Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Looking back at the TEDDY study: lessons and future directions

Abstract

The goal of the TEDDY (The Environmental Determinants of Diabetes in the Young) study is to elucidate factors leading to the initiation of islet autoimmunity (first primary outcome) and those related to progression to type 1 diabetes mellitus (T1DM; second primary outcome). This Review outlines the key findings so far, particularly related to the first primary outcome. The background, history and organization of the study are discussed. Recruitment and follow-up (from age 4 months to 15 years) of 8,667 children showed high retention and compliance. End points of the presence of autoantibodies against insulin, GAD65, IA-2 and ZnT8 revealed the HLA-associated early appearance of insulin autoantibodies (1–3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2–4 years). Genetic and environmental factors, including enterovirus infection and gastroenteritis, support mechanistic differences underlying one phenotype of autoimmunity against insulin and another against GAD65. Infant growth and both probiotics and high protein intake affect the two phenotypes differently, as do serious life events during pregnancy. As the end of the TEDDY sampling phase is approaching, major omics approaches are in progress to further dissect the mechanisms that might explain the two possible endotypes of T1DM.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Organizational chart of the TEDDY study data coordinating centre, clinical sites and flow of samples and data.
Fig. 2: Incidence rates of IAA,  GADA and multiple islet autoantibodies at seroconversion.
Fig. 3: Incidence rates comparing IAA-first and GADA-first with coeliac disease autoimmunity (CDA).
Fig. 4: TEDDY observations suggesting that the phenomena associated with either risk or protection from IAA-first are different from those associated with GADA-first.

Similar content being viewed by others

References

  1. Thomas, N. J. et al. Type 1 diabetes defined by severe insulin deficiency occurs after 30 years of age and is commonly treated as type 2 diabetes. Diabetologia 62, 1167–1172 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hermann, R. et al. Temporal changes in the frequencies of HLA genotypes in patients with type 1 diabetes – indication of an increased environmental pressure? Diabetologia 46, 420–425 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Gillespie, K. M. et al. The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes. Lancet 364, 1699–1700 (2004).

    Article  PubMed  Google Scholar 

  4. Resic-Lindehammer, S. et al. Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk. Acta Diabetol. 45, 231–235 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Fourlanos, S. et al. The rising incidence of type 1 diabetes is accounted for by cases with lower-risk human leukocyte antigen genotypes. Diabetes Care 31, 1546–1549 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Hagopian, W. A. et al. TEDDY – The Environmental Determinants of Diabetes in the Young: an observational clinical trial. Ann. N. Y. Acad. Sci. 1079, 320–326 (2006).

    Article  PubMed  Google Scholar 

  7. TEDDY Study Group The Environmental Determinants of Diabetes in the Young (TEDDY) study. Ann. N. Y. Acad. Sci. 1150, 1–13 (2008).

    Article  PubMed Central  Google Scholar 

  8. Norris, J. M. Infant and childhood diet and type 1 diabetes risk: recent advances and prospects. Curr. Diab Rep. 10, 345–349 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Elding Larsson, H. et al. Children followed in the TEDDY study are diagnosed with type 1 diabetes at an early stage of disease. Pediatr. Diabetes 15, 118–126 (2014).

    Article  PubMed  Google Scholar 

  10. Lernmark, A. et al. Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes. J. Intern. Med. 294, 145–158 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rewers, M. et al. The Environmental Determinants of Diabetes in the Young (TEDDY) study: 2018 update. Curr. Diab Rep. 18, 136 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  12. Stahl, M. et al. Coeliac disease: what can we learn from prospective studies about disease risk? Lancet Child. Adolesc. Health 8, 63–74 (2024).

    Article  CAS  PubMed  Google Scholar 

  13. Quinn, L. M., Wong, F. S. & Narendran, P. Environmental determinants of type 1 diabetes: from association to proving causality. Front. Immunol. 12, 737964 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Goodwin, G. Type 1 diabetes mellitus and celiac disease: distinct autoimmune disorders that share common pathogenic mechanisms. Horm. Res. Paediatr. 92, 285–292 (2019).

