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在开发独特人群方面的24年成就以及我们储存的血清和淋巴细胞库。这些资源将用于寻找引发β细胞破坏或促成临床糖尿病的环境触发因素。我们将使用最先进的T淋巴细胞技术，以确定可能的病毒沉淀剂的自身免疫和因素，可能会加速前驱糖尿病的过程中的临床疾病。我们将寻求区分那些具有高风险HLA等位基因的人，这些人迅速发展到完全破坏胰岛素产生β细胞，与那些具有惰性自身免疫过程或临床糖尿病而没有通常的多种自身抗体的人。待检验的假设是：1）典型的T细胞Vbeta偏倚与肠道病毒感染和前驱糖尿病的自身免疫进展相关。2)T细胞自身免疫是由环境触发沉淀和自身抗体的出现之前。越来越多的T细胞反应和自身抗体是进行性糖尿病前期的标志。3)胰岛素抵抗是慢性进行性自身免疫受试者的糖尿病加速器。4)与快速进展者相比，LADA中T细胞和B细胞抗原扩散较少，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。这项研究的数据将为T1D的环境发病机制提供线索，并确定高风险一级亲属中的初始自身免疫异常。这将有助于在未来的研究干预策略的设计。这项研究也将为其他潜在的T淋巴细胞特征亚组研究奠定基础，这些T淋巴细胞特征在非常年轻和年龄较大的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.