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24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vβ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)胰岛素抵抗是缓慢进行性自身免疫患者的糖尿病加速器。4)与快速进展患者相比，lada患者的T细胞和b细胞抗原扩散更少，胰岛素抵抗更多。缓慢进展者比快速进展者有更多的胰岛素抵抗。本研究获得的数据将为T1D的环境发病机制提供线索，并确定高危一级亲属的初始自身免疫异常。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，这些研究在非常年幼和年长的T1D儿童中是不同的。

DESCRIPTION (provided by applicant): The proposed epidemiologic research is based on our prior 24-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 Vbeta 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 is a diabetes accelerator in subjects with slowly progressive autoimmunity. 4) There are less T- and B-cell antigen spreading and more insulin resistance in LADAs compared to rapid progressors. Slow progressors have more insulin resistance than rapid progressors. Data derived from this research will give clues regarding the environmental pathogenesis of T1D and identify the initial autoimmune abnormalities in high-risk first-degree 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.