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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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In the citing paper
“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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In the citing paper
“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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Citations
Cites
Eisenbarth (1986) · doi:10.1056/nejm198605223142106 · Cited by 1,659
Self-citationEffects of insulin in relatives of patients with type 1 diabetes mellitus
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Self-citationGale, E. A. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15786-3 · Cited by 534
Rewers, M., Bugawan, T. L., Norris, J. M., Blair, A., Beaty, B., Hoffman, M., McDuffie, R. S., Hamman, R. F., Klingensmith, G., Eisenbarth, G. S., et al. (1996) · Diabetologia · doi:10.1007/s001250050514 · Cited by 422
Self-citationNäntö-Salonen, K., Kupila, A., Simell, S., Siljander, H., Salonsaari, T., Hekkala, A., Korhonen, S., Erkkola, R., Sipilä, J. I., Haavisto, L., et al. (2008) · The Lancet · doi:10.1016/s0140-6736(08)61309-4 · Cited by 382
Self-citationQuantification of islet-cell antibodies and prediction of insulin-dependent diabetes
Bonifacio, E. E., Shattock, M., Dean, B. M., Bottazzo, G. F., Bingley, P. J., Gale, E., & Dunger, D. B. (1990) · The Lancet · doi:10.1016/0140-6736(90)90013-u · Cited by 344
Self-citationStratification of Type 1 Diabetes Risk on the Basis of Islet Autoantibody Characteristics
Achenbach, P., Warncke, K., Reiter, J., Naserke, H. E., Williams, A. J. K., Bingley, P. J., Bonifacio, E. E., & Ziegler, A. (2004) · Diabetes · doi:10.2337/diabetes.53.2.384 · Cited by 276
Self-citationOrban, T., Sosenko, J. M., Cuthbertson, D., Krischer, J. P., Skyler, J. S., Jackson, R., Yu, L., Palmer, J. P., Schatz, D., Eisenbarth, G., et al. (2009) · Diabetes Care · doi:10.2337/dc09-0934 · Cited by 260
Self-citationPREDICTING INSULIN-DEPENDENT DIABETES
Tarn, A., Dean, B., Schwarz, G., Thomas, J. M., Ingram, D., Bottazzo, G. F., & Gale, E. M. (1988) · The Lancet · doi:10.1016/s0140-6736(88)91601-7 · Cited by 260
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Flarup, P. B., Grabowski, D., DeCosta, P., Antvorskov, J. C., Pociot, F., & Jespersen, L. N. (2026) · Frontiers in Clinical Diabetes and Healthcare · doi:10.3389/fcdhc.2026.1796164 · Cited by 1
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
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