    Article  CAS  PubMed  Google Scholar 

  15. TEDDY Study Group The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr. Diabetes 8, 286–298 (2007).

    Article  Google Scholar 

  16. Bonifacio, E. et al. Harmonization of glutamic acid decarboxylase and islet antigen-2 autoantibody assays for National Institute of Diabetes and Digestive and Kidney Diseases consortia. J. Clin. Endocrinol. Metab. 95, 3360–3367 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Onengut-Gumuscu, S. et al. Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers. Nat. Genet. 47, 381–386 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Lee, H. S. et al. Biomarker discovery study design for type 1 diabetes in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Diabetes Metab. Res. Rev. 30, 424–434 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hagopian, W. A. et al. The Environmental Determinants of Diabetes in the Young (TEDDY): genetic criteria and international diabetes risk screening of 421 000 infants. Pediatr. Diabetes 12, 733–743 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Baxter, J. et al. Differences in recruitment and early retention among ethnic minority participants in a large pediatric cohort: the TEDDY study. Contemp. Clin. Trials 33, 633–640 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  21. Johnson, S. B. et al. The Environmental Determinants of Diabetes in the Young (TEDDY) study: predictors of early study withdrawal among participants with no family history of type 1 diabetes. Pediatr. Diabetes 12, 165–171 (2011).

    Article  PubMed  Google Scholar 

  22. Lernmark, B. et al. Enrollment experiences in a pediatric longitudinal observational study: The Environmental Determinants of Diabetes in the Young (TEDDY) study. Contemp. Clin. Trials 32, 517–523 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Johnson, S. B. et al. Predicting later study withdrawal in participants active in a longitudinal birth cohort study for 1 year: the TEDDY study. J. Pediatr. Psychol. 41, 373–383 (2016).

    Article  PubMed  Google Scholar 

  24. Lernmark, B. et al. Participant experiences in The Environmental Determinants of Diabetes in the Young study: common reasons for withdrawing. J. Diabetes Res. 2016, 2720650 (2016).

    Article  PubMed  Google Scholar 

  25. Lernmark, B. et al. Reasons for staying as a participant in The Environmental Determinants of Diabetes in the Young (TEDDY) longitudinal study. J. Clin. Trials 2, 1000114 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Melin, J. et al. Factors assessed in the first year of a longitudinal study predict subsequent study visit compliance: the TEDDY study. Eur. J. Med. Res. 28, 592 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  27. Yang, J. et al. Factors associated with longitudinal food record compliance in a paediatric cohort study. Public. Health Nutr. 19, 804–813 (2016).

    Article  PubMed  Google Scholar 

  28. Roth, R. et al. The feasibility of salivary sample collection in an international pediatric cohort: the the TEDDY study. Dev. Psychobiol. 59, 658–667 (2017).

    Article  CAS  PubMed  Google Scholar 

  29. Driscoll, K. A. et al. Adherence to oral glucose tolerance testing in children in stage 1 of type 1 diabetes: the TEDDY study. Pediatr. Diabetes 22, 360–368 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Vehik, K. et al. Hierarchical order of distinct autoantibody spreading and progression to type 1 diabetes in the TEDDY study. Diabetes Care 43, 2066–2073 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Insel, R. A. et al. Staging presymptomatic type 1 diabetes: a scientific statement of JDRF, the Endocrine Society, and the American Diabetes Association. Diabetes Care 38, 1964–1974 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Krischer, J. P. et al. The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study. Diabetologia 58, 980–987 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bonifacio, E. et al. An age-related exponential decline in the risk of multiple islet autoantibody seroconversion during childhood. Diabetes Care 44, 2260–2268 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Battaglia, M. et al. Understanding and preventing type 1 diabetes through the unique working model of TrialNet. Diabetologia 60, 2139–2147 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ilonen, J. et al. Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 62, 3636–3640 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Parkes, M., Cortes, A., van Heel, D. A. & Brown, M. A. Genetic insights into common pathways and complex relationships among immune-mediated diseases. Nat. Rev. Genet. 14, 661–673 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Törn, C. et al. Telomere length is not a main factor for the development of islet autoimmunity and type 1 diabetes in the TEDDY study. Sci. Rep. 12, 4516 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Rich, S. S. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes 39, 1315–1319 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Bonifacio, E. et al. Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: a prospective study in children. PLoS Med. 15, e1002548 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Beyerlein, A. et al. Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study. J. Med. Genet. 56, 602–605 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Singal, D. P. & Blajchman, M. A. Histocompatibility (HL-A) antigens, lymphocytotoxic antibodies and tissue antibodies in patients with diabetes mellitus. Diabetes 22, 429–432 (1973).

