Natural course of preclinical type 1 diabetes in siblings of affected children

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Abstract
To define the dynamics of preclinical type 1 diabetes in siblings of affected children and to characterize the siblings experiencing a progressive process. From 801 families taking part in the "Childhood Diabetes in Finland" (DiMe) Study, 715 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case, while another classification system covering 641 of the siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to intravenous glucose. Based on the first classification, there was a total of 95 siblings with initial signs of prediabetes, out of whom 34 (36%) progressed, 26 (27%) remained stable and 35 (37%) regressed during prospective observation for a median of 3.6 y (range 0.01-9.8 y). The siblings who progressed were younger, had a higher initial number of detectable autoantibodies, higher initial levels of various antibodies, with the exception of insulin autoantibodies, lower FPIR and a retarded glucose elimination rate in the first intravenous glucose tolerance test as compared with those that regressed. According to the second classification there were 41 siblings with initial signs of prediabetes, among whom 23 (56%) progressed, 14 (34%) remained stable and 4 (10%) regressed during the observation period. These data show that almost half of the siblings with signs of prediabetes at the time of diagnosis of the index case progressed further in their preclinical disease process during prospective observation. Young age, a strong humoral immune response to beta-cell antigens and reduced insulin secretory capacity appeared to be characteristic of those with a progressive process. Advanced and late prediabetes seem to represent a point of no return, as regression from these stages to no prediabetes was extremely rare.

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