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

项目总结。 1型糖尿病(T1D)历史上被描述为一种内分泌(β细胞)特异性自身免疫性疾病。 然而，在T1D诊断时，胰腺外分泌细胞团也显著减少，从而导致 减少20-50%的胰腺器官大小和亚临床胰腺外分泌功能不全。这些机制， T1D的自然病史和胰腺外分泌肿块减少在T1D发病中的作用尚不清楚。 磁共振成像(MRI)和粪便弹性蛋白酶(FE-1)对胰腺体积和功能的评价 已经表明，外分泌萎缩甚至可能先于多发性胰岛自身抗体的发病(阶段1 T1D)。 一些受试者，意味着这些措施可能有助于早期T1D生物标志物。的主要目标是 这项建议是通过测量全程FE-1来调查T1D外分泌损失的自然历史。 Teddy(青少年糖尿病的环境决定因素)受试者的T1D前病程 样本(目标1A)。我们假设这些患者的FE-1水平甚至在第一阶段T1D之前就会降低 而FE-1的下降速度可以作为疾病预测的生物标记物。 Fe-1将是第一个研究胰腺外分泌功能的标记物，已经告知了大量数据 在泰迪体内收集的。这将使今后能够合作研究潜在的机制和 T1D前胰腺功能下降的下游影响，包括与营养相关 脂溶维生素缺乏或脂质异常等变化，以及脂类的其他变化， 高危Teddy受试者的蛋白质组或微生物组。即将由R01资助的TrialNet(TN)受试者研究 (Campbell-Thompson and Haller，MPIs)将通过MRI和血清前瞻性地检查胰腺体积 单项胰岛自身抗体阳性(AAB+)、多项AAB+和AAB- T1D患者的一级亲属(FDR)来评估这些措施的预后效用。在此，我们 建议在这项试验中增加FE-1的评估，以检验其作为疾病预测生物标志物的有效性 (目标1B)。最后，T1D患者胰腺外分泌质量和功能减少的机制仍然存在。 不清楚。以前的研究发现受试者存在胰腺外分泌AABS和免疫浸润物 对于T1D，使自身免疫破坏外分泌和内分泌组织成为一种看似合理的机制 进一步调查。这项研究的次要目标是使用来自网络的样本来检测胰腺 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 T1D中胰腺大小和功能的变化(目标2)。我们假设外分泌自身免疫 存在于多个无血糖紊乱的胰岛AAB+的受试者以及临床T1D的受试者中，并且它 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中起作用 在T1D受试者体内看到的外分泌变化，这将代表我们传统理解的范式转变 T1D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.