JUVENILE DIABETES MELLITUS: EPIDEMIOLOGY AND ETIOLOGY

青少年糖尿病：流行病学和病因学

基本信息

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
项目类别：
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

项目摘要

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在独特人群的发展以及我们储存的血清和淋巴细胞库中的28年成就。这些资源将用于寻找启动β细胞破坏或沉淀临床糖尿病的环境触发因素。我们将使用尖端T淋巴细胞技术，以确定自身免疫性的病毒性沉淀剂和可能加速糖尿病前期过程的因素。我们将寻求区分那些迅速发展为胰岛素产生β细胞的高危HLA等位基因的人，与那些患有自身免疫性懒惰的人或患有临床糖尿病的人，而没有通常的多个自身抗体。要测试的假设是：1）典型的T细胞V2偏置与肠病毒感染以及糖尿病前期的自身免疫进展有关。 2）T细胞自身免疫由环境触发器沉淀，并在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器。 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高风险一级T1D亲戚中多种抗体阳性。这些将有助于设计未来研究的干预策略。这项研究还将构成在非常年轻和年龄较大的T1D儿童中不同的T淋巴细胞特征的其他潜在物质的基础，从而可以进一步研究与这些T细胞反应和新的自身抗体标记相关的新遗传Marke。公共卫生相关性：人类和动物的研究表明，针对胰岛细胞的自身抗体的发展是胰岛素是临床上公开的1型糖尿病的序幕，但在破坏这些胰岛细胞的情况下是相对较晚的事件。这种破坏是由血液（T细胞）的白细胞介导的，我们已经表明这些T细胞可以在人类血液中测量。这些白细胞的外观可能会标志着启动破坏性过程的环境触发因素。我们的研究旨在找出该触发因素是否可能是病毒感染，以及肥胖症的流行是否可能引发或加速某些个体的胰岛细胞破坏。