Looking back at the TEDDY study: lessons and future directions

Åke Lernmark; Daniel Agardh; Beena Akolkar; Patricia Gesualdo; William A. Hagopian; Michael J. Haller; Heikki Hyöty; Suzanne Bennett Johnson; Helena Elding Larsson; Edwin Liu; Kristian F. Lynch; Eoin F. McKinney; Richard McIndoe; Jessica Melin; Jill M. Norris; Marian Rewers; Stephen S. Rich; Jorma Toppari; Eric Triplett; Kendra Vehik; Suvi M. Virtanen; Anette G. Ziegler; Desmond A. Schatz; Jeffrey Krischer

doi:10.1038/s41574-024-01045-0

Looking back at the TEDDY study: lessons and future directions

Åke Lernmark^*
, Daniel Agardh
, Beena Akolkar
, Patricia Gesualdo
, William A. Hagopian
, Michael J. Haller
, Heikki Hyöty
, Suzanne Bennett Johnson
, Helena Elding Larsson
, Edwin Liu
, Kristian F. Lynch
, Eoin F. McKinney
, Richard McIndoe
, Jessica Melin
, Jill M. Norris
, Marian Rewers
, Stephen S. Rich
, Jorma Toppari
, Eric Triplett
, Kendra Vehik

Suvi M. Virtanen, Anette G. Ziegler, Desmond A. Schatz, Jeffrey Krischer

^*Corresponding author for this work

Research output: Contribution to journal › Review Article › peer-review

29 Citations (Scopus)

4 Downloads (Pure)

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.

Original language	English
Pages (from-to)	154-165
Journal	Nature Reviews Endocrinology
Volume	21
Early online date	2024
DOIs	https://doi.org/10.1038/s41574-024-01045-0
Publication status	Published - 2025
Publication type	A2 Review article in a scientific journal

Funding

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.

Funders	Funder number
Centers for Disease Control and Prevention
Eunice Kennedy Shriver National Institute of Child Health and Human Development
National Institute of Diabetes and Digestive and Kidney Diseases
National Institutes of Health
National Institute of Allergy and Infectious Diseases
National Institute of Environmental Health Sciences
Juvenile Diabetes Research Foundation United States of America
National Center for Advancing Translational Sciences
University of Colorado	UL1 TR002535
University of Florida	UL1 TR000064

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Publication forum classification

Publication forum level 2

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Endocrinology
Pediatrics, Perinatology, and Child Health

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Looking back at the TEDDY study
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Cite this

Lernmark, Å., Agardh, D., Akolkar, B., Gesualdo, P., Hagopian, W. A., Haller, M. J., Hyöty, H., Johnson, S. B., Larsson, H. E., Liu, E., Lynch, K. F., McKinney, E. F., McIndoe, R., Melin, J., Norris, J. M., Rewers, M., Rich, S. S., Toppari, J., Triplett, E., ... Krischer, J. (2025). Looking back at the TEDDY study: lessons and future directions. Nature Reviews Endocrinology, 21, 154-165. https://doi.org/10.1038/s41574-024-01045-0

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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{\textendash}3 years of age) and the later appearance of GAD65 autoantibodies. Competing autoantibodies against tissue transglutaminase (marking coeliac disease autoimmunity) also appeared early (2{\textendash}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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Lernmark, Å, Agardh, D, Akolkar, B, Gesualdo, P, Hagopian, WA, Haller, MJ, Hyöty, H, Johnson, SB, Larsson, HE, Liu, E, Lynch, KF, McKinney, EF, McIndoe, R, Melin, J, Norris, JM, Rewers, M, Rich, SS, Toppari, J, Triplett, E, Vehik, K, Virtanen, SM, Ziegler, AG, Schatz, DA & Krischer, J 2025, 'Looking back at the TEDDY study: lessons and future directions', Nature Reviews Endocrinology, vol. 21, pp. 154-165. https://doi.org/10.1038/s41574-024-01045-0

TY - JOUR

T1 - Looking back at the TEDDY study

T2 - lessons and future directions

AU - Lernmark, Åke

AU - Agardh, Daniel

AU - Akolkar, Beena

AU - Gesualdo, Patricia

AU - Hagopian, William A.

AU - Haller, Michael J.

AU - Hyöty, Heikki

AU - Johnson, Suzanne Bennett

AU - Larsson, Helena Elding

AU - Liu, Edwin

AU - Lynch, Kristian F.

AU - McKinney, Eoin F.

AU - McIndoe, Richard

AU - Melin, Jessica

AU - Norris, Jill M.

AU - Rewers, Marian

AU - Rich, Stephen S.

AU - Toppari, Jorma

AU - Triplett, Eric

AU - Vehik, Kendra

AU - Virtanen, Suvi M.

AU - Ziegler, Anette G.

AU - Schatz, Desmond A.

AU - Krischer, Jeffrey

PY - 2025

Y1 - 2025

N2 - 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.

AB - 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.

U2 - 10.1038/s41574-024-01045-0

DO - 10.1038/s41574-024-01045-0

M3 - Review Article

AN - SCOPUS:85208097101

SN - 1759-5029

VL - 21

SP - 154

EP - 165

JO - Nature Reviews Endocrinology

JF - Nature Reviews Endocrinology

ER -

Looking back at the TEDDY study: lessons and future directions

Abstract

Funding

UN SDGs

Publication forum classification

ASJC Scopus subject areas

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