    Article  CAS  PubMed  Google Scholar 

  42. Nerup, J. et al. HL-A antigens and diabetes mellitus. Lancet 2, 864–866 (1974).

    Article  CAS  PubMed  Google Scholar 

  43. Barbosa, J., Bach, F. H. & Rich, S. S. Genetic heterogeneity of diabetes and HLA. Clin. Genet. 21, 25–32 (1982).

    Article  CAS  PubMed  Google Scholar 

  44. Todd, J. A., Bell, J. I. & McDevitt, H. O. HLA-DQβ gene contributes to susceptibility and resistance to insulin-dependent diabetes mellitus. Nature 329, 599–604 (1987).

    Article  CAS  PubMed  Google Scholar 

  45. Hu, X. et al. Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk. Nat. Genet. 47, 898–905 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bell, G. I., Horita, S. & Karam, J. H. A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus. Diabetes 33, 176–183 (1984).

    Article  CAS  PubMed  Google Scholar 

  47. Nistico, L. et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum. Mol. Genet. 5, 1075–1080 (1996).

    Article  CAS  PubMed  Google Scholar 

  48. Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Vella, A. et al. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms. Am. J. Hum. Genet. 76, 773–779 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sharp, S. A. et al. Development and standardization of an improved type 1 diabetes genetic risk score for use in newborn screening and incident diagnosis. Diabetes Care 42, 200–207 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Ferrat, L. A. et al. A combined risk score enhances prediction of type 1 diabetes among susceptible children. Nat. Med. 26, 1247–1255 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Redondo, M. J. et al. Type 1 diabetes in diverse ancestries and the use of genetic risk scores. Lancet Diabetes Endocrinol. 10, 597–608 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Vehik, K. et al. Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. Nat. Med. 25, 1865–1872 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Krischer, J. P. et al. Predictors of the initiation of islet autoimmunity and progression to multiple autoantibodies and clinical diabetes: the TEDDY study. Diabetes Care 45, 2271–2281 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Norris, J. M. et al. Plasma 25-hydroxyvitamin D concentration and risk of islet autoimmunity. Diabetes 67, 146–154 (2018).

    Article  CAS  PubMed  Google Scholar 

  56. Aydemir, O. et al. Genetic variation within the HLA-DRA1 gene modulates susceptibility to type 1 diabetes in HLA-DR3 homozygotes. Diabetes 68, 1523–1527 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Andersson Svärd, A. et al. Possible relationship between the HLA-DRA1 intron haplotype of three single-nucleotide polymorphisms in intron 1 of the HLA-DRA1 gene and autoantibodies in children at increased genetic risk for autoimmune type 1 diabetes. Immunohorizons 6, 614–629 (2022).

    Article  PubMed  Google Scholar 

  58. Aydemir, O. et al. Polymorphisms in Intron 1 of HLA-DRA differentially associate with type 1 diabetes and celiac disease and implicate involvement of complement system genes C4A and C4B. eLife 12, RP89068 (2023).

