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

囊性纤维化竞争性更新中肠岛（肠促胰岛素）轴的评估。

• 批准号: 10665655
• 负责人: ANDREA Bridget KELLY
• 金额: $ 67.21万
• 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/10665655
• 关键词: Acute; Adolescence; Adult; Affect; Age; Agonist; Alpha Cell; Arginine; Attention; Beta Cell; Body Composition; Cell physiology; 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; Exocrine pancreatic insufficiency; 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; Participant; Pathogenesis; Patients; Persons; Phase; Placebo Control; Placebos; Prevalence; Randomized; Resistance; Role; Secretory Cell; Testing; Tissues; Translating; Translations; VX-770; 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; progression risk; 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 囊性纤维化相关糖尿病（CFRD）不仅伯恩顿影响了第二次注意的患者 疾病，但威胁着营养状况，肺功能和生存。制定保留β-的策略 细胞功能对于中断CFRD发育及其对CF相关结果的危害至关重要。总体 该应用的目的是更好地了解异常葡萄糖耐受性的出现和发展 在胰腺不足（PI-CF）中，并测试了恢复β细胞功能的潜在策略。此应用程序 扩展了我们最近的研究表明1）胰岛素分泌缺陷存在于葡萄糖阈值处 传统上认为是正常的（一小时的口服葡萄糖耐量试验[OGTT]葡萄糖> 155，但<200 mg/dl; 被称为早期葡萄糖interance [egi]），2）这种微妙的葡萄糖异常与增加 CFRD风险，可能预示着肺功能下降的增加，3）输注增加激素， 胰高血糖素样肽-1（GLP-1），但不依赖葡萄糖胰岛素多肽（GIP），增强葡萄糖 - PI-CF中的依赖性胰岛素分泌。我们在CF中的横断面研究表明，餐 EGI中相关的早期胰岛素分泌和β细胞秘书能力。具有令人担忧的葡萄糖耐受性， 葡萄糖耐量受损（IGT，两个小时的OGTT葡萄糖> 140但<200 mg/dl）和CFRD的CF受试者 表现出进一步损害与进餐相关的早期胰岛素分泌和β细胞秘书的能力。程度 葡萄糖肠的出现和进展是令人担忧的β细胞分泌的表现 能力尚不清楚，将在对PI-CF的青年和成人的纵向研究中进行研究，其中 将执行混合膜耐受性测试（MMTT），以表征早期胰岛素分泌和葡萄糖 - 将完成增强的精氨酸（GPA）测试，以量化β细胞秘书能力。在AIM 1中，我们将利用 我们的小儿和成人CF队列（n = 350）测试T2D的影响的基因分型和临床表型 关于出现和 葡萄糖耐药性的进展以及葡萄糖肠道与营养状况，肺的关系 功能和身体组成在4 - 5年内纵向。在AIM 2中，我们将测试我们的β细胞发现是否 对急性GLP-1输注的反应能力有可能转化为慢性GLP-1治疗的使用 作为保留β细胞功能的机制。具体而言，我们将追求一个概念证明为6周的随机， GLP-1激动剂Dulaglutide的安慰剂对照跨界研究；主要结果将是 Dulaglutide在与膳食相关的早期胰岛素分泌上，这是最早在临床上检测到的缺陷之一。如果 成功，这项工作将为一项旨在识别和早期治疗的多中心研究奠定基础 PI-CF中的胰​​岛素分泌缺陷，并中断向CFRD的进展。

项目成果

Bone resorption and incretin hormones following glucose ingestion in healthy emerging adults.

• DOI: 10.1016/j.jcte.2023.100314
• 发表时间: 2023-03
• 期刊: JOURNAL OF CLINICAL AND TRANSLATIONAL ENDOCRINOLOGY
• 影响因子: 3
• 作者: Lei, Wang Shin;Rodrick, Eugene B.;Belcher, Staci L.;Kelly, Andrea;Kindler, Joseph M.
• 通讯作者: Kindler, Joseph M.

Defining outcomes for beta cell replacement therapy: a work in progress.

• DOI: 10.1007/s00125-018-4588-0
• 发表时间: 2018-06
• 期刊: Diabetologia
• 影响因子: 8.2
• 作者: Piemonti L;de Koning EJP;Berney T;Odorico JS;Markmann JF;Stock PG;Rickels MR
• 通讯作者: Rickels MR

Endocrine Complications of Cystic Fibrosis.

• DOI: 10.1016/j.ccm.2022.06.013
• 发表时间: 2022-12
• 期刊: CLINICS IN CHEST MEDICINE
• 影响因子: 5.7
• 作者: Kelly, Andrea;Marks, Brynn E.;Stalvey, Michael S.
• 通讯作者: Stalvey, Michael S.

Genetic potential and height velocity during childhood and adolescence do not fully account for shorter stature in cystic fibrosis.

• DOI: 10.1038/s41390-020-0940-4
• 发表时间: 2021-03
• 期刊: Pediatric research
• 影响因子: 3.6
• 作者: Zysman-Colman ZN;Kilberg MJ;Harrison VS;Chesi A;Grant SFA;Mitchell J;Sheikh S;Hadjiliadis D;Rickels MR;Rubenstein RC;Kelly A
• 通讯作者: Kelly A

Abnormal glucose tolerance and the 50-gram glucose challenge test in Cystic fibrosis.

• DOI: 10.1016/j.jcf.2020.01.003
• 发表时间: 2020-09
• 期刊: Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society
• 作者: Sheikh S;Localio AR;Kelly A;Rubenstein RC
• 通讯作者: Rubenstein RC