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.
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References
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).
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).
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).
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).
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).
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).
TEDDY Study Group The Environmental Determinants of Diabetes in the Young (TEDDY) study. Ann. N. Y. Acad. Sci. 1150, 1–13 (2008).
Norris, J. M. Infant and childhood diet and type 1 diabetes risk: recent advances and prospects. Curr. Diab Rep. 10, 345–349 (2010).
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).
Lernmark, A. et al. Possible heterogeneity of initial pancreatic islet beta-cell autoimmunity heralding type 1 diabetes. J. Intern. Med. 294, 145–158 (2023).
Rewers, M. et al. The Environmental Determinants of Diabetes in the Young (TEDDY) study: 2018 update. Curr. Diab Rep. 18, 136 (2018).
Stahl, M. et al. Coeliac disease: what can we learn from prospective studies about disease risk? Lancet Child. Adolesc. Health 8, 63–74 (2024).
Quinn, L. M., Wong, F. S. & Narendran, P. Environmental determinants of type 1 diabetes: from association to proving causality. Front. Immunol. 12, 737964 (2021).
Goodwin, G. Type 1 diabetes mellitus and celiac disease: distinct autoimmune disorders that share common pathogenic mechanisms. Horm. Res. Paediatr. 92, 285–292 (2019).
TEDDY Study Group The Environmental Determinants of Diabetes in the Young (TEDDY) study: study design. Pediatr. Diabetes 8, 286–298 (2007).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Yang, J. et al. Factors associated with longitudinal food record compliance in a paediatric cohort study. Public. Health Nutr. 19, 804–813 (2016).
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).
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).
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).
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).
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).
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).
Battaglia, M. et al. Understanding and preventing type 1 diabetes through the unique working model of TrialNet. Diabetologia 60, 2139–2147 (2017).
Ilonen, J. et al. Patterns of β-cell autoantibody appearance and genetic associations during the first years of life. Diabetes 62, 3636–3640 (2013).
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).
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).
Rich, S. S. Mapping genes in diabetes. Genetic epidemiological perspective. Diabetes 39, 1315–1319 (1990).
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).
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).
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).
Nerup, J. et al. HL-A antigens and diabetes mellitus. Lancet 2, 864–866 (1974).
Barbosa, J., Bach, F. H. & Rich, S. S. Genetic heterogeneity of diabetes and HLA. Clin. Genet. 21, 25–32 (1982).
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).
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).
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).
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).
Bottini, N. et al. A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat. Genet. 36, 337–338 (2004).
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).
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).
Ferrat, L. A. et al. A combined risk score enhances prediction of type 1 diabetes among susceptible children. Nat. Med. 26, 1247–1255 (2020).
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).
Vehik, K. et al. Prospective virome analyses in young children at increased genetic risk for type 1 diabetes. Nat. Med. 25, 1865–1872 (2019).
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).
Norris, J. M. et al. Plasma 25-hydroxyvitamin D concentration and risk of islet autoimmunity. Diabetes 67, 146–154 (2018).
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).
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).
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).
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).
Braenne, I. et al. Dynamic changes in immune gene co-expression networks predict development of type 1 diabetes. Sci. Rep. 11, 22651 (2021).
Xhonneux, L. P. et al. Transcriptional networks in at-risk individuals identify signatures of type 1 diabetes progression. Sci. Transl. Med. 13, eabd5666 (2021).
Vatanen, T. et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature 562, 589–594 (2018).
Stewart, C. J. et al. Temporal development of the gut microbiome in early childhood from the TEDDY study. Nature 562, 583–588 (2018).
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).
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).
Dunne, J. L. et al. Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes. Diabetologia 62, 744–753 (2019).
Lonnrot, M. et al. Respiratory infections are temporally associated with initiation of type 1 diabetes autoimmunity: the TEDDY study. Diabetologia 60, 1931–1940 (2017).
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).
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).
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).
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).
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).
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).
Hagopian, W. et al. Co-occurrence of type 1 diabetes and celiac disease autoimmunity. Pediatrics 140, e20171305 (2017).
Liu, E. et al. Risk of pediatric celiac disease according to HLA haplotype and country. N. Engl. J. Med. 371, 42–49 (2014).
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).
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).
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).
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).
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).
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).
Aronsson, C. A. et al. Age at gluten introduction and risk of celiac disease. Pediatrics 135, 239–245 (2015).
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).
Uusitalo, U. et al. Early probiotic supplementation and the risk of celiac disease in children at genetic risk. Nutrients 11, 1790 (2019).
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).
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).
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).
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).
Wilkin, T. J. The accelerator hypothesis: weight gain as the missing link between type I and type II diabetes. Diabetologia 44, 914–922 (2001).
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).
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).
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).
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).
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).
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).
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).
Knip, M. et al. Hydrolyzed infant formula and early β-cell autoimmunity: a randomized clinical trial. JAMA 311, 2279–2287 (2014).
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).
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).
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).
Uusitalo, U. et al. Early infant diet and islet autoimmunity in the TEDDY study. Diabetes Care 41, 522–530 (2018).
Uusitalo, U. et al. Association of early exposure of probiotics and islet autoimmunity in the TEDDY study. JAMA Pediatr. 170, 20–28 (2016).
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).
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).
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).
Niinistö, S. et al. Children’s erythrocyte fatty acids are associated with the risk of islet autoimmunity. Sci. Rep. 11, 3627 (2021).
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).
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).
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).
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).
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).
Sepa, A. & Ludvigsson, J. Psychological stress and the risk of diabetes-related autoimmunity: a review article. Neuroimmunomodulation 13, 301–308 (2006).
Sharif, K. et al. Psychological stress and type 1 diabetes mellitus: what is the link? Expert. Rev. Clin. Immunol. 14, 1081–1088 (2018).
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).
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).
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).
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).
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).
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).
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).
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).
Hahl, J., Simell, T., Ilonen, J., Knip, M. & Simell, O. Costs of predicting IDDM. Diabetologia 41, 79–85 (1998).
Rewers, M. et al. Newborn screening for HLA markers associated with IDDM: Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia 39, 807–812 (1996).
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).
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).
Larsson, K. et al. Genetic and perinatal factors as risk for childhood type 1 diabetes. Diabetes Metab. Res. Rev. 20, 429–437 (2004).
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).
Ludvigsson, J., Ludvigsson, M. & Sepa, A. Screening for prediabetes in the general child population: maternal attitude to participation. Pediatr. Diabetes 2, 170–174 (2001).
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).
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).
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).
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).
Endesfelder, D. et al. Time-resolved autoantibody profiling facilitates stratification of preclinical type 1 diabetes in children. Diabetes 68, 119–130 (2019).
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).
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).
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).
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).
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).
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).
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.
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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.
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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.
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NIDDK TEDDY data: https://repository.niddk.nih.gov/studies/teddy/
The PROMISE study: https://www.thepromisestudy.com/
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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
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DOI: https://doi.org/10.1038/s41574-024-01045-0