JUVENILE DIABETES MELLITUS: EPIDEMIOLOGY AND ETIOLOGY

摘要 拟议的流行病学研究是基于我们先前28年的成就， 开发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 破坏或促成临床糖尿病。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剂的自身免疫和因素 这可能会加速前驱糖尿病发展为临床疾病。我们将寻求 区分那些具有高风险HLA等位基因的人，他们迅速发展到完全破坏， 产生胰岛素的β细胞，来自那些有惰性自身免疫过程的人， 临床糖尿病，无常见的多种自身抗体。的假设 需要测试的是：1）典型的T细胞V？偏倚与肠道病毒感染有关， 糖尿病前期自身免疫性疾病的进展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。增加 T细胞反应和自身抗体的数量是进行性 糖尿病前期3)胰岛素抵抗和/或肥胖是受试者的糖尿病加速器 缓慢进行性自身免疫4)T细胞和B细胞抗原的扩散 与快速进展相比， 进展性一级亲属，进展定义为抗原扩散， 临床糖尿病 从这些研究战略中获得的数据，4年前开始，将提供数据 关于T1D的环境发病机制，并确定最初的自身免疫性 异常和深入了解进展速度变化的原因， 高风险的一级T1D亲属中的多种抗体阳性。这些将有助于 在未来的研究中设计干预策略。这项研究也将成为 对于T淋巴细胞特征的其他潜在亚组研究， 非常年轻和年龄较大的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志物相关。

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 .