This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypothesis: The underlying hypothesis of this trial is the concept of induction of immunologic tolerance to the insulin secreting beta cell through the presentation of the autoantigen (insulin) orally. Animal studies have suggested that tolerance is accompanied by characteristic changes in immune phenotypes;however, whether these changes are associated with tolerance induction in humans is unknown. A goal of this study therefore, will be to study immune function through studies of B and T cell phenotype and function including antigen specific responses.
Specific Aims : The primary outcome is the elapsed time from random treatment assignment to the development of diabetes among those enrolled in the primary analysis cohort consisting of subjects with insulin autoimmunity and absence of metabolic abnormalities. Criteria for diabetes onset are as defined by the American Diabetes Association (ADA) based on glucose testing, or the presence of symptoms and unequivocal hyperglycemia. The primary objective is to determine whether intervention with repeated oral administration of recombinant human insulin will prevent or delay the development of clinical Type 1 Diabetes Mellitus (T1DM) in subjects at risk for T1DM. Secondary objectives include the description of the effects of treatment with oral insulin versus placebo in other categories of subjects defined using different combinations of autoantibodies and metabolic status (the Secondary Analysis Strata) and an assessment of the consistency of treatment effect among strata. Secondary objectives also include the assessment of the effects of treatment on immunologic and metabolic markers, and the association of these markers with the risk of diabetes onset, among other possible risk factors. The operational objectives are to recruit, screen, randomize, and follow sufficient numbers of subjects to provide adequate statistical power to determine whether T1DM can be delayed through the administration of oral insulin.
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