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Seroconversion to Multiple Islet Autoantibodies and Risk of Progression to Diabetes in Children
Open accessAbstract
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.
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“The presence of multiple islet autoantibodies (IAA, GADA, IA-2A/IA-2bA, or ZnT8A) is associated with a risk of type 1 diabetes of >90% (408,422,423).”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [408]
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“Most people with a single autoantibody do not progress to type 1 diabetes, but seroconversion to the presence of two or more serum autoantibodies in children is associated with an 84% risk of clinical type 1 diabetes by the age of 18 years (figure 2A).16”
From Type 1 diabetes (2018) · cites this paper as [16]
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“Because of the low prevalence of type 1 diabetes (approximately 0.3% in the general population), the positive predictive value of a single islet autoantibody is low (408).”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [408]
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“Most individuals without diabetes who have only one autoantibody will not develop type 1 diabetes, as the 10-year risk is about 15% (408).”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [408]
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“It is clear from prospective studies that the persistent presence of two or more islet autoantibodies is a nearcertain predictor of clinical diabetes (42).”
From 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2024 (2024) · cites this paper as [42]
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“Of the 585 children who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (42).”
From 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes—2024 (2024) · cites this paper as [42]
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“It is clear from prospective studies that the persistent presence of two or more islet autoantibodies is a near-certain predictor of clinical diabetes (40).”
From 2. Diagnosis and classification of diabetes: standards of care in diabetes-2025 (2025) · cites this paper as [40]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Of the 585 children who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (40).”
From 2. Diagnosis and classification of diabetes: standards of care in diabetes-2025 (2025) · cites this paper as [40]
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“A seminal analysis of four different birth cohorts from the USA, Finland and Germany demonstrated that the presence of a single islet autoantibody is associated with a 13% risk of developing type 1 diabetes over 15 years. In contrast, having two or more antibodies is associated with a 70% risk over 10 years of observation and an 84% risk over 15 years63.”
From 100 years of insulin: celebrating the past, present and future of diabetes therapy (2021) · cites this paper as [63]
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“However, studies of the offspring of people with diabetes show that young children with multiple autoantibodies develop diabetes during childhood [ 12 ]”
From Islet autoantibody profiles associated with higher diabetes risk in Lithuanian compared with English schoolchildren (2020) · cites this paper as [12]
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“In children with only one persistent islet autoantibody, the risk of diabetes within 10 years is 15% while two or more islet autoantibodies predict type 1 diabetes in 70% within 10 years (408,409).”
From Guidelines and Recommendations for Laboratory Analysis in the Diagnosis and Management of Diabetes Mellitus (2023) · cites this paper as [408]
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Metadata
- Authors
- Ziegler, A. G., Rewers, M., Simell, O., Simell, T., Lempainen, J., Steck, A., Winkler, C., Ilonen, J., Veijola, R., Knip, M., Bonifacio, E., & Eisenbarth, G. S.
- Affiliations
- TUM Klinikum (DE)
- University of Helsinki (FI)
- ORCID
- Venue
- JAMA
- Publisher
- American Medical Association (AMA)
- Published
- 2013-06-19
- Volume
- 309
- Issue
- 23
- Pages
- 2473
- ISSN
- 0002-9955 (ISSN-L)
- 0098-7484
- PMC
- PMC4878912
- OpenAlex
- W2095256598
- Semantic Scholar
- 5a7a8cb24a1d4a727e23b19c717a8328b3ce09d6
- Cited by
- 1,312
- References
- 29
- Citations by year
- 2026: 118 · 2025: 133 · 2024: 103 · 2023: 124 · 2022: 107 · 2021: 127 · 2020: 83 · 2019: 92 · 2018: 92 · 2017: 86 · 2016: 89 · 2015: 83 · 2014: 55 · 2013: 18
- FWCI
- 54.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- JAMA (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- mediaTUM (Technical University of Munich) (submittedVersion)
- Site cant be reached (submittedVersion)
- Funders
- Juvenile Diabetes Research Foundation International (4‐1999‐731, 4‐2001‐435)
- Deutsche Forschungsgemeinschaft (/14-2, /14-1)
- Bundesministerium für Bildung und Forschung
- Novo Nordisk
- Lastentautien Tutkimussäätiö
- National Institutes of Health (DK32493)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK32493, R01DK032493, U01DK063821)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- type 1 diabetes, islet autoantibodies, seroconversion, multiple autoantibodies, progression to diabetes, insulin autoantibodies, GAD65 antibodies, IA-2 autoantibodies, preclinical diabetes, risk prediction, age at seroconversion, islet transplantation
- MeSH terms
- Adolescent, Autoantibodies, Child, Child, Preschool, Colorado, Diabetes Mellitus, Type 1, Female, Finland, Follow-Up Studies, Genotype, Germany, Glutamate Decarboxylase, Humans, Infant, Insulin, Islets of Langerhans, Male, Prospective Studies, Risk, Disease Progression, Genetic Predisposition to Disease, Receptor-Like Protein Tyrosine Phosphatases, Class 8
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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