Type 1 diabetes (T1DM) is one of the most common and severe chronic diseases in children and is increasing in incidence. T1DM risk is modified by both genetic and environmental factors. The objective of this study is to identify environmental factors, which promote or attenuate the initiation of islet autoimmunity and progression to T1DM. Our hypothesis is that an immature gut is a primary defect in T1DM and that some environmental agents which enter the organism via the gut can modify diabetes risk. We hypothesize that dietary gluten is one of these agents, and that its presence in the immature gut can provoke inflammation and lead to islet autoimmunity in genetically susceptible individuals. Accordingly, reduction of the incidence of islet autoimmunity and T1DM could be achieved by delaying the introduction of gluten into the diet until the gut is mature. This will be investigated through an intensive prospective study from birth of offspring or siblings of patients with T1DM. Neonates will be selected for the high risk (>20%) T1DM (HLA DR3/4-DQ2/8 or DR4/4-DQ8/8) or celiac disease (DR3/3) genotypes. A total of 140 neonates will be recruited and followed with collection of 3 monthly blood and urine samples, fortnightly stool samples and life style questionnaires, and 3 day food records up to the age of 3 years. Neonates will be randomized into one of two arms with gluten introduction at 6 mo or 12 mo. Outcome markers will be the development of islet autoantibodies, TIDM and CD-associated antibodies, and antibodies to food antigens. This clinical center and study will contribute all samples, data and questionnaire material to a consortium for the identification of T1DM environmental triggers. The consortium will establish a prospectively collected bank of cell, serum, RNA, DNA, stool, and urine specimens for international collaborative studies to address this problem with sufficient statistical power. Within the consortium, we will examine gluten exposure and immune responses to foods. Ancilliary studies will be performed to determine the natural history of autoantibody responses to islet autoantigens and whether T1D-associated autoimmunity is preceded by more wide-spread immune irregularities. If successful this consortium will identify environmental factors, which can be manipulated in order to reduce T1DM incidence.
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