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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 假设：本试验的基本假设是通过口服自身抗原（胰岛素）诱导对胰岛素分泌β细胞的免疫耐受的概念。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，本研究的目标是通过研究B和T细胞表型和功能（包括抗原特异性应答）来研究免疫功能。 具体目标：主要结局是入组主要分析队列的受试者从随机治疗分配至发生糖尿病的时间，该队列由胰岛素自身免疫和无代谢异常的受试者组成。糖尿病发作的标准由美国糖尿病协会（ADA）根据血糖检测或症状和明确的高血糖症的存在来定义。主要目的是确定重组人胰岛素重复口服给药干预是否会预防或延迟有T1 DM风险的受试者发生临床1型糖尿病（T1 DM）。次要目的包括在使用自身抗体和代谢状态的不同组合定义的其他类别受试者中描述口服胰岛素与安慰剂治疗的效果（次要分析分层），并评估分层之间治疗效果的一致性。次要目的还包括评估治疗对免疫学和代谢标志物的影响，以及这些标志物与糖尿病发作风险的相关性，以及其他可能的风险因素。操作目的是招募、筛选、随机化和随访足够数量的受试者，以提供足够的统计学把握度来确定口服胰岛素是否可以延迟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.