Epidemiologic patterns suggest that viruses, nutrition, toxic agents or socioeconomic psychosocial factors may contribute to the etiology alone or in combination. Elucidation is confounded by the long interval between exposure and onset of clinical disease, as well as the interaction of multiple genes and/or insults, which appear to interact in a complex manner. Numerous studies have investigated environmental influences but have yielded conflicting results. This may be in part due to the failure to account for genetic susceptibility, begin observation at early ages or in utero, and/or monitor subjects long term and frequently.

Hypotheses:

1. Initiation of persistent beta-cell autoimmunity and progression from beta-cell autoimmunity to diabetes is increased with:

   1. Exposure to a trigger factor during pregnancy, such as infections, preeclampsia, blood incompatibility, or birth weight.
   2. Differences in the timing of the introduction and/or the type of dietary constituents that include exposure to cereals or gluten, exposure to cow's milk during infancy and/or childhood, and short duration of breast- feeding;
   3. Lower intake of serum 25 hydroxyvitamin D in early infancy, vitamin E, anti-oxidants (e.g., carotenoids, ascorbic acid, selenium, or omega-3 fatty acids);
   4. Higher frequency of specific (e.g., enterovirus, rotavirus, or bacterial) infections, or non-specific childhood infections including those that exhibit molecular mimicry;
   5. Increased exposure to routine childhood immunizations and their timing;
   6. Environmental factors that may be contained in drinking water (e.g., low concentrations of zinc or high concentrations of nitrates, or lower pH levels);
   7. Exposure to household pets, and various allergies;
   8. Excessive weight gain;
   9. Increased psychological stress.
2. The risk of persistent beta-cell autoimmunity is lower in children from the general population than in offspring or siblings of T1DM patients when stratifying for the HLA DR-DQ genotype and exposure to environmental triggers.
3. The interaction of HLA DR-DQ genotype with exposure to dietary or infectious factors leads to increased incidence of beta-cell autoimmunity and T1DM.
4. We expect that in some families study participation will be associated with affective (anxiety, depression) and behavioral responses (e.g. actions to prevent possible T1DM).