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Pathogenesis of type 1 diabetes mellitus

Author
Massimo Pietropaolo, MD
Section Editor
Irl B Hirsch, MD
Deputy Editor
Jean E Mulder, MD

INTRODUCTION

Type 1A diabetes mellitus results from autoimmune destruction of the insulin-producing beta cells in the islets of Langerhans [1]. This process occurs in genetically susceptible subjects, is probably triggered by one or more environmental agents, and usually progresses over many months or years during which the subject is asymptomatic and euglycemic. Thus, genetic markers for type 1A diabetes are present from birth, immune markers are detectable after the onset of the autoimmune process, and metabolic markers can be detected with sensitive tests once enough beta cell damage has occurred, but before the onset of symptomatic hyperglycemia [2]. This long latent period is a reflection of the large number of functioning beta cells that must be lost before hyperglycemia occurs (figure 1). Type 1B diabetes mellitus refers to nonautoimmune islet destruction (Type 1B diabetes). (See "Classification of diabetes mellitus and genetic diabetic syndromes".)

The pathogenesis of type 1A diabetes is quite different from that of type 2 diabetes mellitus, in which both decreased insulin release (not on an autoimmune basis) and insulin resistance play an important role. Genome-wide association studies indicate that type 1 and type 2 diabetes' genetic loci do not overlap, although inflammation (eg, interleukin-1 mediated) may play a role in islet beta cell loss in both types [3]. (See "Pathogenesis of type 2 diabetes mellitus".)

The pathogenesis of type 1 diabetes mellitus will be reviewed here. The diagnosis and management of type 1 diabetes are discussed separately. (See "Epidemiology, presentation, and diagnosis of type 1 diabetes mellitus in children and adolescents" and "Prevention of type 1 diabetes mellitus" and "Management of type 1 diabetes mellitus in children and adolescents" and "Associated autoimmune diseases in children and adolescents with type 1 diabetes mellitus".)

GENETIC SUSCEPTIBILITY

Polymorphisms of multiple genes are reported to influence the risk of type 1A diabetes (including, HLA-DQalpha, HLA-DQbeta, HLA-DR, preproinsulin, the PTPN22 gene, CTLA-4, interferon-induced helicase, IL2 receptor (CD25), a lectin-like gene (KIA0035), ERBB3e, and undefined gene at 12q) [4-10]. A meta-analysis of data from genome-wide association studies confirmed the above associations and identified four additional risk loci (BACH2, PRKCQ, CTSH, C1QTNF6) associated with an increased risk of type 1 diabetes [11].

In addition, some loci conferring shared risk for celiac disease (RGS1, IL18RAP, CCR5, TAGAP, SH2B3, PTPN2) have been identified [12]. Most loci have small effects, and the variants studied are common. The CCR5 association is of interest in that a 32-base pair insertion deletion in a chemokine receptor, CCR5, results in a loss of function and, when homozygous, a twofold decrease in risk of type 1 diabetes. (See 'MHC genes' below and 'Non-MHC genes' below and 'Association with other autoimmune diseases' below.)

                            

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Literature review current through: Nov 2016. | This topic last updated: Tue Oct 11 00:00:00 GMT+00:00 2016.
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References
Top
  1. Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med 1994; 331:1428.
  2. McCulloch DK, Palmer JP. The appropriate use of B-cell function testing in the preclinical period of type 1 diabetes. Diabet Med 1991; 8:800.
  3. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007; 356:1517.
  4. Smyth DJ, Cooper JD, Bailey R, et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 2006; 38:617.
  5. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007; 447:661.
  6. Todd JA, Walker NM, Cooper JD, et al. Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes. Nat Genet 2007; 39:857.
  7. Hakonarson H, Grant SF, Bradfield JP, et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 2007; 448:591.
  8. Lowe CE, Cooper JD, Brusko T, et al. Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 2007; 39:1074.
  9. Concannon P, Onengut-Gumuscu S, Todd JA, et al. A human type 1 diabetes susceptibility locus maps to chromosome 21q22.3. Diabetes 2008; 57:2858.
  10. Concannon P, Rich SS, Nepom GT. Genetics of type 1A diabetes. N Engl J Med 2009; 360:1646.
  11. Cooper JD, Smyth DJ, Smiles AM, et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 2008; 40:1399.
  12. Smyth DJ, Plagnol V, Walker NM, et al. Shared and distinct genetic variants in type 1 diabetes and celiac disease. N Engl J Med 2008; 359:2767.
