JUVENILE DIABETES MELLITUS: EPIDEMIOLOGY AND ETIOLOGY

青少年糖尿病：流行病学和病因学

• 批准号: 8034945
• 负责人: DOROTHY J BECKER
• 金额: $ 15.15万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034945
• 关键词: Acceleration; Achievement; Alleles; Animal Experimentation; Antibodies; Antigens; Appearance; Applications Grants; Autoantibodies; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Lymphocytes; Beta Cell; Biological Assay; Blood; Blood specimen; Cells; Characteristics; Child; Clinical; Control Groups; County; Data; Development; Diabetes Mellitus; Disease; Early Diagnosis; Epidemic; Epidemiologic Studies; Epidemiology; Etiology; Evaluation; Event; First Degree Relative; Frequencies; Funding; Future; Genetic; Genetic Risk; Genomics; Genotype; Growth; Human; Immune response; Immunity; Incidence; Individual; Indolent; Infection; Insulin; Insulin Resistance; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Islet Cell; Leukocytes; Libraries; Longevity; Longitudinal Studies; Lymphocyte; Measures; Mediating; Modeling; Monitor; Natural History; Obesity; Pathogenesis; Patients; Pediatric Hospitals; Population; Precipitating Factors; Prediabetes syndrome; Process; Prospective Studies; Public Health; Registries; Relative (related person); Research; Resources; Risk Factors; Role; Sampling; Screening procedure; Serological; Serum; Signal Transduction; Staging; Surrogate Markers; T cell response; T-Lymphocyte; Technology; Testing; Text; Time; Variant; Viral; Virus Diseases; base; clinically significant; cohort; design; endocrine pancreas development; environmental agent; high risk; human leukocyte antigen gene; innovation; insight; insulin dependent diabetes mellitus onset; islet; macrovascular disease; non-diabetic; population based; proband; public health relevance; response; tool

DESCRIPTION (provided by applicant): 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 V2 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 marke associated with these T cell responses and new autoantibody markers . PUBLIC HEALTH RELEVANCE: Human and animal research has demonstrated that the development of autoantibodies directed against the islet cells that make insulin is a prelude of clinically overt type 1 diabetes mellitus, but is a relatively late event in the destruction of these islet cells. This destruction is mediated by the white cells of the blood (T-cells) and we have shown that these T-cells can be measured in human blood. It is likely that the appearance of these white cells will mark the environmental trigger which initiates of the destructive process. Our research is directed at finding out whether this trigger could be viral infection and whether the epidemic of obesity might initiate or accelerate islet cell destruction in some individuals.

描述（由申请人提供）：拟议的流行病学研究基于我们之前 28 年在独特人群开发方面取得的成就以及我们存储的血清和淋巴细胞库。这些资源将用于寻找引发β细胞破坏或诱发临床糖尿病的环境触发因素。我们将使用尖端的 T 淋巴细胞技术来识别可能的自身免疫病毒促发因素以及可能加速糖尿病前期发展为临床疾病的因素。我们将设法将那些具有高风险 HLA 等位基因且迅速进展至产生胰岛素的 β 细胞完全破坏的患者与具有惰性自身免疫病程或患有临床糖尿病而没有通常的多种自身抗体的患者区分开来。要测试的假设是：1）典型的 T 细胞 V2 偏向与肠道病毒感染和糖尿病前期的自身免疫进展相关。 2) T细胞自身免疫是由环境触发因素引发的，并且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行性糖尿病前期的标志。 3) 胰岛素抵抗和/或肥胖是患有缓慢进行性自身免疫的受试者的糖尿病加速因素。 4) 与快速进展的一级亲属相比，肥胖且进展缓慢的患者 T 和 B 细胞抗原扩散较少，胰岛素抵抗较多，进展定义为抗原扩散和临床糖尿病。来自这些研究策略的数据，发起 4多年前，我们将提供有关 T1D 环境发病机制的数据，并确定最初的自身免疫异常，并深入了解高危一级 T1D 亲属中多种抗体阳性进展率变化的原因。这些将有助于未来研究中干预策略的设计。这项研究还将为幼儿和年长 T1D 儿童中不同的 T 淋巴细胞特征的其他潜在亚组研究奠定基础，从而进一步研究与这些 T 细胞反应相关的新遗传标记和新的自身抗体标记。公共健康相关性：人类和动物研究表明，针对产生胰岛素的胰岛细胞产生自身抗体是临床上明显的 1 型糖尿病的前奏，但在这些胰岛细胞的破坏中却是一个相对较晚的事件。这种破坏是由血液中的白细胞（T 细胞）介导的，我们已经证明可以在人体血液中测量这些 T 细胞。这些白细胞的出现很可能标志着破坏过程的环境触发因素。我们的研究旨在查明这种触发因素是否可能是病毒感染，以及肥胖的流行是否可能引发或加速某些个体的胰岛细胞破坏。