The goal of this proposal is to investigate the natural history of autoimmunity to pancreatic beta-cells that precedes, by years, the development of insulin-dependent diabetes mellitus (IDDM). It is hypothesized that this process is initiated by an environmental agent(s) before the age of 6 years. We postulate that beta-cell autoimmunity is relatively frequent in early childhood and that it remits in 10-25% of the cases. This study is designed to: 1) identify and prospectively follow a cohort of children aged 0-6 years, who are at a 12-40 times increased life-time risk of IDDM compared to the general population, including an estimated 166 siblings and 169 offspring of persons with IDDM in Colorado; and 200 infants with the HLA-DR3/4 phenotype and no family history of IDDM; 2) determine, in this cohort, the age-specific incidence of beta-cell autoimmunity and the sequence of autoantibodies development; 3) evaluate, in a nested case-control substudy (60 cases and 180 controls), whether a picornavirus or a cow's milk protein triggers beta- cell autoimmunity; and The participants will be recruited from an estimated 980 families with a diabetic sibling or parent and a non-diabetic child aged 0-6 years, identified mainly from the databases of the Colorado IDDM Registry. Conservatively, a 50% participation rate is assumed for those living close to Denver, though a pilot study suggested a 95% participation rate. In addition, cord blood samples from 10,000 infants born to members of The Kaiser Permanente HMO in Denver will be screened for the HLA-DR3/4 marker. A pilot study indicated that approximately 200 of the expected 560 families with HLA-DR3/4 infants (36%) will participate. The primary endpoint of this study is development of humoral autoimmunity as defined by the presence of one or more of the following autoantibodies: to cytoplasmic islet antigen (ICA), to insulin (IAA), to the GAD65 antigen and to the ICA69 islet antigen. Based on preliminary studies in Denver and Boston, 61-83 endpoints are expected. The detectable relative risk for the candidate environmental exposures is 2.3-2.7, and these exposures will be measured directly. T-cells and DNA samples will be obtained for future studies of beta-cell specific cellular autoimmunity and of its non-HLA genetic determinants. This proposed study will provide important new information urgently needed for optimal planning of primary or secondary interventions to prevent IDDM.