  13. Aly TA, Ide A, Jahromi MM, et al. Extreme genetic risk for type 1A diabetes. Proc Natl Acad Sci U S A 2006; 103:14074.
  14. Redondo MJ, Rewers M, Yu L, et al. Genetic determination of islet cell autoimmunity in monozygotic twin, dizygotic twin, and non-twin siblings of patients with type 1 diabetes: prospective twin study. BMJ 1999; 318:698.
  15. Kaprio J, Tuomilehto J, Koskenvuo M, et al. Concordance for type 1 (insulin-dependent) and type 2 (non-insulin-dependent) diabetes mellitus in a population-based cohort of twins in Finland. Diabetologia 1992; 35:1060.
  16. Davies JL, Kawaguchi Y, Bennett ST, et al. A genome-wide search for human type 1 diabetes susceptibility genes. Nature 1994; 371:130.
  17. Tisch R, McDevitt H. Insulin-dependent diabetes mellitus. Cell 1996; 85:291.
  18. Khalil I, d'Auriol L, Gobet M, et al. A combination of HLA-DQ beta Asp57-negative and HLA DQ alpha Arg52 confers susceptibility to insulin-dependent diabetes mellitus. J Clin Invest 1990; 85:1315.
  19. Rowe RE, Leech NJ, Nepom GT, McCulloch DK. High genetic risk for IDDM in the Pacific Northwest. First report from the Washington State Diabetes Prediction Study. Diabetes 1994; 43:87.
  20. Barker JM, Barriga KJ, Yu L, et al. Prediction of autoantibody positivity and progression to type 1 diabetes: Diabetes Autoimmunity Study in the Young (DAISY). J Clin Endocrinol Metab 2004; 89:3896.
  21. Undlien DE, Friede T, Rammensee HG, et al. HLA-encoded genetic predisposition in IDDM: DR4 subtypes may be associated with different degrees of protection. Diabetes 1997; 46:143.
  22. Baschal EE, Aly TA, Babu SR, et al. HLA-DPB1*0402 protects against type 1A diabetes autoimmunity in the highest risk DR3-DQB1*0201/DR4-DQB1*0302 DAISY population. Diabetes 2007; 56:2405.
  23. Pugliese A, Gianani R, Moromisato R, et al. HLA-DQB1*0602 is associated with dominant protection from diabetes even among islet cell antibody-positive first-degree relatives of patients with IDDM. Diabetes 1995; 44:608.
  24. 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.
  25. Barratt BJ, Payne F, Lowe CE, et al. Remapping the insulin gene/IDDM2 locus in type 1 diabetes. Diabetes 2004; 53:1884.
  26. 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.
  27. Smyth D, Cooper JD, Collins JE, et al. Replication of an association between the lymphoid tyrosine phosphatase locus (LYP/PTPN22) with type 1 diabetes, and evidence for its role as a general autoimmunity locus. Diabetes 2004; 53:3020.
  28. Pugliese A. Genetics of type 1 diabetes. Endocrinol Metab Clin North Am 2004; 33:1.
  29. Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am J Hum Genet 2004; 75:330.
  30. Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymorphism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet 2004; 75:504.
  31. Kavvoura FK, Ioannidis JP. CTLA-4 gene polymorphisms and susceptibility to type 1 diabetes mellitus: a HuGE Review and meta-analysis. Am J Epidemiol 2005; 162:3.
  32. Kolb H. Mouse models of insulin dependent diabetes: low-dose streptozocin-induced diabetes and nonobese diabetic (NOD) mice. Diabetes Metab Rev 1987; 3:751.
  33. Rothe H, Jenkins NA, Copeland NG, Kolb H. Active stage of autoimmune diabetes is associated with the expression of a novel cytokine, IGIF, which is located near Idd2. J Clin Invest 1997; 99:469.
  34. Almawi WY, Tamim H, Azar ST. Clinical review 103: T helper type 1 and 2 cytokines mediate the onset and progression of type I (insulin-dependent) diabetes. J Clin Endocrinol Metab 1999; 84:1497.
