CLINICAL TRIAL: TRIALNET SCREENING TO ASSESS RISK OF TYPE 1 DIABETES

该子项目是利用 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。列出的机构是 中心，不一定是研究者的机构。 1型糖尿病（T1 D）是一种由胰腺β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。 虽然所有的人都是易感的，但个体的亲属患T1 D的风险要大得多。 很明显，遗传因素导致大多数T1 D病例。已发现HLA相关抗原是T1 D的强预测性。 然而，环境因素似乎也有助于这种疾病。虽然T1 D患者的同卵双胞胎风险很高，但许多人从未患上这种疾病。 此外，一些流行病学研究表明，其他因素，如病毒感染可能参与T1 D的发病机制。 据认为，大多数T1 D病例的发病机制涉及胰腺β细胞的免疫破坏。 有很好的证据表明，细胞介导的免疫有助于这一点。此外，大多数T1 D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ICA、GAD 65、IAA和IA 2自身抗体。 产生这些自身抗体的T1 D患者的亲属比自身抗体阴性的亲属患T1 D的风险更大，并且即使在非糖尿病状态下，当轻微的代谢异常明显时，风险也会更大。 最近人们对T1 D是可以预防的可能性感兴趣。 其发病机制的阐明表明，免疫环境的操作可以破坏疾病的过程。 此外，预防试验变得更加可行，因为现在可以确定T1 D高风险的个体。 1型糖尿病预防试验（DPT-1）研究是第一个大规模的T1 D预防试验之一。 本试验的目的是研究低剂量肠外胰岛素或口服胰岛素给药是否可以预防T1 D的发生。 对T1 D患者的亲属进行筛查，以确定是否存在与T1 D相关的自身抗体。 然后通过HLA和代谢测试对那些具有自身抗体的人进行分期，以确定是否存在会增加T1 D风险的细微异常。 符合标准的个体被提供进入临床试验。 风险较高的患者有资格参加肠外胰岛素研究，而风险较低的患者则有资格参加口服胰岛素研究。 肠外胰岛素试验最近完成，其结果发表在新英格兰医学杂志上。糖尿病预防试验-1型糖尿病研究组。 胰岛素对1型糖尿病患者亲属的影响。 新英格兰医学杂志2002; 346：1685-91。 口服胰岛素研究仍在继续。 虽然在肠外胰岛素试验中没有胰岛素作用的证据令人失望，但从这项研究中学到了很多东西。 关于T1 D发展的自然史的许多信息已经确定。 重要的是，DPT-1的研究结果证实，T1 D的发病率可以根据自身抗体和HLA检测以及代谢分期准确预测。 由于对预防T1 D的持续兴趣，NIDDK已向14个中心提供资金，以建立一个研究者联盟（TrialNet），以开发和执行预防试验。 其理由是，这一领域的专家组将有助于开展这类研究。 除了对T1 D高危人群进行研究外，TrialNet还将对新发糖尿病患者进行研究。 这些研究将检查预防这些患者进一步代谢恶化的策略。 高风险个体研究的TrialNet筛选过程将在DPT-1之后建模。 DPT-1参与者的增加需要一个大规模的项目来筛选T1 D患者的自身抗体阳性亲属。 这就需要在美国和加拿大建立一个由临床中心、附属机构和卫星机构组成的网络。 收集了10万多名亲属的筛查样本。 这些研究中心中的大多数将参与TrialNet筛选。 目前正在开展具体的预防研究。 然而，在此期间将需要筛查计划，以确定未来预防研究的潜在参与者。 如果尚未进行预防试验，则筛选出自身抗体阳性的个人将参加自然史研究。 本文所述的筛查计划是实施TrialNet预防T1 D研究过程中的第一步。

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. Type 1 diabetes mellitus (T1D) is a disease that results from the destruction of pancreatic beta-cells. It can occur at any age, but its incidence is highest in children and adolescents. Although all people are susceptible, relatives of individuals are at a much greater risk for T1D. It is clear that genetic factors contribute to most cases of T1D. HLA-associated antigens have been found to be strongly predictive of T1D. However, environmental factors also appear to contribute to the disorder. Although identical twins of T1D patients are at very high risk, many never develop the condition. Also, some epidemiologic studies have suggested that other factors such as viral infections may be involved in the pathogenesis of T1D. It is thought that the pathogenesis for most cases of T1D involves the immunologic destruction of pancreatic beta-cells. There is good evidence that cell-mediated immunity contributes to this. In addition, most patients who develop T1D have at least one autoantibody to islet cell antigens. These autoantibodies include ICAs, GAD65, IAA, and IA2 autoantibodies. Relatives of T1D patients who develop these autoantibodies are at greater risk for T1D than relatives negative for autoantibodies and the risk becomes greater when subtle metabolic abnormalities are evident even within the nondiabetic state. There has been recent interest in the possibility that T1D is preventable. The elucidation of the mechanisms of its pathogenesis suggests that manipulations of the immunologic milieu could disrupt the disease process. In addition, prevention trials have become more feasible because it is now possible to identify individuals who are at high risk for T1D. The Diabetes Prevention Trial-Type 1 (DPT-1) study was one of the first large-scale prevention trials of T1D. The aim of this trial was to study whether either low dose parenteral insulin or oral insulin administration would prevent the development of T1D. Relatives of patients with T1D were screened for the presence of autoantibodies associated with T1D. Those with autoantibodies were then staged through HLA and metabolic testing to determine whether subtle abnormalities were present that would increase the risk for T1D. Individuals who met criteria were offered entry in the clinical trial. Those at greater risk were eligible for enrollment in the parenteral insulin study, while those at lower risk were offered enrollment in the oral insulin study. The parenteral insulin trial was recently completed and its findings published in the New England Journal of Medicine. (Diabetes Prevention Trial - Type 1 Diabetes Study Group. Effects of Insulin in Relatives of Patients with Type 1 Diabetes Mellitus. New England Journal of Medicine 2002; 346:1685-91. The oral insulin study continues. Although it was disappointing that there was no evidence of an insulin effect in the parenteral insulin trial, a great deal was learned from this study. Much information was ascertained about the natural history of the development of T1D. Importantly, the findings from DPT-1 confirmed that the incidence of T1D could be accurately predicted on the basis of autoantibody and HLA testing and metabolic staging. Because of the continuing interest in the prevention of T1D, the NIDDK has provided funding to 14 centers to build a consortium (TrialNet) of investigators to develop and perform prevention trials. The rationale was that this group of experts in the field would facilitate the implementation of such studies. In addition to performing studies of individuals at high risk for T1D, TrialNet will also perform studies of individuals with new-onset diabetes. These studies will examine strategies for the prevention of further metabolic deterioration in those patients. The TrialNet screening process for studies of high risk individuals will be modeled after that for DPT-1. The accrual of participants for DPT-1 required a massive program to screen for autoantibody positive relatives of patients with T1D. This necessitated the development of a network of Clinical Centers, Affiliate Sites and Satellite Sites throughout the United States and Canada. Over 100,000 relatives had screening samples collected. Most of these sites will participate in TrialNet screening. The specific prevention studies are currently being developed. However, the screening program will be needed in the interim to identify potential participants for future prevention studies. Individuals who screen positive for autoantibodies will be offered participation in a Natural History Study if a prevention trial is not yet available to them. The screening program described herein represents the first step in the process of implementing the TrialNet prevention studies for T1D.