Zonulin and cytokines as markers of autoimmunity in Type 1 diabetes

描述（由申请人提供）：长期目标是研究谷蛋白摄入、链蛋白依赖性肠通透性持续增加与1型糖尿病发病之间的可能联系，以制定治疗该疾病的策略，并最终制定预防方法。几项研究表明，由连蛋白介导的肠紧密连接改变引起的肠通透性增加可能参与包括1型糖尿病在内的自身免疫性疾病的发病机制。麸质被认为是1型糖尿病发病机制中可能的环境触发因素之一。我们已经开发了一种新的机制的方法，基于识别的患者改变zonulin系统，以评估的作用，麸质在自身免疫性破坏胰腺β细胞。本提案的主要具体目的是1）评价zonulin和HLA类型作为1型糖尿病发展的标志物，2）评价无麸质饮食（GFD）后zonulin升高和新发1型糖尿病儿童的外周血单核细胞（PBMC）细胞因子表达。目前正在评估这种饮食干预对新诊断为1型糖尿病的儿童胰腺β细胞群的保护作用。这种策略，如果被证明是成功的，可以防止胰腺β细胞的进一步损失。第一个目标是通过测定在T1D发展风险儿童中连续收集的样品中的zonulin来解决的。对于第二个目标，将具有升高的zonulin的儿童随机化，15名患有新发糖尿病的儿童在对照（正常饮食）组中，15名儿童在干预（无麸质饮食）组中，并且在基线时连续评估PBMC细胞因子、胰腺β细胞储备（通过C肽刺激测试）和zonulin，然后以3个月的间隔持续一年。与公共卫生的相关性：本研究的目的是评估连蛋白作为TlD风险的标志物的作用，以及连蛋白和细胞因子作为TlD中自身免疫进展的标志物的作用。如果成功，这些标记物可用于检测有风险的患者，以制定针对性的预防策略，并评估新发糖尿病儿童干预措施的成功率。

DESCRIPTION (provided by applicant): The long-term objective is to investigate possible links between gluten ingestion, zonulin-dependent sustained increase in intestinal permeability, and the onset of Type 1 diabetes in order to develop strategies for the treatment of the disease, and eventually methods for prevention as well. Several studies suggest that an increased intestinal permeability due to alteration of intestinal tight junctions, mediated by zonulin, can be involved in the pathogenesis of autoimmune diseases, including Type 1 diabetes. Gluten has been implicated as one of the possible environmental triggers involved in type 1 diabetes pathogenesis. We have developed a novel mechanistic approach, based on identification of patients with alteration of the zonulin system, to evaluate the role of gluten in the autoimmune destruction of pancreatic beta cells. The primary specific aims of this proposal are to 1) evaluate zonulin and HLA type as a marker for the development of Type 1 diabetes, and 2) evaluate peripheral blood mononuclear cell (PBMC) cytokine expression in children with elevated zonulin and new onset Type 1 diabetes following a gluten-free diet (GFD). This diet intervention is being evaluated for its effect on the preservation of pancreatic beta-cell mass in children newly diagnosed with Type 1 diabetes. This strategy, if proven successful could preventing further loss of pancreatic beta cells. The first aim is addressed by assaying zonulin in samples collected serially in children at risk for the development of T1D. For the second aim, children with elevated zonulin will be randomized, 15 children with new onset diabetes in the control (normal diet) group, 15 children in the intervention (gluten-free diet) group, and evaluated serially for PBMC cytokines, pancreatic beta-cell reserve (by C-peptide stimulation testing) and zonulin at baseline, and then at 3 month intervals for one year. Relevance to public health: The goal of this study is to evaluate the role of zonulin as a marker for T1D risk, and the role of zonulin and cytokines as a marker for autoimmune progression in T1 D. If successful, these markers could be used for detecting at risk patients for targeting prevention strategies, and also in evaluating the success of interventions for children with new onset diabetes.