TRIALNET NATURAL HISTORY STUDY OF THE DEVELOPMENT OF TYPE 1 DIABETES

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来源获得主要资金， 因此可以在其他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：1型糖尿病（T1D）是一种由胰腺细胞破坏引起的疾病。它可以发生在任何年龄，但其发病率最高的是儿童和青少年。虽然所有人都是易感的，但T1D患者的亲属患该病的风险要大得多。很明显，遗传因素导致大多数T1D病例。已发现相关的人类白细胞抗原（HLA）强烈预测T1D。然而，环境因素似乎也有助于这种疾病。这在双胞胎的研究中很明显。如果一个同卵双胞胎患有T1D，尽管另一个双胞胎显然处于高风险中，但T1D的发展远非不可避免。此外，流行病学研究表明，其他因素，如病毒感染可能参与T1D的发病机制。有充分的证据表明，细胞介导的免疫有助于T1D的发病机制。此外，大多数T1D患者至少有一种胰岛细胞抗原的自身抗体。这些自身抗体包括抗GAD 65、抗ICA512、ICA和IAA。当T1D患者的亲属产生这些自身抗体时，他们患T1D的风险更大。当细微的代谢异常明显时，风险变得更大。TrialNet T1D发展自然史研究的目标是获得有关T1D发病机制和自然史的信息，并促进招募和评估可能有资格参加T1D预防试验的个人。重要的是，从这项研究中获得的信息将有助于制定和实施预防试验。本方案中描述的T1D发展的TrialNet自然史研究的设计旨在实现这些目标。 具体目标： 1.根据口服葡萄糖耐量试验（OGTT）、C肽水平、生化自身抗体（抗GAD 65、抗ICA512和IAA）、胰岛细胞自身抗体（ICA）、细胞介导免疫标志物、静脉葡萄糖耐量试验（IVGTT）和与T1D风险相关的HLA遗传标志物，确定T1D发生的风险。 2.检查TrialNet风险评估程序预测未来T1D的准确性。 3.确定至少有一项生化自身抗体检测阳性的个体中糖耐量受损和ICA阳性的患病率。 4.通过连续研究生化自身抗体、ICA和细胞介导免疫的标志物来表征T1D发展中免疫异常的进展。 5.通过连续研究胰岛素、C肽和葡萄糖水平，表征T1D发展中代谢失代偿的进展，并确定与这种失代偿相关的免疫学和其他因素。 6.确定重度急性代谢失代偿的发生率，作为已确定为T1D风险增加的个体的初始临床表现。 7.确定有资格参加TrialNet T1D预防试验的个人。 8.通过分析储存的血液样本，获得与T1D发病机制相关的免疫和代谢因素的额外信息。免疫耐受网络将作为TrialNet的核心实验室，用于开发专门的免疫程序。 9.通过分析储存的血液样本，积累与T1D发生风险相关的遗传标志物的额外信息。 10.对于参与DPT-1研究的患者，检查特征（例如人口统计学、免疫学、代谢等）在DPT-1研究期间进行评估，在TrialNet中评估特征和结局。

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: Type 1 diabetes (T1D) is a disease that results from the destruction of pancreatic ¿-cells. It can occur at any age, but its incidence is highest in children and adolescents. Although all people are susceptible, relatives of individuals with T1D are at much greater risk for development of the disease. It is clear that genetic factors contribute to most cases of T1D. Associated human leukocyte antigens (HLA) have been found to be strongly predictive of T1D. However, environmental factors also appear to contribute to the disorder. This is evident in studies of twin pairs. If one identical twin has T1D, although the other twin is clearly at high risk, it is far from inevitable that T1D will develop. Also, epidemiological studies have suggested that other factors such as viral infections may be involved in the pathogenesis of T1D. There is good evidence that cell-mediated immunity contributes to the pathogenesis of T1D. In addition, most patients who develop T1D have at least one autoantibody to islet cell antigens. These autoantibodies include anti-GAD65, anti-ICA512, ICA and IAA. When relatives of T1D patients develop these autoantibodies, they are at greater risk for T1D. The risk becomes even greater when subtle metabolic abnormalities are evident. The goals of the TrialNet Natural History Study of the Development of T1D are to both gain information about the pathogenesis and natural history of T1D and to facilitate the recruitment and assessment of individuals who might qualify for T1D prevention trials. Importantly, the information obtained from this study will serve to enable the development and implementation of prevention trials. The design of the TrialNet Natural History Study of the Development of T1D as described in this protocol is intended to achieve these goals. Specific Aims: 1. To determine the risk for the occurrence of T1D according to oral glucose tolerance tests (OGTT), C-peptide levels, biochemical autoantibodies (anti-GAD65, anti-ICA512 and IAA), islet cell autoantibodies (ICA), markers of cell-mediated immunity, intravenous glucose tolerance tests (IVGTT), and HLA genetic markers that are associated with risk for T1D. 2. To examine the accuracy of TrialNet risk assessment procedures for predicting future T1D. 3. To determine the prevalence of impaired glucose tolerance and ICA positivity in individuals with at least one positive biochemical autoantibody test. 4. To characterize the progression of immunologic abnormalities in the development of T1D by serially studying biochemical autoantibodies, ICA, and markers of cell-mediated immunity. 5. To characterize the progression of metabolic decompensation in the development of T1D by serially studying insulin, C-peptide and glucose levels, and to identify immunologic and other factors associated with this decompensation. 6. To determine the incidence of severe acute metabolic decompensation as the initial clinical presentation in individuals who have been identified as being at increased risk for T1D. 7. To identify individuals who qualify for TrialNet prevention trials for T1D. 8. To accrue additional information about immunologic and metabolic factors related to the pathogenesis of T1D by analyzing stored blood samples. The Immune Tolerance Network will function as a core laboratory for TrialNet for the development of specialized immunologic procedures. 9. To accrue additional information about genetic markers associated with risk for the development of T1D by analyzing stored blood samples. 10. For those who participated in the DPT-1 study, to examine associations of characteristics (e.g. demographics, immunologic, metabolic, etc.) assessed during the DPT-1 study with characteristics and outcomes assessed in TrialNet.