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Original Contribution
June 19, 2013

Seroconversion to Multiple Islet Autoantibodies and Risk of Progression to Diabetes in Children

Author Affiliations

Author Affiliations: Institute of Diabetes Research, Helmholtz Zentrum München, and Forschergruppe Diabetes, Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany (Drs Ziegler and Winkler); Barbara Davis Center for Childhood Diabetes, University of Colorado School of Medicine, Aurora (Drs Rewers, Steck, and Eisenbarth); Department of Pediatrics (Drs O. Simell, T. Simell, and Lempainen) and Immunogenetics Laboratory (Dr Lempainen and Ilonen), University of Turku, and Department of Pediatrics, Turku University Hospital (Drs O. Simell, T. Simell, and Lempainen), Turku, Finland; Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland (Dr Ilonen); Department of Pediatrics, Institute of Clinical Medicine, University of Oulu, Oulu, Finland (Dr Veijola); Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, and Department of Pediatrics, Tampere University Hospital, Tampere, Finland (Dr Knip); Center for Regenerative Therapies Dresden, and Paul Langerhans Institute Dresden, German Center for Diabetes Research, Dresden University of Technology, Dresden, Germany (Dr Bonifacio).
†Died November 13, 2012.

JAMA. 2013;309(23):2473-2479. doi:10.1001/jama.2013.6285

Importance Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain.

Objective To determine the rate of progression to diabetes after islet autoantibody seroconversion.

Design, Setting, and Participants Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes. Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818). Follow-up assessment in each study was concluded by July 2012.

Main Outcomes and Measures The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies. The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies.

Results Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years. Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09; P < .001]; 10-year risk, 74.9% [95% CI, 69.7%-80.1%]) vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]); for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68; P = .007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]); and for girls (HR, 1.28 [95% CI, 1.04-1.58; P = .02];10-year risk, 74.8% [95% CI, 68.0%-81.6%]) vs boys (65.7% [95% CI, 59.3%-72.1%]).

Conclusions and Relevance The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years. Future prevention studies should focus on this high-risk population.