JUVENILE DIABETES MELLITUS: EPIDEMIOLOGY AND ETIOLOGY

描述(由申请人提供)：拟议的流行病学研究是基于我们过去28年在发展独特人群和我们储存的血清和淋巴细胞库方面的成就。这些资源将用于寻找启动β细胞破坏或引发临床糖尿病的环境诱因。我们将使用尖端的T淋巴细胞技术，以确定可能是自身免疫的病毒沉淀物，以及可能加速糖尿病前期向临床疾病转化的因素。我们将寻求区分那些携带高危HLA等位基因的人，这些人进展迅速，导致胰岛素产生的β细胞完全破坏，与那些有无痛苦的自身免疫过程或患有临床糖尿病的人区分开来，这些人通常没有多种自身抗体。要检验的假设是：1)典型的T细胞V2偏向与肠道病毒感染和糖尿病前期的自身免疫进展有关。2)T细胞自身免疫是由环境因素引起的，并先于自身抗体的出现。不断增加的T细胞反应和自身抗体是进行性糖尿病前期的标志。3)胰岛素抵抗和/或肥胖是缓慢进行性自身免疫受试者的糖尿病加速剂。4)与进展较快的一级亲属相比，肥胖者和慢进者的T、B细胞抗原扩散较少，胰岛素抵抗较多，进展定义为抗原扩散和临床糖尿病。从4年前开始的这些研究策略中获得的数据将提供关于T1D环境致病机制的数据，识别最初的自身免疫异常，并深入了解高危一级T1D亲属进展到多种抗体阳性的不同原因。这些将有助于在未来的研究中设计干预策略。这项研究还将为T淋巴细胞特性的其他潜在亚研究奠定基础，这些T淋巴细胞特性在非常小的T1D儿童和年长的T1D儿童中是不同的，允许进一步研究与这些T细胞反应相关的新的遗传标记和新的自身抗体标记。公共卫生相关性：人类和动物研究表明，针对制造胰岛素的胰岛细胞的自身抗体的产生是临床上明显的1型糖尿病的前奏，但在破坏这些胰岛细胞方面是相对较晚的事件。这种破坏是由血液中的白细胞(T细胞)介导的，我们已经证明，这些T细胞可以在人类血液中检测到。这些白血球的出现很可能标志着启动破坏性过程的环境触发因素。我们的研究旨在找出这种触发因素是否可能是病毒感染，以及肥胖症的流行是否会引发或加速某些人的胰岛细胞破坏。

DESCRIPTION (provided by applicant): The proposed epidemiologic research is based on our prior 28-year achievements in the development of unique populations and our stored serum and lymphocyte libraries. These resources will be used to search for environmental triggers that initiate beta cell destruction or precipitate clinical diabetes. We will use cutting edge T lymphocyte technology in order to identify presumably viral precipitators of autoimmunity and factors that may accelerate the prediabetes process to clinical disease. We will seek to differentiate those with high-risk HLA alleles who progress rapidly to total destruction of insulin producing beta cells, from those who have an indolent autoimmune course or present with clinical diabetes without the usual multiple autoantibodies. The hypotheses to be tested are: 1) a typical T-cell V2 bias is associated with enteroviral infection and with the autoimmune progression of prediabetes. 2) T-cell autoimmunity is precipitated by environmental triggers and precedes the appearance of autoantibodies. Increasing numbers of T-cell responses and autoantibodies are markers of progressive prediabetes. 3) Insulin resistance and / or obesity are diabetes accelerators in subjects with slowly progressive autoimmunity. 4) There are less T- and B-cell antigen spreading and more insulin resistance in obese and slowly progressive compared to rapidly progressing first degree relatives, with progression defined as antigen spreading and clinical diabetes.. Data derived from these research strategies, initiated 4 years ago, will give data regarding the environmental pathogenesis of T1D and identify the initial autoimmune abnormalities and insight into the reasons for variations of rates of progression to multiple antibody positivity in high-risk first-degree T1D relatives. These will assist in the design of intervention strategies in future studies. This research will also form the basis for other potential substudies of the T lymphocyte characteristics that are different in very young and older T1D children, allow further investigation of new genetic marke associated with these T cell responses and new autoantibody markers . PUBLIC HEALTH RELEVANCE: Human and animal research has demonstrated that the development of autoantibodies directed against the islet cells that make insulin is a prelude of clinically overt type 1 diabetes mellitus, but is a relatively late event in the destruction of these islet cells. This destruction is mediated by the white cells of the blood (T-cells) and we have shown that these T-cells can be measured in human blood. It is likely that the appearance of these white cells will mark the environmental trigger which initiates of the destructive process. Our research is directed at finding out whether this trigger could be viral infection and whether the epidemic of obesity might initiate or accelerate islet cell destruction in some individuals.