JUVENILE DIABETES MELLITUS: EPIDEMIOLOGY AND ETIOLOGY

摘要 拟议的流行病学研究是基于我们过去28年在 发展独特的人群和我们储存的血清和淋巴细胞库。 这些资源将用于搜索启动β细胞的环境触发因素 破坏或诱发临床糖尿病。我们将使用尖端的T淋巴细胞 技术，以确定可能的病毒沉淀物的自身免疫和因素 这可能会加速糖尿病前期转化为临床疾病的过程。我们将寻求 鉴别那些快速进展到完全破坏人类白细胞抗原的高危等位基因 产生胰岛素的β细胞，来自那些有无痛的自身免疫过程或 临床表现为糖尿病，没有常见的多发性自身抗体。假说 需要测试的是：1)典型的T细胞V型偏爱与肠道病毒感染和 糖尿病前期的自身免疫进展。2)T细胞自身免疫沉淀 由环境触发，并先于自身抗体的出现。渐增 T细胞反应和自身抗体的数量是进行性的标志 糖尿病前期。3)胰岛素抵抗和/或肥胖是糖尿病的促进剂 患有缓慢进展的自身免疫性疾病。4)T、B细胞抗原扩散较少 肥胖和缓慢进展者的胰岛素抵抗比快速进展者更多 进展的一级亲属，进展被定义为抗原扩散和 临床糖尿病.. 从4年前开始的这些研究战略中获得的数据将提供数据 关于T1D的环境致病机制和鉴定最初的自身免疫 反常现象和对进展率变化原因的洞察 高危一级T1D亲属多种抗体阳性。这些将有助于 未来研究中干预策略的设计。这项研究也将构成基础 对于T淋巴细胞特性的其他潜在的子研究， 非常小和更大的T1D儿童，允许进一步研究新的遗传标记 与这些T细胞反应和新的自身抗体标记物相关。

ABSTRACT 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 V¿ 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 markers associated with these T cell responses and new autoantibody markers .