Reversion of β-Cell Autoimmunity Changes Risk of Type 1 Diabetes: TEDDY Study.
β-Cell autoantibodies are a feature of the preclinical phase of type 1 diabetes. Here, we asked how frequently they revert in a cohort of children at risk for type 1 diabetes and whether reversion has any effect on type 1 diabetes risk.



Children were up to 10 years of age and screened more than once for insulin autoantibody, GAD antibody, and insulinoma antigen-2 antibodies. Persistent autoantibody was defined as an autoantibody present on two or more consecutive visits and confirmed in two reference laboratories. Reversion was defined as two or more consecutive negative visits after persistence. Time-dependent Cox regression was used to examine how reversion modified the risk of development of multiple autoantibodies and type 1 diabetes.



Reversion was relatively frequent for autoantibodies to GAD65 (19%) and insulin (29%), but was largely restricted to children who had single autoantibodies (24%) and rare in children who had developed multiple autoantibodies (<1%). Most (85%) reversion of single autoantibodies occurred within 2 years of seroconversion. Reversion was associated with HLA genotype, age, and decreasing titer. Children who reverted from single autoantibodies to autoantibody negative had, from birth, a risk for type 1 diabetes of 0.14 per 100 person-years; children who never developed autoantibodies, 0.06 per 100 person-years; and, children who remained single-autoantibody positive, 1.8 per 100 person-years.



Type 1 diabetes risk remained high in children who had developed multiple β-cell autoantibodies even when individual autoantibodies reverted. We suggest that monitoring children with single autoantibodies for at least 1 year after seroconversion is beneficial for stratification of type 1 diabetes risk.
Health Informatics Institute, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL kendra.vehik@epi.usf.edu.
Kendra
K
Vehik
Health Informatics Institute, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL.
Kristian F
KF
Lynch
Department of Pediatrics, College of Medicine, University of Florida, Gainesville, FL.
Desmond A
DA
Schatz
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD.
Beena
B
Akolkar
Pacific Northwest Diabetes Research Institute, Seattle, WA.
William
W
Hagopian
Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO.
Marian
M
Rewers
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA.
Jin-Xiong
JX
She
Department of Pediatrics, Turku University Hospital, Turku, Finland.
Olli
O
Simell
Department of Pediatrics, Turku University Hospital, Turku, Finland.
Jorma
J
Toppari
Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V. Neuherberg, Neuherberg, Germany.
Anette-G
AG
Ziegler
Department of Clinical Sciences, Lund University/CRC, Skåne University, Malmö, Sweden.
Åke
Å
Lernmark
Center for Regenerative Therapies, University of Technology, Dresden, Germany Paul Langerhans Institute Dresden, German Center for Diabetes Research (DZD), Dresden, Germany.
Ezio
E
Bonifacio
Health Informatics Institute, Department of Pediatrics, Morsani College of Medicine, University of South Florida, Tampa, FL.
Jeffrey P
JP
Krischer
D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D005838:Genotype; D005968:Glutamate Decarboxylase / Q000276:immunology; D006801:Humans; D007328:Insulin / Q000276:immunology; D007330:Insulin Antibodies / Q000097:blood / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000276:immunology*; D008297:Male; D011446:Prospective Studies; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000276:immunology; D018570:Risk Assessment / Q000379:methods; D012307:Risk Factors; D000069078:Seroconversion
D001323:Autoantibodies; D007328:Insulin; D007330:Insulin Antibodies; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase