Natural History and Mechanisms of Exocrine Pancreatic Dysfunction in Pre-Type 1 Diabetes

项目摘要。 1型糖尿病（T1 D）在历史上被描述为内分泌（β细胞）特异性自身免疫性疾病。 然而，在T1 D诊断时也存在胰腺外分泌细胞质量的实质性减少，导致 胰腺器官大小减少20-50%和亚临床外分泌胰腺功能不全。机制， 自然史和胰腺外分泌减少在T1 D发病机制中的作用尚不清楚。 磁共振成像（MRI）和粪便弹性蛋白酶（FE-1）评价胰腺体积和功能 已经表明，外分泌萎缩甚至可能早于多种胰岛自身抗体（T1 D 1期）的发作。 一些受试者，这意味着这些措施可能是有用的早期T1 D生物标志物。的主要目的 这项建议是通过测量T1 D患者的FE-1来研究T1 D患者外分泌丧失的自然史。 TEDDY（年轻人糖尿病的环境决定因素）受试者库中的T1 D前病程 样品（目标1A）。我们假设FE-1水平甚至在T1 D第1阶段之前就会降低， 注定要发展T1 D，并且FE-1的下降速率可以用作疾病预测生物标志物。 FE-1将是第一个被研究的胰腺外分泌功能的标志物，以告知已经获得的大量数据 在TEDDY中收集。这将有助于今后对潜在机制进行合作研究， T1 D前胰腺功能下降的下游效应，包括与营养相关性 变化如脂溶性维生素缺乏或脂质异常以及脂质组的其他变化， 蛋白质组或微生物组。一项即将由R 01资助的TrialNet（TN）受试者研究 （Campbell-Thompson和Haller，mPI）将通过MRI和血清 在单个胰岛自身抗体阳性（AAb+）、多个AAb+和AAb-中胰腺外分泌功能的标志物 T1 D患者的一级亲属（FDR），以评估这些措施的预后效用。在此我们 我建议在本试验中增加FE-1的评价，以检查其作为疾病预测生物标志物的有效性 (Aim 1B）。最后，T1 D患者胰腺外分泌质量和功能降低的潜在机制仍然存在 不清楚先前的研究发现受试者中存在胰腺外分泌Aabs和免疫浸润 与T1 D，使自身免疫性破坏外分泌和内分泌组织的一个合理的机制，值得 进一步调查本研究的次要目的是使用来自胰腺癌网络的样本， 糖尿病器官捐献者（nPOD）队列研究外分泌自身免疫作为糖尿病的潜在机制 在T1 D中观察到的胰腺大小和功能的变化（目的2）。我们假设外分泌自身免疫 存在于具有多个胰岛AAb+但无发育异常的受试者以及具有临床T1 D的受试者中，并且 与外分泌组织病理学改变有关。如果我们发现自身免疫在胰腺癌中起作用， 在T1 D受试者中观察到的外分泌变化，这将代表我们传统理解的范式转变 T1 D作为一种内分泌特异性自身免疫性疾病的发病机制。

PROJECT SUMMARY. Type 1 diabetes (T1D) is historically described as an endocrine (β-cell) specific autoimmune disease. However, a substantial reduction in pancreatic exocrine cell mass is also present at T1D diagnosis resulting in a 20-50% reduction in pancreas organ size and subclinical exocrine pancreatic insufficiency. The mechanisms, natural history, and role of reduced exocrine pancreatic mass in T1D pathogenesis remains unclear. Evaluation of pancreatic volume and function by magnetic resonance imaging (MRI) and fecal elastase (FE-1) has shown that exocrine atrophy may even precede the onset of multiple islet autoantibodies (Stage 1 T1D) in some subjects, signifying that these measures could be helpful early T1D biomarkers. The primary objective of this proposal is to investigate the natural history of exocrine loss in T1D by measuring FE-1 throughout the course of pre-T1D within TEDDY (The Environmental Determinants of Diabetes in the Young) subject banked samples (Aim 1A). We hypothesize that FE-1 levels will be reduced even prior to Stage 1 T1D in those destined to develop T1D and that the rate of decline in FE-1 can be used as a disease-predictive biomarker. FE-1 will be the first studied marker of exocrine pancreatic function to inform the large body of data already collected within TEDDY. This will allow for future collaborative studies of potential mechanisms and downstream effects of a decline in pancreatic function within pre-T1D, including associations with nutritional changes such as fat-soluble vitamin deficiencies or lipid abnormalities and with other changes in the lipidome, proteome or microbiome of at-risk TEDDY subjects. An upcoming R01-funded study of TrialNet (TN) subjects (Campbell-Thompson and Haller, mPIs) will prospectively examine pancreas volume by MRI and serum markers of pancreatic exocrine function in single islet autoantibody positive (AAb+), multiple AAb+, and AAb- first degree relatives (FDRs) of T1D patients to evaluate the prognostic utility of these measures. Herein we propose to add evaluation of FE-1 to this trial in order to examine its efficacy as a disease predictive biomarker (Aim 1B). Lastly, the mechanisms underlying reduced exocrine pancreatic mass and function in T1D remain unclear. Previous studies have found exocrine pancreas Aabs and immune infiltrates to be present in subjects with T1D, making autoimmune destruction of both exocrine and endocrine tissue a plausible mechanism worth further investigation. The secondary objective of this study is to use samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) cohort to investigate exocrine autoimmunity as a potential mechanism for the changes in pancreatic size and function seen in T1D (Aim 2). We hypothesize that exocrine autoimmunity is present in subjects with multiple islet AAb+ without dysglycemia as well as those with clinical T1D and that it is associated with exocrine histopathologic changes. If we find that autoimmunity plays a role in the pancreatic exocrine changes seen within T1D subjects, this will represent a paradigm shift in our traditional understanding of the pathogenesis of T1D as an endocrine-specific autoimmune disease.