Autoantibodies to IA-2β improve diabetes risk assessment in high-risk relatives

Aims/hypothesis: The aim of this study was to evaluate the prognostic significance of autoantibodies to IA-2β (IA2βA) in a large, well-characterised population of islet cell antibody (ICA)-positive relatives followed for 5 years in the European Nicotinamide Diabetes Intervention Trial. Methods: Autoantibodies to insulin (IAA), glutamate decarboxylase (GADA) and IA-2 (IA2A) were measured in 549 participants at study entry, and IA2A-positive samples tested for IA2βA. First-phase insulin response (FPIR) and oral glucose tolerance were determined at baseline. Results: Of 212 ICA/IA2A-positive participants (median age 12.1 years; 57% male), 113 developed diabetes (5 year cumulative risk 56%), and 148 were also GADA-positive and IAA-positive (4Ab-positive). IA2βA were detected in 137 (65%) ICA/IA2A-positive participants and were associated with an increased 5 year diabetes risk (IA2βA-positive 65 vs 39% in IA2βA-negative, p=0.0002). The effect was most marked in 4Ab-positive relatives (72% vs 52%, p =0.003). Metabolic testing further refined risk assessment. Among 101 4Ab-positive relatives with IA2βA, the 5 year risk was 94% in those with a low FPIR (vs 50% in those with a normal FPIR, p<0.0001), and 95% in those with impaired glucose tolerance (IGT) (vs 66% in those with normal glucose tolerance, p<0.0001). The median time to diagnosis of 4Ab/IA2βA-positive participants with a low FPIR was 1.5 years. Multivariate analysis confirmed IA2βA status, antibody number, young age, FPIR and IGT as independent determinants of risk. Conclusions/interpretation: IA2βA are associated with a very high risk of diabetes in ICA/IA2A-positive relatives. Testing for IA2A/IA2βA compares favourably with the IVGTT in identifying a subgroup of autoantibody-positive relatives at increased risk. IA2βA determination should be added to screening protocols of future intervention trials.