  35. Bluestone JA, Tang Q. Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells. Proc Natl Acad Sci U S A 2004; 101 Suppl 2:14622.
  36. Wildin RS, Freitas A. IPEX and FOXP3: clinical and research perspectives. J Autoimmun 2005; 25 Suppl:56.
  37. Flanagan SE, Haapaniemi E, Russell MA, et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat Genet 2014; 46:812.
  38. Sabbah E, Savola K, Kulmala P, et al. Diabetes-associated autoantibodies in relation to clinical characteristics and natural course in children with newly diagnosed type 1 diabetes. The Childhood Diabetes In Finland Study Group. J Clin Endocrinol Metab 1999; 84:1534.
  39. Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N Engl J Med 2000; 342:301.
  40. Boitard C. The differentiation of the immune system towards anti-islet autoimmunity. Clinical prospects. Diabetologia 1992; 35:1101.
  41. Nakayama M, Abiru N, Moriyama H, et al. Prime role for an insulin epitope in the development of type 1 diabetes in NOD mice. Nature 2005; 435:220.
  42. Krishnamurthy B, Dudek NL, McKenzie MD, et al. Responses against islet antigens in NOD mice are prevented by tolerance to proinsulin but not IGRP. J Clin Invest 2006; 116:3258.
  43. Baekkeskov S, Aanstoot HJ, Christgau S, et al. Identification of the 64K autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 1990; 347:151.
  44. Pietropaolo M, Hutton JC, Eisenbarth GS. Protein tyrosine phosphatase-like proteins: link with IDDM. Diabetes Care 1997; 20:208.
  45. Hawa M, Rowe R, Lan MS, et al. Value of antibodies to islet protein tyrosine phosphatase-like molecule in predicting type 1 diabetes. Diabetes 1997; 46:1270.
  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.
  47. Ziegler AG, Hillebrand B, Rabl W, et al. On the appearance of islet associated autoimmunity in offspring of diabetic mothers: a prospective study from birth. Diabetologia 1993; 36:402.
  48. Achenbach P, Koczwara K, Knopff A, et al. Mature high-affinity immune responses to (pro)insulin anticipate the autoimmune cascade that leads to type 1 diabetes. J Clin Invest 2004; 114:589.
  49. Wong FS, Karttunen J, Dumont C, et al. Identification of an MHC class I-restricted autoantigen in type 1 diabetes by screening an organ-specific cDNA library. Nat Med 1999; 5:1026.
  50. Alleva DG, Crowe PD, Jin L, et al. A disease-associated cellular immune response in type 1 diabetics to an immunodominant epitope of insulin. J Clin Invest 2001; 107:173.
  51. Moriyama H, Abiru N, Paronen J, et al. Evidence for a primary islet autoantigen (preproinsulin 1) for insulitis and diabetes in the nonobese diabetic mouse. Proc Natl Acad Sci U S A 2003; 100:10376.
  52. Bonifacio E, Atkinson M, Eisenbarth G, et al. International Workshop on Lessons From Animal Models for Human Type 1 Diabetes: identification of insulin but not glutamic acid decarboxylase or IA-2 as specific autoantigens of humoral autoimmunity in nonobese diabetic mice. Diabetes 2001; 50:2451.
  53. Bonifacio E, Atkinson M, Eisenbarth G, et al. International Workshop on Lessons from Animal Models for Human Type 1 Diabetes: analyzing target autoantigens of humoral immunity in nonobese diabetic mice. Ann N Y Acad Sci 2002; 958:1.
  54. Jaeckel E, Klein L, Martin-Orozco N, von Boehmer H. Normal incidence of diabetes in NOD mice tolerant to glutamic acid decarboxylase. J Exp Med 2003; 197:1635.
  55. Mziaut H, Trajkovski M, Kersting S, et al. Synergy of glucose and growth hormone signalling in islet cells through ICA512 and STAT5. Nat Cell Biol 2006; 8:435.
  56. Ellis TM, Schatz DA, Ottendorfer EW, et al. The relationship between humoral and cellular immunity to IA-2 in IDDM. Diabetes 1998; 47:566.
  57. 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.
  58. Wenzlau JM, Walter M, Gardner TJ, et al. Kinetics of the post-onset decline in zinc transporter 8 autoantibodies in type 1 diabetic human subjects. J Clin Endocrinol Metab 2010; 95:4712.
