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， 胰腺体积缩小和亚临床外分泌不足也出现在T1D诊断中。这个 这些发现在T1D发病机制中的机制、自然病史和作用尚不清楚。外分泌萎缩 甚至可能在某些受试者出现多个胰岛自身抗体(阶段1 T1D)之前，这意味着 外分泌质量和功能的临床检测可能有助于T1D的早期生物标志物。首要目标是 这一建议的目的是建立T1D前外分泌丧失的自然历史，并确定外分泌T1D- 预测性生物标志物。我们将全程检测粪便弹性蛋白酶(FE-1)，这是外分泌功能的临床标志。 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)。一项由R01资助的TrialNet(TN)受试者研究(Campbell-Thompson和Haller， 单项自身抗体阳性(AAB+)、多发性胰岛抗体阳性(AAB+) AAB+和AAB-T1D一级亲属(FDR)评估其预后价值。在此，我们建议添加 对这一互补人群血清和粪便外分泌功能标志物的评价 预测效用和确定外分泌丧失的时间(目标1B)。我们假设外分泌标记物将是 在第一阶段T1D之前减少的那些注定要进展的人，他们的下降速度可以用于 预测疾病的发生。最后，T1D患者胰腺外分泌质量和功能减少的机制 尚不清楚；主要假说包括缺乏胰岛素分泌或对外分泌组织的自身免疫导致 胰腺萎缩。这项研究的次要目标将使用来自胰腺研究网络的样本 糖尿病器官捐献者(NPOD)队列研究这些潜在机制并评估外分泌 胰腺自身抗体作为风险生物标记物(目标2)。我们假设存在外分泌自身免疫。 在多发性胰岛AAB+和临床T1D并导致外分泌质量减少和 功能。我们假设在临床T1D患者中存在胰岛素减少，并导致进一步的外分泌。 萎缩。如果我们的假设得到证实，这将代表着我们对 T1D作为一种内分泌特异性自身免疫性疾病的发病机制这项建议将促进我早期的职业生涯 目的更好地了解T1D胰腺外分泌改变的时间和作用，并将这一知识应用于 预防和干预试验。这份研究计划和职业发展计划中提出的技能 将促进临床研究人员的独立性，并包括在几个大型T1D研究中的合作 1)人类受试者研究试验设计、实施和分析方面的联合和培训2)生物标志物 评价和3)翻译科学设计与技术。合作关系融洽，优秀的导师关系， 以及培训佛罗里达大学各研究所和机构的下一代调查人员的使命 部门为事业成功提供了理想的环境。

PROJECT SUMMARY. Type 1 diabetes (T1D) is historically described as an endocrine (β-cell) specific autoimmune disease. However, reduced pancreatic size and subclinical exocrine insufficiency are also present at T1D diagnosis. The mechanisms, natural history, and role of these findings in T1D pathogenesis remains unclear. Exocrine atrophy may even precede the onset of multiple islet autoantibodies (Stage 1 T1D) in some subjects, signifying that clinical measures of exocrine mass and function could be helpful early T1D biomarkers. The primary objective of this proposal is to establish the natural history of exocrine loss in pre-T1D and to identify exocrine T1D- predictive biomarkers. We will measure fecal elastase (FE-1), a clinical marker of exocrine function, throughout the course of pre-T1D within TEDDY (The Environmental Determinants of Diabetes in the Young) subject banked samples (Aim 1A). An enrolling R01-funded study of TrialNet (TN) subjects (Campbell-Thompson and Haller, mPIs) will prospectively examine pancreas volume by MRI in single islet autoantibody positive (AAb+), multiple AAb+, and AAb- T1D first degree relatives (FDRs) to evaluate its prognostic utility. Herein we propose to add evaluation of serum and stool exocrine functional markers in this complementary population to evaluate their prognostic utility and determine timing of exocrine loss (Aim 1B). We hypothesize that exocrine markers will be reduced prior to Stage 1 T1D in those destined for progression and that their rate of decline can be used to predict disease onset. Lastly, the mechanisms underlying reduced exocrine pancreatic mass and function in T1D remain unclear; leading hypotheses include a lack of insulin secretion or autoimmunity to exocrine tissue leading to pancreas atrophy. The secondary objective of this study will use samples from the Network for Pancreatic Organ donors with Diabetes (nPOD) cohort to investigate these potential mechanisms and evaluate exocrine pancreatic autoantibodies as biomarkers of risk (Aim 2). We hypothesize that exocrine autoimmunity is present in subjects with multiple islet AAb+ and those with clinical T1D and leads to diminished exocrine mass and function. We hypothesize that insulinopenia is present in those with clinical T1D and leads to further exocrine atrophy. If our hypothesis is proven, this will represent a paradigm shift in our traditional understanding of the pathogenesis of T1D as an endocrine-specific autoimmune disease. This proposal will advance my early career goal to better understanding the timing and role of T1D exocrine pancreas changes and apply this knowledge in prevention and intervention trials. The skills set forth within this research proposal and career development plan will promote independence as a clinical investigator and include collaborations in several large T1D research consortia and training in 1) human subjects research trial design, implementation, and analysis 2) biomarker evaluation and 3) translational science design and technique. The collaborative rapport, excellent mentorship, and mission of training the next generation of investigators across University of Florida institutes and departments provides an ideal environment for career success.