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

By A. Ziegler, M. Rewers, O. Simell, T. Simell, J. Lempainen, A. Steck, C. Winkler, J. Ilonen, R. Veijola, M. Knip and 2 more. Journal of the American Medical Association (JAMA), 2013

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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.

Subfields: Endocrinology, Diabetes and Metabolism, Genetics, Surgery

View Paper: https://www.semanticscholar.org/paper/5a7a8cb24a1d4a727e23b19c717a8328b3ce09d6

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Citations in the corpus

Staging Presymptomatic Type 1 Diabetes: A Scientific Statement of JDRF, the Endocrine Society, and the American Diabetes Association (2015, background): “In firstdegree relatives of individuals with type 1 diabetes, IA-2 and/or ZnT8 autoantibody seroconversion is associatedwith a 5-year progression rate to diabetes of 45% (57), and the presence of either of these autoantibodies is detected in 78% of progressors to symptomatic disease (58).”
Standards of Medical Care in Diabetes—2014 (2013, background): “There is evidence to suggest that early diagnosis may limit acute complications (39) and extend long-term endogenous insulin production (41).”
Type 1 Diabetes Through the Life Span: A Position Statement of the American Diabetes Association (2014, background): “Studies evaluating children at risk for developing type 1 diabetes have shown that the presence of more than two autoantibodies was associated with a nearly 70% risk for disease development within 10 years and 84% within 15 years (19).”
The Dynamics of the Human Infant Gut Microbiome in Development and in Progression towards Type 1 Diabetes (2015, neutral): “Although the probability of progression to T1D after positivity for two islet autoantibodies is greater than 80% after follow-up for 15 years (Ziegler et al., 2013), there is significant variability in when progression occurs, ranging from weeks to more than two decades (Knip et al.”
2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2019 (2018, background): “Of the 585 children who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (34).”
2. Classification and Diagnosis of Diabetes (2014, background): “There is evidence to suggest that early diagnosis may limit acute complications (16) and extend long-term endogenous insulin production (17).”
Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis (2016, background): “The presence of two or more islet autoantibodies in children with HLA risk genotypes or with relatives who have type 1 diabetes is associated with a 75% risk of developing clinical diabetes within 10 years (105).”
2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes-2022. (2021, background): “studies that the persistent presence of two or more islet autoantibodies is a near certain predictor of clinical diabetes (14).”
2. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes—2018 (2017, background): “Of the 585 children who developed more than two autoantibodies, nearly 70% developed type 1 diabetes within 10 years and 84% within 15 years (31).”
Classification and Diagnosis of Diabetes. (2022, background): “There is evidence to suggest that early diagnosis may limit acute complications (16) and extend long-term endogenous insulin production (17).”
Development and Standardization of an Improved Type 1 Diabetes Genetic Risk Score for Use in Newborn Screening and Incident Diagnosis (2019, neutral): “years before the clinical diagnosis (2).”