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

评估囊性纤维化竞争性更新中的肠岛（肠促胰岛素）轴。

• 批准号: 10207611
• 负责人: ANDREA Bridget KELLY
• 金额: $ 68.97万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-17 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10207611
• 关键词: Acute; Adolescence; Adult; Affect; Age; Agonist; Arginine; Attention; Beta Cell; Body Composition; Cell physiology; Cell secretion; Childhood; Chronic; Clinical; Cross-Over Studies; Cross-Sectional Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defect; Development; Diabetes Mellitus; Diet; Disease; Double-Blind Method; Early Diagnosis; Early Intervention; Evaluation; Exhibits; Exocrine pancreas; Exposure to; Foundations; Functional disorder; Genetic; Genetic Risk; Genotype; Glucose; Glucose Intolerance; Glucose tolerance test; Goals; Grant; Guidelines; Hormones; Hour; Impairment; Individual; Inflammation; Infusion procedures; Insulin; Insulin Resistance; Insulin deficiency; Interruption; Intervention; Intestines; Longitudinal Studies; Lung; Lung Transplantation; Multicenter Studies; Non-Insulin-Dependent Diabetes Mellitus; Nutritional; Nutritional status; OGTT; Outcome; Pancreas; Participant; Pathogenesis; Patients; Phase; Placebos; Prevalence; Randomized; Resistance; Risk; Role; Secretory Cell; Testing; Tissues; Translating; Translations; Variant; Work; Youth; aged; clinical phenotype; cohort; comorbidity; cystic fibrosis related diabetes; diabetes risk; dietary; early childhood; efficacy testing; gastric inhibitory polypeptide receptor; genetic variant; glucagon-like peptide 1; glucose tolerance; hazard; high risk; hyperglucagonemia; impaired glucose tolerance; improved; incretin hormone; insulin secretagogues; insulin secretion; islet; mortality; multidisciplinary; non-diabetic; nutrition; preservation; prevent; primary outcome; pulmonary function; recruit; screening; young adult

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.

项目摘要 囊性纤维化相关的糖尿病（CFRD）不仅负担影响患者的第二，注意力要求 疾病，但威胁营养状况，肺功能和生存。制定保护β- 细胞功能是至关重要的中断面板堆石坝的发展和危害CF相关的结果。整体 本申请的目的是更好地了解异常葡萄糖耐量的出现和进展 在胰腺CF不足（PI-CF）中，并测试恢复β细胞功能的潜在策略。本申请 扩展了我们最近的研究，证明1）胰岛素分泌缺陷存在于葡萄糖阈值 传统上认为正常（一小时口服葡萄糖耐量试验[OGTT]葡萄糖>155但<200 mg/dL; 称为早期葡萄糖耐受不良[EGI]），2）这种轻微的葡萄糖异常与增加的 CFRD风险，并可能预示着肺功能的更大下降，和3）肠促胰岛素激素的输注， 胰高血糖素样肽-1（GLP-1），而不是葡萄糖依赖性促胰岛素多肽（GIP）， PI-CF中依赖胰岛素分泌。我们对CF的横断面研究表明， 相关的早期胰岛素分泌和EGI中β细胞分泌能力。葡萄糖耐量恶化，PI- 糖耐量受损（IGT，两小时OGTT葡萄糖>140但<200 mg/dL）和CFRD的CF受试者 表现出进一步受损的膳食相关的早期胰岛素分泌和β细胞分泌能力。程度 葡萄糖耐受不良的出现和进展是β细胞分泌功能恶化的表现， 能力尚不清楚，将在PI-CF青年和成人的纵向研究中进行调查， 将进行混合餐耐受性试验（MMTT）以表征早期胰岛素分泌和葡萄糖- 将完成增强精氨酸（GPA）试验以定量β细胞分泌能力。在目标1中，我们将 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T2 D的影响 遗传变异、饮食、CFTR调节剂治疗和肺部急性加重， 葡萄糖耐受不良的进展及其与营养状况、肺功能、 功能和身体组成纵向超过4-5年。在目标2中，我们将测试我们的β细胞发现是否 对急性GLP-1输注的反应性有可能转化为长期GLP-1治疗的使用 作为保护β细胞功能的机制。具体来说，我们将进行一项为期6周的随机、 GLP-1激动剂dullavine的安慰剂对照交叉研究;主要结局将是 在与膳食相关的早期胰岛素分泌时感到兴奋，这是临床上检测到的最早的缺陷之一。如果 如果成功，这项工作将为旨在早期识别和治疗的多中心研究提供基础。 PI-CF中的胰岛素分泌缺陷并中断向CFRD的进展。