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Vbeta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)胰岛素抵抗是缓慢进行性自身免疫受试者的糖尿病加速剂。4)LADA患者较快进展者T、B细胞抗原扩散较少，胰岛素抵抗较多。进展缓慢的人比进展快的人有更多的胰岛素抵抗。来自这项研究的数据将为T1D的环境致病机制提供线索，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。这项研究还将为其他潜在的T淋巴细胞特性的亚研究奠定基础，这些特性在非常小的T1D儿童和非常大的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.