Evaluation of the entero-insular (incretin) axis in cystic fibrosis-competitive renewal.

项目总结 囊性纤维化相关糖尿病(CFRD)不仅给患者带来了第二个负担，而且需要注意 疾病，但威胁营养状况、肺功能和生存。制定保存β的策略- 细胞功能对于阻断CFRD的发展及其对CF相关结局的危害至关重要。整体而言 这项应用的目的是更好地了解糖耐量异常的发生和发展 在胰腺功能不足的CF(PI-CF)中，并测试恢复β细胞功能的潜在策略。此应用程序 扩展我们最近的研究表明：1)胰岛素分泌缺陷存在于血糖阈值 传统上被认为是正常的(一小时口服葡萄糖耐量试验[OGTT]葡萄糖&gt；155但；200 mg/dL； 称为早期糖耐量异常[EGI])，2)这种微妙的血糖异常与 CFRD的风险，并可能预示着肺功能的更大下降，以及3)胰岛素激素的注射， 胰高血糖素样肽-1(GLP-1)，而不是葡萄糖依赖型胰岛素样多肽(GIP)，能增加血糖- PI-CF的胰岛素依赖性分泌。我们在CF的横断面研究显示，膳食显著减少- 早期相关的胰岛素分泌和β细胞分泌能力。随着糖耐量的恶化，PI- Cf糖耐量受损(IGT，两小时OGTT血糖140BUT；200 mg/dL)和CFRD患者 表现出与进食相关的早期胰岛素分泌和β细胞分泌能力进一步受损。广度 糖耐量异常的出现和进展是β细胞分泌恶化的表现 容量尚不清楚，将在对患有PI-CF的年轻人和成年人的纵向研究中进行调查 将进行混合膳食耐量试验(MMTT)，以表征早期胰岛素分泌和血糖- 将完成增强精氨酸(GPA)测试，以量化β细胞的分泌能力。在目标1中，我们将利用 我们的儿童和成人CF队列(n=350)的基因分型和临床表型，以测试T2D的影响 基因变异，饮食，CFTR调节剂治疗，和肺恶化的出现和 糖耐量异常的进展及其与营养状况、肺功能的关系 身体机能和身体成分纵向超过4-5年。在目标2中，我们将测试我们对β-CELL的发现 对急性GLP-1输注的反应性有可能转化为慢性GLP-1治疗的使用 作为一种保存β细胞功能的机制。具体地说，我们将进行为期6周的概念验证， GLP-1激动剂度拉卢肽的安慰剂对照交叉研究；主要结果将是 达格路德对进食相关的早期胰岛素分泌的影响，这是临床上最早发现的缺陷之一。如果 这项工作的成功将为旨在早期识别和治疗的多中心研究奠定基础 PI-CF中的胰岛素分泌缺陷和中断进展为CFRD。

PROJECT SUMMARY Cystic fibrosis-related diabetes (CFRD) not only burdens affected patients with a second, attention-demanding disease but threatens nutritional status, pulmonary function, and survival. Developing strategies to preserve β- cell function are crucial for interrupting CFRD development and its hazard to CF-relevant outcomes. The overall aims of this application are to better understand the emergence and progression of abnormal glucose tolerance in pancreatic insufficient CF (PI-CF) and to test a potential strategy for restoring β-cell function. This application extends our recent studies demonstrating that 1) insulin secretion defects are present at glucose thresholds traditionally considered normal (one-hour oral glucose tolerance test [OGTT] glucose >155 but <200 mg/dL; referred to as early glucose intolerance [EGI]), 2) such subtle glucose abnormalities associate with increased CFRD risk and may portend greater declines in pulmonary function, and 3) infusion of the incretin hormone, glucagon-like peptide-1 (GLP-1), but not glucose-dependent insulinotropic polypeptide (GIP), augments glucose- dependent insulin secretion in PI-CF. Our cross-sectional studies in CF demonstrate marked reductions in meal- related early-phase insulin secretion and β-cell secretory capacity in EGI. With worsening glucose tolerance, PI- CF subjects with impaired glucose tolerance (IGT, two-hour OGTT glucose >140 but <200 mg/dL) and CFRD exhibit further compromised meal-related early-phase insulin secretion and β-cell secretory capacity. The extent to which emergence and progression of glucose intolerance is a manifestation of worsening β-cell secretory capacity is not known and will be investigated in longitudinal studies of youth and adults with PI-CF in whom mixed-meal tolerance tests (MMTT) will be performed to characterize early-phase insulin secretion and glucose- potentiated arginine (GPA) tests will be completed to quantify β-cell secretory capacity. In Aim 1, we will leverage the genotyping and clinical phenotyping of our pediatric and adult CF cohort (n=350) to test the impact of T2D genetic variants, diet, CFTR modulator therapy, and pulmonary exacerbations on the emergence and progression of glucose intolerance and the relationship of glucose intolerance with nutritional status, pulmonary function, and body composition longitudinally over 4-5 years. In Aim 2 we will test whether our findings of β-cell responsiveness to acute GLP-1 infusion has the potential to be translated into the use of chronic GLP-1 therapy as a mechanism to preserve β-cell function. Specifically, we will pursue a proof-of-concept 6-week randomized, placebo-controlled cross-over study of the GLP-1 agonist, dulaglutide; the primary outcome will be the impact of dulaglutide upon meal-related early-phase insulin secretion, one of the earliest defects detected clinically. If successful, this work will provide the foundation for a multi-center study aimed at identifying and treating early insulin secretion defects in PI-CF and interrupting progression to CFRD.