  59. Winer S, Tsui H, Lau A, et al. Autoimmune islet destruction in spontaneous type 1 diabetes is not beta-cell exclusive. Nat Med 2003; 9:198.
  60. Pietropaolo M, Towns R, Eisenbarth GS. Humoral autoimmunity in type 1 diabetes: prediction, significance, and detection of distinct disease subtypes. Cold Spring Harb Perspect Med 2012; 2.
  61. Martin S, Wolf-Eichbaum D, Duinkerken G, et al. Development of type 1 diabetes despite severe hereditary B-lymphocyte deficiency. N Engl J Med 2001; 345:1036.
  62. Yang M, Charlton B, Gautam AM. Development of insulitis and diabetes in B cell-deficient NOD mice. J Autoimmun 1997; 10:257.
  63. Greeley SA, Katsumata M, Yu L, et al. Elimination of maternally transmitted autoantibodies prevents diabetes in nonobese diabetic mice. Nat Med 2002; 8:399.
  64. Di Lorenzo TP, Peakman M, Roep BO. Translational mini-review series on type 1 diabetes: Systematic analysis of T cell epitopes in autoimmune diabetes. Clin Exp Immunol 2007; 148:1.
  65. Peakman M, Stevens EJ, Lohmann T, et al. Naturally processed and presented epitopes of the islet cell autoantigen IA-2 eluted from HLA-DR4. J Clin Invest 1999; 104:1449.
  66. Allen JS, Pang K, Skowera A, et al. Plasmacytoid dendritic cells are proportionally expanded at diagnosis of type 1 diabetes and enhance islet autoantigen presentation to T-cells through immune complex capture. Diabetes 2009; 58:138.
  67. Ko IY, Jun HS, Kim GS, Yoon JW. Studies on autoimmunity for initiation of beta-cell destruction. X. Delayed expression of a membrane-bound islet cell-specific 38 kDa autoantigen that precedes insulitis and diabetes in the diabetes-prone BB rat. Diabetologia 1994; 37:460.
  68. Jolicoeur C, Hanahan D, Smith KM. T-cell tolerance toward a transgenic beta-cell antigen and transcription of endogenous pancreatic genes in thymus. Proc Natl Acad Sci U S A 1994; 91:6707.
  69. Pugliese A, Zeller M, Fernandez A Jr, et al. The insulin gene is transcribed in the human thymus and transcription levels correlated with allelic variation at the INS VNTR-IDDM2 susceptibility locus for type 1 diabetes. Nat Genet 1997; 15:293.
  70. Gardner JM, Devoss JJ, Friedman RS, et al. Deletional tolerance mediated by extrathymic Aire-expressing cells. Science 2008; 321:843.
  71. Nitta T, Murata S, Ueno T, et al. Thymic microenvironments for T-cell repertoire formation. Adv Immunol 2008; 99:59.
  72. Hanahan D. Peripheral-antigen-expressing cells in thymic medulla: factors in self-tolerance and autoimmunity. Curr Opin Immunol 1998; 10:656.
  73. DeVoss JJ, Anderson MS. Lessons on immune tolerance from the monogenic disease APS1. Curr Opin Genet Dev 2007; 17:193.
  74. Palumbo MO, Levi D, Chentoufi AA, Polychronakos C. Isolation and characterization of proinsulin-producing medullary thymic epithelial cell clones. Diabetes 2006; 55:2595.
  75. Fan Y, Rudert WA, Grupillo M, et al. Thymus-specific deletion of insulin induces autoimmune diabetes. EMBO J 2009; 28:2812.
  76. Sabater L, Ferrer-Francesch X, Sospedra M, et al. Insulin alleles and autoimmune regulator (AIRE) gene expression both influence insulin expression in the thymus. J Autoimmun 2005; 25:312.
  77. Vafiadis P, Bennett ST, Todd JA, et al. Insulin expression in human thymus is modulated by INS VNTR alleles at the IDDM2 locus. Nat Genet 1997; 15:289.
  78. Vafiadis P, Bennett ST, Todd JA, et al. Divergence between genetic determinants of IGF2 transcription levels in leukocytes and of IDDM2-encoded susceptibility to type 1 diabetes. J Clin Endocrinol Metab 1998; 83:2933.
