ORAL INSULIN FOR PREVENTION OF DIABETES IN RELATIVES AT RISK FOR TYPE 1 DIABE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 假设：本试验的基本假设是通过口服自身抗原(胰岛素)诱导对分泌胰岛素的β细胞产生免疫耐受的概念。动物研究表明，耐受性伴随着免疫表型的特征性变化；然而，这些变化是否与人类耐受性诱导有关尚不清楚。因此，这项研究的一个目标是通过研究B和T细胞的表型和功能，包括抗原特异性反应来研究免疫功能。 具体目标：主要结果是那些登记在初步分析队列中的人从随机分配治疗到发展为糖尿病所经过的时间，这些人包括患有胰岛素自身免疫且没有代谢异常的受试者。糖尿病的发病标准是由美国糖尿病协会(ADA)根据血糖测试或症状的存在和明确的高血糖来定义的。主要目的是确定反复口服重组人胰岛素的干预措施是否可以预防或延缓1型糖尿病高危人群的临床1型糖尿病(T1 DM)的发展。次要目标包括描述口服胰岛素与安慰剂在使用不同自身抗体和代谢状态组合定义的其他类别受试者中的治疗效果(二级分析层级)，以及评估不同层级之间治疗效果的一致性。次要目标还包括评估治疗对免疫和代谢标记物的影响，以及这些标记物与糖尿病发病风险的关系，以及其他可能的危险因素。操作目标是招募、筛选、随机选择和跟踪足够数量的受试者，以提供足够的统计能力来确定是否可以通过口服胰岛素来延迟T1 DM。

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.