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Looking back at the TEDDY study: lessons and future directions

Nature Reviews Endocrinology volume 21, pages 154–165 (2025)Cite this article

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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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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.

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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

  1. Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden

    Åke Lernmark, Daniel Agardh, Helena Elding Larsson & Jessica Melin

  2. National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

    Beena Akolkar

  3. Barbara Davis Center for Diabetes, University of Colorado, Aurora, CO, USA

    Patricia Gesualdo & Marian Rewers

  4. Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA

    William A. Hagopian

  5. Department of Pediatrics, University of Florida, Gainesville, FL, USA

    Michael J. Haller & Desmond A. Schatz

  6. Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

    Heikki Hyöty

  7. Department of Behavioral Sciences and Social Medicine, Florida State University College of Medicine, Tallahassee, FL, USA

    Suzanne Bennett Johnson

  8. Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Edwin Liu

  9. Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA

    Kristian F. Lynch, Kendra Vehik & Jeffrey Krischer

  10. Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, UK

    Eoin F. McKinney

  11. Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA

    Richard McIndoe

  12. Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, USA

    Jill M. Norris

  13. Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA

    Stephen S. Rich

  14. Department of Paediatrics, Turku University Hospital, Turku, Finland

    Jorma Toppari

  15. Institute of Biomedicine, Research Centre for Integrated Physiology and Pharmacology, University of Turku, Turku, Finland

    Jorma Toppari

  16. University of Florida, Department of Microbiology and Cell Science, Gainesville, FL, USA

    Eric Triplett

  17. Center for Child Health Research, Tampere University and University Hospital and Research, Tampere, Finland

    Suvi M. Virtanen

  18. Institute of Diabetes Research, Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Munich, Germany

    Anette-G. Ziegler

  19. Forschergruppe Diabetes e.V. at Helmholtz Zentrum München, Deutsches Forschungszentrum für Gesundheit und Umwelt, Munich, Germany

    Anette-G. Ziegler

  20. Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München and e.V., Munich, Germany

    Anette-G. Ziegler

Authors
  1. Åke Lernmark
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  2. Daniel Agardh
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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.

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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.

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Related links

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

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

Supplementary information

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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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