  79. Vafiadis P, Ounissi-Benkalha H, Palumbo M, et al. Class III alleles of the variable number of tandem repeat insulin polymorphism associated with silencing of thymic insulin predispose to type 1 diabetes. J Clin Endocrinol Metab 2001; 86:3705.
  80. Pietropaolo M, Castaño L, Babu S, et al. Islet cell autoantigen 69 kD (ICA69). Molecular cloning and characterization of a novel diabetes-associated autoantigen. J Clin Invest 1993; 92:359.
  81. Karges W, Pietropaolo M, Ackerley CA, Dosch HM. Gene expression of islet cell antigen p69 in human, mouse, and rat. Diabetes 1996; 45:513.
  82. Song A, Winer S, Tsui H, et al. Deviation of islet autoreactivity to cryptic epitopes protects NOD mice from diabetes. Eur J Immunol 2003; 33:546.
  83. Mathews CE, Pietropaolo SL, Pietropaolo M. Reduced thymic expression of islet antigen contributes to loss of self-tolerance. Ann N Y Acad Sci 2003; 1005:412.
  84. Dogra RS, Vaidyanathan P, Prabakar KR, et al. Alternative splicing of G6PC2, the gene coding for the islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), results in differential expression in human thymus and spleen compared with pancreas. Diabetologia 2006; 49:953.
  85. Bonner SM, Pietropaolo SL, Fan Y, et al. Sequence variation in promoter of Ica1 gene, which encodes protein implicated in type 1 diabetes, causes transcription factor autoimmune regulator (AIRE) to increase its binding and down-regulate expression. J Biol Chem 2012; 287:17882.
  86. Chong AS, Shen J, Tao J, et al. Reversal of diabetes in non-obese diabetic mice without spleen cell-derived beta cell regeneration. Science 2006; 311:1774.
  87. Nishio J, Gaglia JL, Turvey SE, et al. Islet recovery and reversal of murine type 1 diabetes in the absence of any infused spleen cell contribution. Science 2006; 311:1775.
  88. Suri A, Calderon B, Esparza TJ, et al. Immunological reversal of autoimmune diabetes without hematopoietic replacement of beta cells. Science 2006; 311:1778.
  89. Melton DA. Reversal of type 1 diabetes in mice. N Engl J Med 2006; 355:89.
  90. Decochez K, Truyen I, van der Auwera B, et al. Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes. Diabetologia 2005; 48:687.
  91. Hoffenberg EJ, Emery LM, Barriga KJ, et al. Clinical features of children with screening-identified evidence of celiac disease. Pediatrics 2004; 113:1254.
  92. Jaeger C, Hatziagelaki E, Petzoldt R, Bretzel RG. Comparative analysis of organ-specific autoantibodies and celiac disease--associated antibodies in type 1 diabetic patients, their first-degree relatives, and healthy control subjects. Diabetes Care 2001; 24:27.
  93. Brewer KW, Parziale VS, Eisenbarth GS. Screening patients with insulin-dependent diabetes mellitus for adrenal insufficiency. N Engl J Med 1997; 337:202.
  94. Barker JM, Eisenbarth GS. Autoimmune Polyendocrine Syndromes. In: Immunology of Type 1 Diabetes, Eisenbarth GS (Ed), 2003.
  95. Vehik K, Hamman RF, Lezotte D, et al. Increasing incidence of type 1 diabetes in 0- to 17-year-old Colorado youth. Diabetes Care 2007; 30:503.
  96. Gale EA. The rise of childhood type 1 diabetes in the 20th century. Diabetes 2002; 51:3353.
  97. Bach JF. The effect of infections on susceptibility to autoimmune and allergic diseases. N Engl J Med 2002; 347:911.
  98. Redondo MJ, Yu L, Hawa M, et al. Late progression to type 1 diabetes of discordant twins of patients with type 1 diabetes: Combined analysis of two twin series (United States and United Kingdom). Diabetes 1999; 48:780.
  99. Dahlquist GG, Patterson C, Soltesz G. Perinatal risk factors for childhood type 1 diabetes in Europe. The EURODIAB Substudy 2 Study Group. Diabetes Care 1999; 22:1698.
  100. Stene LC, Magnus P, Lie RT, et al. Birth weight and childhood onset type 1 diabetes: population based cohort study. BMJ 2001; 322:889.
