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: 10483133
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10483133
• 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; Persons; 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; stool sample; treatment response

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) 历来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 诊断中也存在胰腺外分泌细胞量的大幅减少，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， 自然史以及外分泌胰腺质量减少在 T1D 发病机制中的作用仍不清楚。 通过磁共振成像 (MRI) 和粪便弹性蛋白酶 (FE-1) 评估胰腺体积和功能 研究表明，外分泌萎缩甚至可能先于多种胰岛自身抗体的出现（第一阶段 T1D） 一些受试者，表明这些措施可能有助于早期 T1D 生物标志物。主要目标 该提案旨在通过在整个过程中测量 FE-1 来研究 T1D 外分泌丧失的自然史 TEDDY（青少年糖尿病的环境决定因素）主题库中的 T1D 前期课程 样品（目标 1A）。我们假设，即使在 T1D 第 1 阶段之前，这些人群中的 FE-1 水平也会降低。 注定会发展为 T1D，FE-1 的下降率可以用作疾病预测生物标志物。 FE-1 将成为第一个研究的外分泌胰腺功能标记物，为大量数据提供信息 收集在 TEDDY 中。这将有助于未来对潜在机制的合作研究 T1D 前期胰腺功能下降的下游影响，包括与营养的关系 脂溶性维生素缺乏或脂质异常等变化以及脂质组的其他变化， 高危 TEDDY 受试者的蛋白质组或微生物组。即将进行的一项由 R01 资助的 TrialNet (TN) 受试者研究 （Campbell-Thompson 和 Haller，mPI）将通过 MRI 和血清前瞻性检查胰腺体积 单胰岛自身抗体阳性 (AAb+)、多 AAb+ 和 AAb- 中胰腺外分泌功能的标志物 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 建议在本试验中添加 FE-1 的评估，以检查其作为疾病预测生物标志物的功效 （目标 1B）。最后，T1D 中外分泌胰腺质量和功能减少的机制仍然存在 不清楚。先前的研究发现受试者体内存在外分泌胰腺 Aab 和免疫浸润 对于 T1D，使外分泌和内分泌组织的自身免疫破坏成为一种合理的机制，值得 进一步调查。本研究的次要目标是使用胰腺网络的样本 患有糖尿病的器官捐献者 (nPOD) 队列研究外分泌自身免疫作为潜在机制 T1D 中胰腺大小和功能的变化（目标 2）。我们推测外分泌自身免疫 存在于没有血糖异常的多胰岛 AAb+ 受试者以及临床 T1D 受试者中，并且 与外分泌的组织病理学变化有关。如果我们发现自身免疫在胰腺中发挥作用 T1D 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 T1D 作为一种内分泌特异性自身免疫性疾病的发病机制。