Preclinical Type 1 Diabetes: Natural Course and Predictive Characteristics in Siblings of Affected Children

To my family 1 ABSTRACT Type 1 diabetes (T1D) is one of the most common chronic disorders among children and adolescents. It is perceived as an immune-mediated disease with a subclinical prodromal period characterized by the selective loss of insulin-producing beta cells in the pancreatic islets in genetically susceptible subjects. The most important genes contributing to disease susceptibility are located in the HLA class II locus on the short arm of chromosome 6. This work aimed at (i) assessing whether it is clinically relevant to classify individuals with signs of beta-cell autoimmunity into various stages of preclinical T1D, (ii) evaluating the natural history of preclinical diabetes in subjects at risk, (iii) assessing whether HLA-conferred disease susceptibility modifies the risk associated with different stages of preclinical T1D, and (iv) establishing predictive models for T1D that integrate sociodemographic, genetic, immunological and metabolic markers and testing their utility for the prediction of T1D in siblings of children affected by T1D. The population, derived from the "Childhood Diabetes in Finland" Study, comprised more than 700 initially unaffected siblings of the index cases with newly diagnosed T1D. The mean age of these siblings at the initial sampling was 9.9 years (range 0.8-19.7 years). The first three objectives were addressed based on observation of the siblings for progression to overt T1D for an average of 9 years, during which time 35 of them (4.6%) presented with clinical disease. The last objective was approached through observation up to the end of 2002, i.e. for an average of 15 years. Twelve additional siblings developed clinical T1D during that time, resulting in a total number of 47 progressors (6.7%). All four diabetes-associated autoantibodies [islet cell antibodies (ICA), insulin autoantibodies (IAA) and antibodies to the 65 kD isoform of glutamic acid decarboxylasze (GADA) and to islet antigen 2 (IA-2A)] were analyzed in the initial sample taken from each sibling close to the time of diagnosis in the index case. Eighty-three autoantibody-positive siblings underwent an intravenous glucose tolerance test (IVGTT) to assess the first-phase insulin response (FPIR). In addition, a homeostasis model assessment of insulin resistance (HOMA-IR) was made based on fasting insulin and blood glucose concentrations. HLA DR and DQ typing was performed in the majority of the subjects. The siblings were divided into four categories of preclinical T1D as follows: no prediabetes (no autoantibodies), early prediabetes (one autoantibody reactivity), advanced prediabetes (two autoantibodies) and late prediabetes (at least three …