  101. Dahlquist GG, Pundziūte-Lyckå A, Nyström L, et al. Birthweight and risk of type 1 diabetes in children and young adults: a population-based register study. Diabetologia 2005; 48:1114.
  102. Stene LC, Joner G, Norwegian Childhood Diabetes Study Group. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: a large, population-based, case-control study. Am J Clin Nutr 2003; 78:1128.
  103. Szopa TM, Titchener PA, Portwood ND, Taylor KW. Diabetes mellitus due to viruses--some recent developments. Diabetologia 1993; 36:687.
  104. Yoon JW, Austin M, Onodera T, Notkins AL. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis. N Engl J Med 1979; 300:1173.
  105. Foulis AK, McGill M, Farquharson MA, Hilton DA. A search for evidence of viral infection in pancreases of newly diagnosed patients with IDDM. Diabetologia 1997; 40:53.
  106. Dotta F, Censini S, van Halteren AG, et al. Coxsackie B4 virus infection of beta cells and natural killer cell insulitis in recent-onset type 1 diabetic patients. Proc Natl Acad Sci U S A 2007; 104:5115.
  107. King ML, Shaikh A, Bidwell D, et al. Coxsackie-B-virus-specific IgM responses in children with insulin-dependent (juvenile-onset; type I) diabetes mellitus. Lancet 1983; 1:1397.
  108. Hyöty H, Hiltunen M, Knip M, et al. A prospective study of the role of coxsackie B and other enterovirus infections in the pathogenesis of IDDM. Childhood Diabetes in Finland (DiMe) Study Group. Diabetes 1995; 44:652.
  109. Kaufman DL, Erlander MG, Clare-Salzler M, et al. Autoimmunity to two forms of glutamate decarboxylase in insulin-dependent diabetes mellitus. J Clin Invest 1992; 89:283.
  110. Atkinson MA, Bowman MA, Campbell L, et al. Cellular immunity to a determinant common to glutamate decarboxylase and coxsackie virus in insulin-dependent diabetes. J Clin Invest 1994; 94:2125.
  111. Menser MA, Forrest JM, Bransby RD. Rubella infection and diabetes mellitus. Lancet 1978; 1:57.
  112. Hyöty H, Taylor KW. The role of viruses in human diabetes. Diabetologia 2002; 45:1353.
  113. Zipris D, Lien E, Xie JX, et al. TLR activation synergizes with Kilham rat virus infection to induce diabetes in BBDR rats. J Immunol 2005; 174:131.
  114. Devendra D, Jasinski J, Melanitou E, et al. Interferon-alpha as a mediator of polyinosinic:polycytidylic acid-induced type 1 diabetes. Diabetes 2005; 54:2549.
  115. Hummel M, Füchtenbusch M, Schenker M, Ziegler AG. No major association of breast-feeding, vaccinations, and childhood viral diseases with early islet autoimmunity in the German BABYDIAB Study. Diabetes Care 2000; 23:969.
  116. Cainelli F, Manzaroli D, Renzini C, et al. Coxsackie B virus-induced autoimmunity to GAD does not lead to type 1 diabetes. Diabetes Care 2000; 23:1021.
  117. Dyrberg T, Schwimmbeck PL, Oldstone MB. Inhibition of diabetes in BB rats by virus infection. J Clin Invest 1988; 81:928.
  118. Oldstone MB. Prevention of type I diabetes in nonobese diabetic mice by virus infection. Science 1988; 239:500.
  119. Like AA, Guberski DL, Butler L. Influence of environmental viral agents on frequency and tempo of diabetes mellitus in BB/Wor rats. Diabetes 1991; 40:259.
  120. Hviid A, Stellfeld M, Wohlfahrt J, Melbye M. Childhood vaccination and type 1 diabetes. N Engl J Med 2004; 350:1398.
  121. Yoon JW. The role of viruses and environmental factors in the induction of diabetes. Curr Top Microbiol Immunol 1990; 164:95.
  122. Virtanen SM, Saukkonen T, Savilahti E, et al. Diet, cow's milk protein antibodies and the risk of IDDM in Finnish children. Childhood Diabetes in Finland Study Group. Diabetologia 1994; 37:381.
  123. Norris JM, Beaty B, Klingensmith G, et al. Lack of association between early exposure to cow's milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY). JAMA 1996; 276:609.
