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细胞破坏或沉淀临床糖尿病的环境触发因素。我们将使用尖端的T淋巴细胞技术，以确定可能的自身免疫的病毒沉淀因子和可能加速糖尿病前期发展为临床疾病的因素。我们将寻求区分那些具有高风险HLA等位基因的患者，这些患者进展迅速，产生胰岛素的β细胞被完全破坏，而那些自身免疫过程缓慢或临床糖尿病患者没有常见的多种自身抗体。需要验证的假设是：1)典型的t细胞V2偏倚与肠病毒感染和前驱糖尿病的自身免疫进展有关。2) t细胞自身免疫是由环境触发沉淀的，先于自身抗体的出现。t细胞反应和自身抗体数量的增加是进展性前驱糖尿病的标志。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因子。4)与快速进展的一级亲属相比，缓慢进展的肥胖患者T细胞和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。从这些4年前开始的研究策略中获得的数据将提供有关T1D的环境发病机制的数据，并确定初始自身免疫异常，并深入了解高危一级T1D亲属中多种抗体阳性进展率变化的原因。这些将有助于在未来的研究中设计干预策略。这项研究也将为其他潜在的T淋巴细胞特征的亚研究奠定基础，这些T淋巴细胞特征在非常年幼和年长的T1D儿童中是不同的，允许进一步研究与这些T细胞反应和新的自身抗体标记相关的新遗传市场。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发展是临床上显性1型糖尿病的前奏，但在这些胰岛细胞的破坏中是相对较晚的事件。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细胞可以在人体血液中测量到。这些白细胞的出现很可能标志着环境触发了破坏性过程的启动。我们的研究是为了找出这个触发因素是否可能是病毒感染，以及肥胖的流行是否会启动或加速某些个体的胰岛细胞破坏。

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.