ESPE Yearbook of Paediatric Endocrinology

Diabetes Care. 2024;47(8):1424-31. PMID: 38861550

Brief summary: This study evaluated the risk of progression to stage 3 T1D (clinically manifested) using a novel similarity algorithm and data from 1,845 children (from 5 prospective longitudinal cohorts) at genetic risk for type 1 diabetes (T1D) who developed at least one islet autoantibody (IAb). Persistent positivity for 3 IAbs during a 5-year period emerged as the highest risk for developing diabetes (69.9%), while the lowest risk (1.6%) was with single and transient IAb positivity.

Presymptomatic T1D is characterized by the presence of autoantibodies (IAb) against pancreatic islet beta cell antigens (1). Testing for IAbs enables the identification of individuals in the early-stages of T1D who have a variable risk of progressing to clinical T1D (stage 3), depending on the number and type of Iab, as well as the individual’s age. Characterizing IAb patterns over time may aid in stratifying individuals by their risk of progression (2).

In the reported T1DI (Type 1 Diabetes Intelligence) study, genetically susceptible children were divided into 5 clusters based on age at seroconversion (appearance of IAb), order of appearance of at least one of 3 measured IAbs (insulin autoantibody [IAA], GAD antibody [GADA] or islet antigen 2 antibody [IA-2A]) and variation in positivity of IAb types, to determine which cluster carried the highest risk for progression to stage 3 T1D. The highest 5-year risk (69.9%) of progression from first positive IAb to stage 3 T1D was observed in the cluster with all 3 IAbs positivity. Lower risk were found in the cluster with persistent IAA and GADA positivity (39.1%), and with persistent GADA and IA-2A (30.9%). The lowest risk (1.6%) was associated with single and transient IAb positivity, either IAA or GADA.

This study provides important insights into the rates of progression to stage 3 T1D by defining temporal patterns of Iab, and proposing an algorithm applicable even in cohorts with different IAb sampling intervals (every 0.6-2 years). Understanding the various progression pathways can inform the design of targeted clinical trials aimed at preventing T1D. In addition, this information will be valuable for counseling individuals with IAb positivity about their risk of progression.

Strengths of this study include the large sample size (>260,000 samples) and long follow-up (median 12.3 years). However, lack of assessment of the ZnT8 antibody and the exclusion of additional informative variables in the algorithm, such as IAb titer, are potential limitations. Future studies are needed to validate these findings in other cohorts.

References: 1. Bonifacio E, Ziegler AG. Type 1 diabetes risk factors, risk prediction and presymptomatic detection: Evidence and guidance for screening. Diabetes ObesMetab. 2025 Mar 25. doi: 10.1111/dom.16354. Epub ahead of print.2. Simmons KM, Sims EK. Screening and Prevention of Type 1 Diabetes: Where Are We? J Clin Endocrinol Metab. 2023 Nov 17;108(12):3067-3079.