    Google Scholar 

  59. Lin, J. et al. Distinct transcriptomic profiles in children prior to the appearance of type 1 diabetes-linked islet autoantibodies and following enterovirus infection. Nat. Commun. 14, 7630 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Braenne, I. et al. Dynamic changes in immune gene co-expression networks predict development of type 1 diabetes. Sci. Rep. 11, 22651 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Xhonneux, L. P. et al. Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression. Sci. Transl. Med. 13, eabd5666 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Vatanen, T. et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 562, 589–594 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Stewart, C. J. et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 562, 583–588 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Sioofy-Khojine, A. B. et al. Coxsackievirus B1 infections are associated with the initiation of insulin-driven autoimmunity that progresses to type 1 diabetes. Diabetologia 61, 1193–1202 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. Cinek, O. et al. Enterovirus RNA in longitudinal blood samples and risk of islet autoimmunity in children with a high genetic risk of type 1 diabetes: the MIDIA study. Diabetologia 57, 2193–2200 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Dunne, J. L. et al. Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes. Diabetologia 62, 744–753 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Lonnrot, M. et al. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. Diabetologia 60, 1931–1940 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Hyoty, H. 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 44, 652–657 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Lonnrot, M. et al. Gastrointestinal infections modulate the risk for insulin autoantibodies as the first-appearing autoantibody in the TEDDY study. Diabetes Care 46, 1908–1915 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  70. Kemppainen, K. M. et al. Association between early-life antibiotic use and the risk of islet or celiac disease autoimmunity. JAMA Pediatr. 171, 1217–1225 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Duong, Q. A., Pittet, L. F., Curtis, N. & Zimmermann, P. Antibiotic exposure and adverse long-term health outcomes in children: a systematic review and meta-analysis. J. Infect. 85, 213–300 (2022).

    Article  CAS  PubMed  Google Scholar 

  72. Elding Larsson, H. et al. Pandemrix® vaccination is not associated with increased risk of islet autoimmunity or type 1 diabetes in the TEDDY study children. Diabetologia 61, 193–202 (2018).

    Article  CAS  PubMed  Google Scholar 

  73. Andrén Aronsson, C. et al. Association of gluten intake during the first 5 years of life with incidence of celiac disease autoimmunity and celiac disease among children at increased risk. JAMA 322, 514–523 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Hagopian, W. et al. Co-occurrence of type 1 diabetes and celiac disease autoimmunity. Pediatrics 140, e20171305 (2017).

    Article  PubMed  Google Scholar 

  75. Liu, E. et al. Risk of pediatric celiac disease according to HLA haplotype and country. N. Engl. J. Med. 371, 42–49 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  76. Sharma, A. et al. Identification of non-HLA genes associated with celiac disease and country-specific differences in a large, international pediatric cohort. PLoS ONE 11, e0152476 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Hadley, D. et al. HLA-DPB1*04:01 protects genetically susceptible children from celiac disease autoimmunity in the TEDDY study. Am. J. Gastroenterol. 110, 915–920 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Koletzko, S. et al. Caesarean section on the risk of celiac disease in the offspring: the teddy study. J. Pediatr. Gastroenterol. Nutr. 66, 417–424 (2017).

    Article  Google Scholar 

  79. Yang, J. et al. Maternal use of dietary supplements during pregnancy is not associated with coeliac disease in the offspring: the environmental determinants of diabetes in the young (TEDDY) study. Br. J. Nutr. 117, 466–472 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Uusitalo, U. et al. Gluten consumption during late pregnancy and risk of celiac disease in the offspring: the TEDDY birth cohort. Am. J. Clin. Nutr. 102, 1216–1221 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Andren Aronsson, C. et al. 25(OH)D levels in infancy is associated with celiac disease autoimmunity in at-risk children: a case-control study. Front. Nutr. 8, 720041 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Aronsson, C. A. et al. Age at gluten introduction and risk of celiac disease. Pediatrics 135, 239–245 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  83. Andren Aronsson, C. et al. Effects of gluten intake on risk of celiac disease: a case-control study on a Swedish birth cohort. Clin. Gastroenterol. Hepatol. 14, 403–409.e3 (2016).

    Article  CAS  PubMed  Google Scholar 

  84. Uusitalo, U. et al. Early probiotic supplementation and the risk of celiac disease in children at genetic risk. Nutrients 11, 1790 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Kemppainen, K. M. et al. Factors that increase risk of celiac disease autoimmunity after a gastrointestinal infection in early life. Clin. Gastroenterol. Hepatol. 15, 694–702.e5 (2017).

    Article  PubMed  Google Scholar 

  86. Lindfors, K. et al. Metagenomics of the faecal virome indicate a cumulative effect of enterovirus and gluten amount on the risk of coeliac disease autoimmunity in genetically at risk children: the TEDDY study. Gut 69, 1416–1422 (2020).

