefGoogle Scholar
  12. 12.
    Vicario JL, Martinez-Laso J, Corell A, et al. Comparison between HLA-DRB and DQ DNA sequences and classic serological markers as type 1 (insulin-dependent) diabetes mellitus predictive risk markers in the Spanish population. Diabetologia. 1992;35:475–81.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Eisenbarth GS. Banting lecture 2009: an unfinished journey: molecular pathogenesis to prevention of type 1A diabetes. Diabetes. 2010;59:759–74.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Thomson G, Robinson W, Kuhner M, et al. HLA and insulin gene associations with IDDM. Genet Epidemiol. 1989;6:155–60.PubMedCrossRefPubMedCentralGoogle Scholar
  15. 15.
    Bennett ST, Lucassen AM, Gough SCL, et al. Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus. Nat Genet. 1995;9:284–92.PubMedCrossRefPubMedCentralGoogle Scholar
  16. 16.
    Bell GI, Horita S, Karam JH. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes. 1984;33:176–83.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Todd JA, Farrall M. Panning for gold: genome-wide scanning for linkage in type 1 diabetes. Hum Mol Genet. 1995;5:1443–8.CrossRefGoogle Scholar
  18. 18.
    Pugliese A, Miceli D. The insulin gene in diabetes. Diabetes Metab Res Rev. 2002;18:13–25.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Davies JL, Kawaguchi Y, Bennett ST, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature. 1994;371:130–6.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Bottini N, Musumeci L, Alonso A, et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36:337–8.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Thompson WS, Pekalski ML, Simons HZ, et al. Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes. Clin Exp Immunol. 2014;177:571–85.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Marron MP, Zeidler A, Raffel LJ, et al. Genetic and physical mapping of a type 1 diabetes susceptibility gene (IDDM12) to a 100-kb phagemid artificial chromosome clone containing D2S72-CTLA4-D2S105 on chromosome 2q33. Diabetes. 2000;49:492–9.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Ueda H, Howson JMM, Esposito L, et al. Association of the T cell regulatory gene CTLA4 with susceptibility to autoimmune disease. Nature. 2003;423:506–11.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Tang W, Cui D, Jiang L, et al. Association of common polymorphisms in the IL2RA gene with type 1 diabetes: evidence of 32,646 individuals from 10 independent studies. J Cell Mol Med. 2015;19:2481–8.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Liu S, Wang H, Jin Y, et al. IFIH1 polymorphisms are significantly associated with type 1 diabetes and IFIH1 gene expression in peripheral blood mononuclear cells. Hum Mol Genet. 2009;18:358–65.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Maziarz M, Hagopian W, Palmer JP, Swedish Childhood Diabetes Register, et al. Diabetes incidence in Sweden study group; type 1 diabetes genetics consortium. Non-HLA type 1 diabetes genes modulate disease risk together with HLA-DQ and islet autoantibodies. Genes Immun. 2015;16:541–51.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
  28. 28.
    Mannering SI, Pathiraja V, Kay TW. The case for an autoimmune aetiology of type 1 diabetes. Clin Exp Immunol. 2016;183:8–15.PubMedCrossRefPubMedCentralGoogle Scholar
  29. 29.
    Foulis AK, Liddle CN, Farquharson MA, et al. The histopathology of the pancreas in type 1 (insulin-dependent) diabetes mellitus: a 25 years review of deaths in patients under 20 years of age in the United Kingdom. Diabetologia. 1986;29:267–74.PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Willcox A, Richardson SJ, Bone AJ, et al. Analysis of islet inflammation in human type 1 diabetes. Clin Exp Immunol. 2009;155:173–81.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Barcala Tabarrozzi AE, Castro CN, Dewey RA, et al. Cell-based interventions to halt autoimmunity in type 1 diabetes mellitus. Clin Exp Immunol. 2013;171:135–46.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Pugliese A. Insulitis in the pathogenesis of type 1 diabetes. Pediatr Diabetes. 2016;17(Suppl 22):31–6.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Krogvold L, Wiberg A, Edwin B, et al. Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia. 2016;59:492–501.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Zubkiewicz-Kucharska A, Noczyńska A. Abnormal distribution of gamma-delta T lymphocytes and their subsets in type 1 diabetes. Adv Clin Exp Med. 2016;25:665–71.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Lundberg M, Krogvold L, Kuric E, et al. Expression of interferon-stimulated genes in insulitic pancreatic islets of patients recently diagnosed with type 1 diabetes. Diabetes. 2016;65:3104–10.PubMedCrossRefPubMedCentralGoogle Scholar
  36. 36.
