TRIALNET SCREENING TO ASSESS RISK OF TYPE-1 DIABETES

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。1型糖尿病(T1D)是一种由胰岛β细胞破坏引起的疾病。它可以发生在任何年龄，但它的发病率最高的是儿童和青少年。虽然所有人都是易感人群，但个人的亲属患T1D的风险要大得多。很明显，遗传因素导致了大多数T1D病例。人类白细胞抗原相关抗原被发现对T1D有很强的预测作用。然而，环境因素似乎也是导致这种疾病的原因之一。尽管同卵双胞胎的T1D患者风险非常高，但许多人从未出现过这种情况。此外，一些流行病学研究表明，其他因素，如病毒感染，可能参与了T1D的发病。大多数T1D的发病机制与胰岛β细胞的免疫破坏有关。有很好的证据表明，细胞介导的免疫对此有贡献。此外，大多数患有T1D的患者至少有一种针对胰岛细胞抗原的自身抗体。这些自身抗体包括ICAS、GAD65、IAA和IA2自身抗体。与自身抗体阴性的亲属相比，患有这些自身抗体的T1D患者的亲属患T1D的风险更大，即使在非糖尿病状态下，当细微的代谢异常明显时，风险也会变得更大。最近，人们对T1D是可以预防的可能性感兴趣。对其发病机制的阐明表明，免疫环境的调节可能会扰乱疾病的进程。此外，预防试验已经变得更加可行，因为现在可以确定T1D的高危个体。糖尿病预防试验-1型(DPT-1)研究是T1D的首批大规模预防试验之一。这项试验的目的是研究小剂量静脉注射胰岛素或口服胰岛素是否可以预防T1D的发生。对T1D患者亲属进行了与T1D相关的自身抗体的筛查。然后，通过人类白细胞抗原和代谢测试对那些具有自身抗体的患者进行分期，以确定是否存在会增加T1D风险的细微异常。符合标准的个人被允许进入临床试验。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型糖尿病研究小组。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；346：1685-1691。口服胰岛素研究仍在继续。虽然令人失望的是，在非肠外胰岛素试验中没有胰岛素效应的证据，但从这项研究中学到了很多。查明了有关T1D发展的自然历史的许多信息。重要的是，DPT-1的发现证实，根据自身抗体和人类白细胞抗原检测以及代谢分期，可以准确预测T1D的发生。由于对预防T1D的持续关注，NIDDK已经向14个中心提供了资金，以建立一个由研究人员组成的联盟(TrialNet)来开发和执行预防试验。其理由是，该领域的这一专家组将促进此类研究的实施。除了对T1D高危人群进行研究外，TrialNet还将对新发糖尿病患者进行研究。这些研究将研究防止这些患者进一步代谢恶化的策略。研究高危个体的TrialNet筛查程序将仿效DPT-1的筛查程序。DPT-1参与者的累积需要一个大规模的计划来筛查T1D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、附属网站和卫星网站组成的网络。超过10万名亲属收集了筛查样本。这些网站中的大多数将参加TrialNet的筛选。目前正在进行具体的预防研究。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。筛查自身抗体呈阳性的个人将被允许参加自然历史研究，如果他们还没有预防试验的话。这里描述的筛查计划代表了实施T1D TrialNet预防研究过程的第一步。

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; 346:1685-1691.) 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.