    Article  CAS  PubMed  Google Scholar 

  87. Kulkarni, A., Muralidharan, C., May, S. C., Tersey, S. A. & Mirmira, R. G. Inside the β cell: molecular stress response pathways in diabetes pathogenesis. Endocrinology 164, bqac184 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Bekris, L. M. et al. Glutamate cysteine ligase catalytic subunit promoter polymorphisms and associations with type 1 diabetes age-at-onset and GAD65 autoantibody levels. Exp. Clin. Endocrinol. Diabetes 115, 221–228 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Wilkin, T. J. The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia 44, 914–922 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Liu, X. et al. Distinct growth phases in early life associated with the risk of type 1 diabetes: the TEDDY study. Diabetes Care 43, 556–562 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Elding Larsson, H. et al. Growth and risk for islet autoimmunity and progression to type 1 diabetes in early childhood: The Environmental Determinants of Diabetes in the Young study. Diabetes 65, 1988–1995 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  92. Andrén Aronsson, C. et al. Dietary intake and body mass index influence the risk of islet autoimmunity in genetically at-risk children: a mediation analysis using the TEDDY cohort. Pediatr. Diabetes 2023, 3945064 (2023).

    Article  Google Scholar 

  93. Warncke, K. et al. The influence of pubertal development on autoantibody appearance and progression to type 1 diabetes in the TEDDY study. J. Endocr. Soc. 8, bvae103 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Uusitalo, U. et al. Food composition database harmonization for between-country comparisons of nutrient data in the TEDDY study. J. Food Compost. Anal. 24, 494–505 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Joslowski, G. et al. Development of a harmonized food grouping system for between-country comparisons in the TEDDY study. J. Food Compost. Anal. 63, 79–88 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Hummel, S. et al. First infant formula type and risk of islet autoimmunity in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Diabetes Care 40, 398–404 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Knip, M. et al. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA 311, 2279–2287 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Writing Group for the TRIGR Study Group Effect of hydrolyzed infant formula vs conventional formula on risk of type 1 diabetes: the TRIGR randomized clinical trial. JAMA 319, 38–48 (2018).

    Article  PubMed Central  Google Scholar 

  99. Hummel, M., Bonifacio, E., Naserke, H. E. & Ziegler, A. G. Elimination of dietary gluten does not reduce titers of type 1 diabetes-associated autoantibodies in high-risk subjects. Diabetes Care 25, 1111–1116 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Fuchtenbusch, M., Ziegler, A. G. & Hummel, M. Elimination of dietary gluten and development of type 1 diabetes in high risk subjects. Rev. Diabet. Stud. 1, 39–41 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Uusitalo, U. et al. Early infant diet and islet autoimmunity in the TEDDY study. Diabetes Care 41, 522–530 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  102. Uusitalo, U. et al. Association of early exposure of probiotics and islet autoimmunity in the TEDDY study. JAMA Pediatr. 170, 20–28 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  103. Uusitalo, U. et al. HLA genotype and probiotics modify the association between timing of solid food introduction and islet autoimmunity in the TEDDY study. Diabetes Care 46, 1839–1847 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Hakola, L. et al. Intake of B vitamins and the risk of developing islet autoimmunity and type 1 diabetes in the TEDDY study. Eur. J. Nutr. 63, 1329–1338 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Thorsen, S. U. et al. Interaction between dietary iron intake and genetically determined iron overload: risk of islet autoimmunity and progression to type 1 diabetes in the TEDDY study. Diabetes Care 46, 1014–1018 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  106. Niinistö, S. et al. Children’s erythrocyte fatty acids are associated with the risk of islet autoimmunity. Sci. Rep. 11, 3627 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Norris, J. M. et al. Omega-3 polyunsaturated fatty acid intake and islet autoimmunity in children at increased risk for type 1 diabetes. JAMA 298, 1420–1428 (2007).

    Article  CAS  PubMed  Google Scholar 

  108. Norris, J. M. et al. Erythrocyte membrane docosapentaenoic acid levels are associated with islet autoimmunity: the Diabetes Autoimmunity Study in the Young. Diabetologia 57, 295–304 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Niinisto, S. et al. Fatty acid status in infancy is associated with the risk of type 1 diabetes-associated autoimmunity. Diabetologia 60, 1223–1233 (2017).