    von Herrath MG, Korsgren O, Atkinson MA. Factors impeding the discovery of an intervention-based treatment for type 1 diabetes. Clin Exp Immunol. 2016;183(1):1–7.CrossRefGoogle Scholar
  37. 37.
    Hannirn A, Jalkanen S, Salmi M, et al. Macrophages, T cell receptor usage, and endothelial cell activation in the pancreas at the onset of insulin-dependent diabetes mellitus. J Clin Invest. 1992;90:1901–10.CrossRefGoogle Scholar
  38. 38.
    Imagawa A, Hanafusa T, Tamura S, et al. Pancreatic biopsy as a procedure for detecting in situ autoimmune phenomena in type 1 diabetes. Close correlation between serological markers and a histological evidence of cellular autoimmunity. Diabetes. 2001;50:1269–73.PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Rabinovitch A, Suares-Pinzon WL, Sorensen O, et al. INF-γ gene expression in pancreatic islet-infiltrating mononuclear cells correlates with autoimmune diabetes in nonobese diabetic mice. J Immunol. 1995;154:4878–82.Google Scholar
  40. 40.
    Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin- dependent) diabetes mellitus in ma-macrophages, lymphocytes, and interferon-gamma containing cells. J Pathol. 1991;165:97–103.PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Fowlkes BJ, Kruisbeek AM, Ton-That H, et al. A novel population of T-cell receptor alpha beta-bearing thymocytes which predominantly expresses a single V beta gene family. Nature. 1987;329:251–4.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Gomez-Tourino I, Arif S, Eichmann M, et al. T cells in type 1 diabetes: instructors, regulators and effectors: a comprehensive review. J Autoimmun. 2016;66:7–16.PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Pathiraja V, Kuehlich JP, Campbell PD, et al. Proinsulin-specific, HLA-DQ8, and HLA-DQ8-transdimer-restricted CD4+ T cells infiltrate islets in type 1 diabetes. Diabetes. 2015;64:172–82.PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Verge CF, Gianani R, Kawasaki E, et al. Prediction of type I diabetes in first-degree relatives using a combination of insulin, GAD, and ICA512bdc/IA-2 autoantibodies. Diabetes. 1996;45:926–33.PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Leslie D, Lipsky P, Notkins AL. Autoantibodies as predictors of disease. J Clin Invest. 2001;108:1417–22.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Wenzlau JM, Juhl K, Yu L, et al. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007;104:17040–5.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Velluzzi F, Secci G, Sepe V, Sardinian Autoimmunity Study Group, et al. Prediction of type 1 diabetes in Sardinian schoolchildren using islet cell autoantibodies: 10-year follow-up of the Sardinian schoolchildren type 1 diabetes prediction study. Acta Diabetol. 2016;53(1):73–9.PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Von Herrath MG, Holz A, Homann D, et al. Role of viruses in type I diabetes. Semin Immunol. 1998;10:87–100.CrossRefGoogle Scholar
  49. 49.
    Hyoty H, Hiltunen M, Reuranen A, et al. Decline of mumps antibodies in type 1(insulin-dependent) diabetic children with a plateau in the rising incidence of type 1 diabetes after introduction of the mumps-measles-rubella vaccine in Finland. Diabetologia. 1993;36:1303–8.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    McIntosh EDG, Menser M. A fifty-year follow-up of congenital rubella. Lancet. 1992;340:414–5.PubMedCrossRefPubMedCentralGoogle Scholar
  51. 51.
    Tavares RG, Trevisol RB, Comerlato J, et al. Enterovirus infections and type 1 diabetes mellitus: is there any relationship? J Venom Anim Toxins Incl Trop Dis. 2012;18:3–15.CrossRefGoogle Scholar
  52. 52.
    de Beeck AO, Eizirik DL. Viral infections in type 1 diabetes mellitus – why the β cells? Nat Rev Endocrinol. 2016;12:263–73.PubMedCentralCrossRefGoogle Scholar
  53. 53.
    Petzold A, Solimena M, Knoch KP. Mechanisms of Beta cell dysfunction associated with viral infection. Curr Diab Rep. 2015;15:73.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Seewaldt S, Thomas HE, Ejrnaes M, et al. Virus-induced autoimmune diabetes: most beta-cells die through inflammatory cytokines and not perforin from autoreactive (anti-viral) cytotoxic T-lymphocytes. Diabetes. 2000;49:1801–9.PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Honeyman MC, Stone NL, Falk BA, Nepom G, Harrison LC. Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens. J Immunol. 2010;15(184):2204–10.CrossRefGoogle Scholar
  56. 56.
    Cooke A. Review series on helminths, immune modulation and the hygiene hypothesis: how might infection modulate the onset of type 1 diabetes? Immunology. 2009;126:12–7.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ylipaasto P, Klingel K, Lindberg AM, et al. Enterovirus infection in human pancreatic islet cells, islet tropism in vivo and receptor involvement in cultured islet beta cells. Diabetologia. 2004;47:225–39.PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Krogvold L, Edwin B, Buanes T, et al. Pancreatic biopsy by minimal tail resection in live adult patients at the onset of type 1 diabetes: experiences from the DiViD study. Diabetologia. 2014;57:841–3.PubMedCrossRefPubMedCentralGoogle Scholar
  59. 59.
    Oikarinen S, Tauriainen S, Hober D, VirDiab Study Group, et al. Virus antibody survey in different European populations indicates risk association between coxsackie virus B1 and type 1 diabetes. Diabetes. 2014;63:655–62.PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Laitinen OH, Honkanen H, Pakkanen O, et al. Coxsackievirus B1 is associated with induction of β-cell autoimmunity that portends type 1 diabetes. Diabetes. 2014;63:446–55.PubMedCrossRefPubMedCentralGoogle Scholar
  61. 61.
    Rodriguez-Calvo T, von Herrath MG. Enterovirus infection and type 1 diabetes: closing in on a link? Diabetes. 2015;64:1503–5.PubMedCrossRefPubMedCentralGoogle Scholar
  62. 62.
    Nucci AM, Virtanen SM, Becker DJ. Infant feeding and timing of complementary foods in the development of type 1 diabetes. Curr Diab Rep. 2015;15:62.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Griebler U, Bruckmüller MU, Kien C, et al. Health effects of cow’s milk consumption in infants up to 3 years of age: a systematic review and meta-analysis. Public Health Nutr. 2016;19:293–307.PubMedCrossRefPubMedCentralGoogle Scholar
  64. 64.
    Krishna CS, Srikanta S. Type 1 diabetes pathogenesis – prevention??? Indian J Endocrinol Metab. 2015;19(Suppl 1):S58–63.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Lamb MM, Miller M, Seifert JA, et al. The effect of childhood cow’s milk intake and HLA-DR genotype on risk of islet autoimmunity and type 1 diabetes: the diabetes autoimmunity study in the young. Pediatr Diabetes. 2015;16:31–8.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Liu C, Lu M, Xia X, et al. Correlation of serum vitamin D level with type 1 diabetes mellitus in children: a meta-analysis. Nutr Hosp. 2015;32:1591–4.PubMedPubMedCentralGoogle Scholar
  67. 67.
    Mäkinen M, Mykkänen J, Koskinen M, et al. Serum 25-hydroxyvitamin D concentrations in children progressing to autoimmunity and clinical type 1 diabetes. J Clin Endocrinol Metab. 2016;101:723–9.PubMedCrossRefPubMedCentralGoogle Scholar
  68. 68.
    Talaat IM, Nasr A, Alsulaimani AA, et al. Association between type 1, type 2 cytokines, diabetic autoantibodies and 25-hydroxyvitamin D in children with type 1 diabetes. J Endocrinol Investig. 2016;39(12):1425–34.CrossRefGoogle Scholar
  69. 69.
    Gianchecchi E, Fierabracci A. On the pathogenesis of insulin-dependent diabetes mellitus: the role of microbiota. Immunol Res. 2017;65(1):242–56.PubMedCrossRefPubMedCentralGoogle Scholar
  70. 70.
    Murri M, Leiva I, Gomez-Zumaquero JM, Tinahones FJ, Cardona F, Soriguer F, Queipo-Ortuño MI. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 2013;11:46. Scholar
  71. 71.
    Mejía-León ME, Petrosino JF, Ajami NJ, Domínguez-Bello MG, de la Barca AM. Fecal microbiota imbalance in Mexican children with type 1 diabetes. Sci Rep. 2014;4:3814. Scholar
  72. 72.
    Armougom F, Henry M, Vialettes B, Raccah D, Raoult D. Monitoring bacterial community of human gut microbiota reveals an increase in lactobacillus in obese patients and methanogens in anorexic patients. PLoS One. 2009;4(9):e7125. Scholar
  73. 73.
    Uusitalo U, Liu X, Yang J, TEDDY Study Group, et al. Association of early exposure of probiotics and islet autoimmunity in the TEDDY study. JAMA Pediatr. 2016;170(1):20–8.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Tard C, Rouxel O, Lehuen A. Regulatory role of natural killer T cells in diabetes. Biom J. 2015;38:484–95.Google Scholar
  75. 75.
    Porcelli S, Yockey CE, Brenner MB, et al. Analysis of T cell antigen receptor (TCR) expression by human peripheral blood CD4-8- alpha/beta T cells demonstrates preferential use of several Vß genes and an invariant TCR alpha chain. J Exp Med. 1993;178:1–16.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Lantz O, Bendelac A. An invariant T cell receptor alpha chain is used by a unique subset of MHC class I-specific CD4+ and CD4-8- T cells in mice and humans. J Exp Med. 1994;180:1097–106.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Baxter AG, Hammond KJ, Scollay R, et al. Association between alphabeta TCR+CD-CD- T-cell deficiency and IDMM in NOD/Lt mice. Diabetes. 1997;46:572–82.PubMedCrossRefPubMedCentralGoogle Scholar
  78. 78.
    Kronenberg M, Gapin L. The unconventional lifestyle of NKT cells. Nat Rev Immunol. 2002;2:557–8.PubMedCrossRefPubMedCentralGoogle Scholar
  79. 79.
    Naumov YN, Bahjat KS, Gausling R, et al. Activation of CD1d-restricted T cells protects NOD mice from developing diabetes by regulating dendritic cell subsets. Proc Natl Acad Sci U S A. 2001;98:13838–43.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Hammond KJ, Pellicci DG, Poulton LD, et al. CD1d-restricted NKT cells: an interstrain comparison. J Immunol. 2001;167:1164–73.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Lehuen A, Lantz O, Beaudoin L, et al. Overexpression of natural killer T cells protects Va14-Ja281 transgenic nonobese mice against diabetes. J Exp Med. 1998;188:1831–9.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Falcone M, Brian Y, Tucker L, et al. A defect in interleukin 12-induced activation and interferon-gamma secretion of peripheral natural killer T cells in nonobese diabetic mice suggests new pathogenic mechanism for insulin-dependent diabetes mellitus. J Exp Med. 1999;190:963–72.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Poulon LD, Smyth MJ, Hawke CG, et al. Cytometric and functional analysis of NK- and NKT cell deficiencies in NOD mice. Int Immunol. 2001;13:887–96.CrossRefGoogle Scholar
  84. 84.
    Berzins SP, Kyparissoudis K, Pellicci DG, et al. Systemic NKT cell deficiency in NOD mice is not detected in peripheral blood: implications for human studies. Immunol Cell Biol. 2004;82:247–52.PubMedCrossRefPubMedCentralGoogle Scholar
  85. 85.
    Wagner MJD, Hussain S, Mehan M, et al. A defect in lineage fate decision during fetal thymic invariant NKT cell development may regulate susceptibility to type 1 diabetes. J Immunol. 2005;174:6764–71.PubMedCrossRefPubMedCentralGoogle Scholar
  86. 86.
    Carnaud C, Gombert J, Donnars O, et al. Protection against diabetes and improved NK/NKT cell performance in NOD.NK1.1 mice congenic at the NK complex. J Immunol. 2001;166:2404–11.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Esteban LM, Tsoutsman T, Jordan MA, et al. Genetic control of NKT cell numbers maps to major diabetes and lupus loci. J Immunol. 2003;171:2873–8.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Rocha-Campos AC, Melki R, Zhu R, et al. Genetic and functional analysis of the Nkt1 locus using congenic NOD mice: improved Vα14-NKT cell performance but failure to protect against type 1 diabetes. Diabetes. 2006;55:1163–70.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Kent S, Chen Y, Clemmings SM, et al. Loss of IL-4 secretion from human type 1a diabetic pancreatic draining lymph node NKT cells. J Immunol. 2005;175:4458–64.PubMedCrossRefPubMedCentralGoogle Scholar
  90. 90.
    Kukreja A, Cost G, Marker J, et al. Multiple immuno-regulatory defects in type 1 diabetes. J Clin Invest. 2002;109:131–40.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Rodacki M, Svoren B, Butty V, et al. Altered natural killer cells in type 1 diabetic patients. Diabetes. 2007;56:177–85.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Janos K, Engelmann P, Farkas K, et al. Reduced CD4- subset and Th1 bias of the human iNKT cells in type 1 diabetes mellitus. J Leukoc Biol. 2006;81:654–62.Google Scholar
  93. 93.
    Roman-Gonzalez A, Moreno ME, Alfaro JM, et al. Frequency and function of circulating invariant NKT cells in autoimmune diabetes mellitus and thyroid diseases in Colombian patients. Human Immunol. 2009;70:262–8.CrossRefGoogle Scholar
  94. 94.
    Montoya CJ, Pollard D, Martinson J, et al. Characterization of human invariant natural killer T subsets in health and disease using a novel invariant natural killer T cell-clonotypic monoclonal antibody, 6B11. Immunology. 2007;122:1–14.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Ortiz-Navarrete V, Canche-Pool E, Gómez-Díaz R, et al. CRTAM molecule is expressed at the cell surface of NKT cells from patients with type 1 diabetes mellitus. Clin Immunol. 2009;131:S145.CrossRefGoogle Scholar
  96. 96.
    Beristain-Covarrubias N, Canche-Pool E, Gomez-Diaz R, et al. Reduced iNKT cells numbers in type 1 diabetes patients and their first-degree relatives. Immun Inflamm Dis. 2015;3:411–9.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Gómez-Díaz RA, Aguilar MV, Meguro EN, et al. The role of natural killer T (NKT) cells in the pathogenesis of type 1 diabetes. Curr Diabetes Rev. 2011;7:278–83.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Beristain-Covarrubias N, Canche-Pool EB, Ramirez-Velazquez C, et al. Class I-restricted T cell-associated molecule is a Marker for IFN-γ-producing iNKT cells in healthy subjects and patients with type 1 diabetes. J Interf Cytokine Res. 2017;37(1):39–49.CrossRefGoogle Scholar
  99. 99.
    Lombardi G, Burzyn D, Mundiñiano J, et al. Cathepsin-L influences the expression of extracellular matrix in lymphoid organs and plays a role in the regulation of thymic output and of peripheral T cell number. J Immunol. 2005;174:7022–32.PubMedCrossRefPubMedCentralGoogle Scholar
  100. 100.
    Gómez-Díaz RA, Medina-Santillán R, Castro Magdonel BE, et al. Association of NKT cells with expression of the CTSL gene in Mexican pediatric population with recently-diagnosed type 1 diabetes. Gac Med Mex. 2016;152:14–21.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Rita A. Gómez-Díaz
    • 1
  1. 1.UIMEC, UMAE Hospital de Especialidades. Centro Médico Nacional Siglo XXI IMSSMexico CityMexico

Personalised recommendations