Early seroconversion and rapidly increasing autoantibody concentrations predict prepubertal manifestation of type 1 diabetes in children at genetic risk

Abstract

Aims/hypothesis: The aim of the study was to investigate the timing of the appearance of autoantibodies associated with type 1 diabetes between birth and puberty, the natural fate of these autoantibodies and the predictive power of autoantibody concentrations for early progression to clinical diabetes.

Methods: Children were recruited to the Type 1 Diabetes Prediction and Prevention Project, an ongoing study based on HLA-conferred genetic risk. Autoantibodies against islet cells, insulin, GAD65 and islet antigen 2 were analysed at 3-12 month intervals, starting from birth.

Results: During the follow-up, 1,320 children (18.4% of the cohort of 7,165 children) were autoantibody positive in at least one sample. Altogether, 184 autoantibody-positive children progressed to type 1 diabetes. Seroconversion occurred at an early age in the progressors (median 1.5 years), among whom 118 (64%) and 150 (82%) seroconverted to autoantibody positivity before the age of 2 and 3 years, respectively. The incidence of seroconversion peaked at 1 year of age. Compared with other autoantibody-positive children, the median autoantibody levels were already markedly higher 3 to 6 months after the seroconversion in children who later progressed to diabetes.

Conclusions/interpretation: Early initiation of autoimmunity and rapid increases in autoantibody titres strongly predict progression to overt diabetes before puberty, emphasising the importance of early life events in the development of type 1 diabetes.