    Article  CAS  PubMed  Google Scholar 

  110. Mattila, M. et al. Plasma ascorbic acid and the risk of islet autoimmunity and type 1 diabetes: the TEDDY study. Diabetologia 63, 278–286 (2020).

    Article  CAS  PubMed  Google Scholar 

  111. Li, Q. et al. Longitudinal metabolome-wide signals prior to the appearance of a first islet autoantibody in children participating in the TEDDY study. Diabetes 69, 465–476 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Sepa, A. & Ludvigsson, J. Psychological stress and the risk of diabetes-related autoimmunity: a review article. Neuroimmunomodulation 13, 301–308 (2006).

    Article  CAS  PubMed  Google Scholar 

  113. Sharif, K. et al. Psychological stress and type 1 diabetes mellitus: what is the link? Expert. Rev. Clin. Immunol. 14, 1081–1088 (2018).

    Article  CAS  PubMed  Google Scholar 

  114. Sepa, A., Frodi, A. & Ludvigsson, J. Mothers’ experiences of serious life events increase the risk of diabetes-related autoimmunity in their children. Diabetes Care 28, 2394–2399 (2005).

    Article  PubMed  Google Scholar 

  115. Lundgren, M., Ellström, K. & Elding Larsson, H. Influence of early-life parental severe life events on the risk of type 1 diabetes in children: the DiPiS study. Acta Diabetol. 55, 797–804 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Roth, R. et al. The association between stressful life events and respiratory infections during the first 4 years of life: The Environmental Determinants of Diabetes in the Young study. Stress. Health 35, 289–303 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Virk, J. et al. Early life disease programming during the preconception and prenatal period: making the link between stressful life events and type-1 diabetes. PLoS ONE 5, e11523 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Lynch, K. F. et al. Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies. J. Autoimmun. 86, 93–103 (2018).

    Article  CAS  PubMed  Google Scholar 

  119. Johnson, S. B. et al. First-appearing islet autoantibodies for type 1 diabetes in young children: maternal life events during pregnancy and the child’s genetic risk. Diabetologia 64, 591–602 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Roll, U. et al. Perinatal autoimmunity in offspring of diabetic parents. the German multicenter BABY-DIAB study: detection of humoral immune responses to islet antigens in early childhood. Diabetes 45, 967–973 (1996).

    Article  PubMed  Google Scholar 

  121. Ziegler, A. G., Hummel, M., Schenker, M. & Bonifacio, E. Autoantibody appearance and risk for development of childhood diabetes in offspring of parents with type 1 diabetes: the 2-year analysis of the German BABYDIAB study. Diabetes 48, 460–468 (1999).

    Article  CAS  PubMed  Google Scholar 

  122. Hahl, J., Simell, T., Ilonen, J., Knip, M. & Simell, O. Costs of predicting IDDM. Diabetologia 41, 79–85 (1998).

    Article  CAS  PubMed  Google Scholar 

  123. Rewers, M. et al. Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 39, 807–812 (1996).

    Article  CAS  PubMed  Google Scholar 

  124. Bennett Johnson, S., Baughcum, A. E., Carmichael, S. K., She, J. X. & Schatz, D. A. Maternal anxiety associated with newborn genetic screening for type 1 diabetes. Diabetes Care 27, 392–397 (2004).

    Article  PubMed  Google Scholar 

  125. Wion, E. et al. Population-wide infant screening for HLA-based type 1 diabetes risk via dried blood spots from the public health infrastructure. Ann. N. Y. Acad. Sci. 1005, 400–403 (2003).

    Article  PubMed  Google Scholar 

  126. Larsson, K. et al. Genetic and perinatal factors as risk for childhood type 1 diabetes. Diabetes Metab. Res. Rev. 20, 429–437 (2004).

    Article  PubMed  Google Scholar 

  127. Stene, L. C. et al. Islet autoantibody development during follow-up of high-risk children from the general Norwegian population from three months of age: design and early results from the MIDIA study. J. Autoimmun. 29, 44–51 (2007).