  124. Couper JJ, Steele C, Beresford S, et al. Lack of association between duration of breast-feeding or introduction of cow's milk and development of islet autoimmunity. Diabetes 1999; 48:2145.
  125. Cavallo MG, Fava D, Monetini L, et al. Cell-mediated immune response to beta casein in recent-onset insulin-dependent diabetes: implications for disease pathogenesis. Lancet 1996; 348:926.
  126. Elliott RB, Harris DP, Hill JP, et al. Type I (insulin-dependent) diabetes mellitus and cow milk: casein variant consumption. Diabetologia 1999; 42:292.
  127. Norris JM, Barriga K, Klingensmith G, et al. Timing of initial cereal exposure in infancy and risk of islet autoimmunity. JAMA 2003; 290:1713.
  128. Ziegler AG, Schmid S, Huber D, et al. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 2003; 290:1721.
  129. Frederiksen B, Kroehl M, Lamb MM, et al. Infant exposures and development of type 1 diabetes mellitus: The Diabetes Autoimmunity Study in the Young (DAISY). JAMA Pediatr 2013; 167:808.
  130. Norris JM, Barriga K, Hoffenberg EJ, et al. Risk of celiac disease autoimmunity and timing of gluten introduction in the diet of infants at increased risk of disease. JAMA 2005; 293:2343.
  131. Krishna Mohan I, Das UN. Prevention of chemically induced diabetes mellitus in experimental animals by polyunsaturated fatty acids. Nutrition 2001; 17:126.
  132. Kleemann R, Scott FW, Wörz-Pagenstert U, et al. Impact of dietary fat on Th1/Th2 cytokine gene expression in the pancreas and gut of diabetes-prone BB rats. J Autoimmun 1998; 11:97.
  133. Norris JM, Yin X, Lamb MM, et al. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 2007; 298:1420.
  134. Parslow RC, McKinney PA, Law GR, et al. Incidence of childhood diabetes mellitus in Yorkshire, northern England, is associated with nitrate in drinking water: an ecological analysis. Diabetologia 1997; 40:550.
  135. McCulloch DK, Palmer JP, Benson EA. Beta cell function in the preclinical period of insulin-dependent diabetes. Diabetes Metab Rev 1987; 3:27.
  136. Thai AC, Eisenbarth GS. Natural history of IDDM. Diabetes Reviews 1993; 1:1.
  137. Sosenko JM, Palmer JP, Greenbaum CJ, et al. Increasing the accuracy of oral glucose tolerance testing and extending its application to individuals with normal glucose tolerance for the prediction of type 1 diabetes: the Diabetes Prevention Trial-Type 1. Diabetes Care 2007; 30:38.
  138. Bingley PJ, Colman P, Eisenbarth GS, et al. Standardization of IVGTT to predict IDDM. Diabetes Care 1992; 15:1313.
  139. McCulloch DK, Bingley PJ, Colman PG, et al. Comparison of bolus and infusion protocols for determining acute insulin response to intravenous glucose in normal humans. The ICARUS Group. Islet Cell Antibody Register User's Study. Diabetes Care 1993; 16:911.
  140. McCulloch DK, Koerker DJ, Kahn SE, et al. Correlations of in vivo beta-cell function tests with beta-cell mass and pancreatic insulin content in streptozocin-administered baboons. Diabetes 1991; 40:673.
  141. Strandell E, Eizirik DL, Sandler S. Reversal of beta-cell suppression in vitro in pancreatic islets isolated from nonobese diabetic mice during the phase preceding insulin-dependent diabetes mellitus. J Clin Invest 1990; 85:1944.
  142. Conget I, Fernández-Alvarez J, Ferrer J, et al. Human pancreatic islet function at the onset of type 1 (insulin-dependent) diabetes mellitus. Diabetologia 1993; 36:358.
  143. Nir T, Melton DA, Dor Y. Recovery from diabetes in mice by beta cell regeneration. J Clin Invest 2007; 117:2553.
  144. George M, Ayuso E, Casellas A, et al. Beta cell expression of IGF-I leads to recovery from type 1 diabetes. J Clin Invest 2002; 109:1153.
  145. Kulkarni RN, Holzenberger M, Shih DQ, et al. beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass. Nat Genet 2002; 31:111.