Indiana University (IU) Clinical Center for Chronic Pancreatitis Clinical Research Network

项目总结/摘要 慢性胰腺炎（CP）是一种进行性疾病，常导致外分泌和内分泌功能丧失 和令人虚弱的腹痛目前尚不清楚为什么有些人的进展和发展的并发症， 包括胰源性糖尿病（PDM）和/或胰腺癌（PDAC）。在这个联盟中，调查人员 建议对风险因素、环境影响和概念验证进行有力的研究 研究推动该领域的发展，特别是那些增加PDM和PDAC风险的因素。我们 提出以下具体目标（SA），以实现RFA-DK-14-027的目标。SA #1：定义自然 对确诊为CP或急性复发性胰腺炎的儿童和成人患者的病史， 提出一项前瞻性观察性队列研究。我们会着重找出风险因素， 对于那些发展PDM和/或PDAC的患者的表型。将获得生物样本， 促进可能有助于早期疾病诊断和管理的生物标志物的研究。SA #2：PDM的发病机制以及非内分泌胰腺疾病与胰岛功能障碍的相互作用 并没有得到很好的理解。我们将使用胰岛功能的测量（口服葡萄糖耐量试验，精氨酸- 增强的高血糖钳夹）的横断面和前瞻性研究，以确定患病率和 CP中代谢失调和糖尿病的生理基础。我们还将前瞻性地确定变化 在胰岛功能和向明显PDM转变中的作用，并将代谢状态的变化与 胰腺炎症和功能。SA #3：评价磁共振（MR）的诊断有效性 影像学在疑似早期CP的非侵入性评估中的应用，我们提出了一项前瞻性研究， 胰腺外分泌功能正常的对照人群。T1加权MR信号降低， 对促胰液素刺激反应的扩散减少和十二指肠液量减少可能提示CP。 SA #4：半乳糖凝集素-3（Gal-3）是一种碳水化合物结合蛋白，似乎参与纤维化， CP的组织重塑。Gal-3抑制剂似乎是安全的，并显示出减少器官纤维化的潜力。 人类为了确定Gal-3抑制剂的安全性和有效性，我们提出了一种随机安慰剂， 在66例CP患者中进行对照试验。治疗后十二指肠液碳酸氢盐水平的改善将是 主要疗效终点。我们预计这种药物将逆转纤维化，表现为改善 十二指肠碳酸氢盐水平。其他终点包括MRI/MRCP外观、Gal-3水平、生活质量， 还将评估腹痛评分和β细胞功能。

PROJECT SUMMARY / ABSTRACT Chronic pancreatitis (CP) is a progressive disease, often leading to loss of exocrine and endocrine function and debilitating abdominal pain. It is unknown why some individuals progress and develop complications, including pancreatogenic diabetes (PDM) and/or pancreas cancer (PDAC). In this consortium, investigators propose to conduct well-powered studies of risk factors, environmental influences, and proof-of-concept studies to move the field forward, particularly those factors that increase the risk of PDM and PDAC. We propose the following specific aims (SA) to meet the goals of RFA-DK-14-027. SA #1: To define the natural history of pediatric and adult patients with an established diagnosis of CP or acute recurrent pancreatitis, we propose a prospective observational cohort study. We will place emphasis on identifying risk factors and phenotypes for those patients who develop PDM and/or PDAC. Biological specimens will be obtained to facilitate the study of possible biomarkers which might facilitate early disease diagnosis and management. SA #2: The pathogenesis of PDM and the interactions of non-endocrine pancreatic disease with islet dysfunction are not well understood. We will use measurements of islet function (oral glucose tolerance tests, arginine- augmented hyperglycemic clamps) in cross-sectional and prospective studies to define the prevalence and physiologic basis for metabolic dysregulation and diabetes in CP. We will also prospectively ascertain changes in islet function and transition to overt PDM, and correlate changes in metabolic status with changes in pancreatic inflammation and function. SA #3: To evaluate the diagnostic efficacy of Magnetic Resonance (MR) imaging in the non-invasive evaluation of suspected early CP, we propose a prospective study comparing CP patients to a control population with normal pancreatic exocrine function. A reduced T1-weighted MR signal, reduced diffusion and decreased duodenal fluid volume in response to secretin stimulation may suggest CP. SA #4: Galectin-3 (Gal-3) is a carbohydrate-binding protein which appears to be involved in fibrogenesis and tissue remodeling in CP. A Gal-3 inhibitor appears to be safe and shows potential for reducing organ fibrosis in humans. To determine the safety and efficacy of a Gal-3 inhibitor, we propose a randomized placebo- controlled trial in 66 CP patients. Improvement in post-therapy duodenal fluid bicarbonate level will be the primary efficacy endpoint. We anticipate that this drug will reverse fibrosis, as manifested by improvement in duodenal bicarbonate level. Additional endpoints including MRI/MRCP appearance, Gal-3 level, quality of life, abdominal pain scores and β-cell function will also be assessed.