    Article  CAS  PubMed  Google Scholar 

  128. Ludvigsson, J., Ludvigsson, M. & Sepa, A. Screening for prediabetes in the general child population: maternal attitude to participation. Pediatr. Diabetes 2, 170–174 (2001).

    Article  CAS  PubMed  Google Scholar 

  129. Lernmark, B., Lynch, K. & Lernmark, A. Cord blood islet autoantibodies are related to stress in the mother during pregnancy. Ann. N. Y. Acad. Sci. 1079, 345–349 (2006).

    Article  PubMed  Google Scholar 

  130. Vehik, K. et al. Methods, quality control and specimen management in an international multicentre investigation of type 1 diabetes: TEDDY. Diabetes Metab. Res. Rev. 29, 557–567 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Williams, A. J., Bingley, P. J., Bonifacio, E., Palmer, J. P. & Gale, E. A. A novel micro-assay for insulin autoantibodies. J. Autoimmun. 10, 473–478 (1997).

    Article  CAS  PubMed  Google Scholar 

  132. Krischer, J. P. et al. Genetic and environmental interactions modify the risk of diabetes-related autoimmunity by 6 years of age: the TEDDY study. Diabetes Care 40, 1194–1202 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  133. Endesfelder, D. et al. Time-resolved autoantibody profiling facilitates stratification of preclinical type 1 diabetes in children. Diabetes 68, 119–130 (2019).

    Article  CAS  PubMed  Google Scholar 

  134. Jacobsen, L. M. et al. Heterogeneity of DKA incidence and age-specific clinical characteristics in children diagnosed with type 1 diabetes in the TEDDY study. Diabetes Care 45, 624–633 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  135. Vehik, K. et al. Rising hemoglobin A1c in the nondiabetic range predicts progression of type 1 diabetes as well as oral glucose tolerance tests. Diabetes Care 45, 2342–2349 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu, X. et al. Physical activity and the development of islet autoimmunity and type 1 diabetes in 5- to 15-year-old children followed in the TEDDY study. Diabetes Care 46, 1409–1416 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Hård Af Segerstad, E. M. et al. Associations of dietary patterns between age 9 and 24 months with risk of celiac disease autoimmunity and celiac disease among children at increased risk. Am. J. Clin. Nutr. 118, 1099–1105 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  138. Nakayasu, E. S. et al. Plasma protein biomarkers predict the development of persistent autoantibodies and type 1 diabetes 6 months prior to the onset of autoimmunity. Cell Rep. Med. 4, 101093 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Penno, M. A. et al. Environmental determinants of islet autoimmunity (ENDIA): a pregnancy to early life cohort study in children at-risk of type 1 diabetes. BMC Pediatr. 13, 124 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank S. Austin-Gonzalez with the Health Informatics Institute at the University of South Florida for assistance with preparing the figures. The authors acknowledge the work of all members of the TEDDY study group. A full list of members and their affiliations appears in the Supplementary information. The TEDDY study is funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, U01 DK124166, U01 DK128847, and Contract no. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Centers for Disease Control and Prevention (CDC), and JDRF. This work is supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR002535). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Contributions

B.A., M.J.H., E.L., E.F.M. and J.M. researched data for the article, made a substantial contribution to discussion of content and reviewed/edited the manuscript before submission. R.M. researched data for the article and reviewed/edited the manuscript before submission. All other authors contributed to all aspects of the preparation of the manuscript.

Corresponding author

Correspondence to Åke Lernmark.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Endocrinology thanks Noel Morgan; Emma Hamilton-Williams; and Karsten Buschard, who co-reviewed with Martin Haupt-Jorgensen, for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Related links

NIDDK TEDDY data: https://repository.niddk.nih.gov/studies/teddy/

The PROMISE study: https://www.thepromisestudy.com/

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lernmark, Å., Agardh, D., Akolkar, B. et al. Looking back at the TEDDY study: lessons and future directions. Nat Rev Endocrinol 21, 154–165 (2025). https://doi.org/10.1038/s41574-024-01045-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41574-024-01045-0

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing