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

1 型糖尿病前期外分泌胰腺功能障碍的自然史和机制

• 批准号: 10295857
• 负责人: Brittany Bruggeman
• 金额: $ 10.68万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-07 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10295857
• 关键词: Affect; Antibodies; Atrophic; Autoantibodies; Autoimmune Diseases; Autoimmunity; Beta Cell; Biological Markers; Birth; Cells; Childhood; Clinical; Cohort Studies; Data; Development; Diabetes Mellitus; Diagnosis; Digestion; Disease; Early identification; Elastases; Endocrine; Endocrinologist; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Evaluation; Event; Exocrine pancreas; Exocrine pancreatic insufficiency; Fat-Soluble Vitamin; Fibrosis; First Degree Relative; Fluorescent Antibody Technique; Functional disorder; Funding; Future; Goals; Heterogeneity; Immune; Immune mediated destruction; Immunohistochemistry; Individual; Inflammatory Infiltrate; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention Trial; Investigation; Knowledge; Learning; Lipids; Magnetic Resonance Imaging; Measures; Mediating; Mentors; Metabolic; Natural History; Nutritional; Organ Donor; Organ Size; Pancreas; Pathogenesis; Patients; Play; Prevention strategy; Prevention trial; Proteome; Research; Research Design; Research Personnel; Research Technics; Risk; Role; Sampling; Scientist; Serum; Serum Markers; Study Subject; TimeLine; Tissues; Tumor-infiltrating immune cells; Vitamin Deficiency; autoimmune pathogenesis; career; cohort; design; diabetes pathogenesis; diabetes risk; early detection biomarkers; experience; functional loss; high risk; imaging biomarker; improved; insulin dependent diabetes mellitus onset; islet; islet cell antibody; lipidome; microbiome; novel; pre-clinical; predictive marker; prognostic value; prospective; research clinical testing; response; stool sample

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.

项目摘要。 1型糖尿病（T1D）历史上被描述为内分泌（β细胞）特定的自身免疫性疾病。 然而，T1D诊断剂也存在胰腺外分泌细胞肿块的大幅度降低，从而导致 胰腺器官大小和亚临床外分泌胰腺功能不全的降低20-50％。机制， 自然病史和降低的外分泌胰腺肿块在T1D发病机理中的作用尚不清楚。 通过磁共振成像（MRI）和粪便弹性酶（FE-1）评估胰腺体积和功能 已经表明，外分泌萎缩甚至可能先于多个胰岛自动抗体的发作（阶段1 T1D） 一些受试者表示这些措施可能是T1D早期生物标志物。主要目标 该建议是通过测量整个FE-1来调查T1D中外分泌损失的自然史 泰迪（Teddy 样品（AIM 1A）。我们假设Fe-1水平甚至在第1阶段T1D之前都会降低 注定要发展T1D，而Fe-1的下降速率可以用作疾病预测的生物标志物。 FE-1将是第一个研究二牙的胰腺功能标记，以告知大量数据 收集在泰迪。这将允许对潜在机制和 Pre-T1D内胰腺功能下降的下游效应，包括与营养的关联 诸如脂溶性维生素缺乏症或脂质异常以及脂质组的其他变化等变化， 处于危险泰迪受试者的蛋白质组或微生物组。即将进行的R01资助的试验网（TN）受试者 （MPIS Campbell-Thompson和Haller）可能会检查MRI和Serial的胰腺体积 单胰岛自身抗体阳性（AAB+），多个AAB+和AAB-中胰腺外分泌功能的标记 T1D患者的一级亲戚（FDR）评估这些措施的预后效用。在这里我们 提议将FE-1评估的提议添加到该试验中，以便研究其作为疾病预测生物标志物的有效性 （AIM 1B）。最后，减少外分泌胰腺质量和T1D功能的基础机制仍然存在 不清楚。先前的研究发现，外分泌胰腺AAB和免疫浸润存在于受试者中 使用T1D，使外分泌组织和内分泌组织的自身免疫性破坏是合理的机制 进一步调查。这项研究的次要目的是使用网络中的样品进行胰腺 具有糖尿病（NPOD）队列的器官供体研究外分泌自身免疫性作为潜在机制 T1D中看到的胰腺大小和功能的变化（AIM 2）。我们假设外分泌自身免疫性 存在于有多个胰岛糖尿病的受试者中，以及临床T1D的受试者 与外分泌组织病理学变化有关。如果我们发现自身免疫力在胰腺中起作用 在T1D主题中看到的外分泌变化，这将代表我们传统理解的范式转变 T1D作为内分泌特异性自身免疫性疾病的发病机理。