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

描述（由申请人提供）：CFRD与更差的营养状况、更大的肺功能下降和更高的死亡率相关。CFRD主要由胰岛素分泌受损引起--传统上认为是胰腺外分泌组织损伤和纤维化的副产品。2型糖尿病（T2 D）领域的最新进展正在推动对这一基本解释的重新审视。例如，胰岛细胞淀粉样蛋白，T2 D的特征和内质网应激的标志物，在CF的胰岛中发现。全基因组关联研究将TCF 7 L2（一种参与肠内分泌功能的转录因子）的遗传变异与T2 D和CFRD的易感性增加相关联。GLP-1分泌减少和胰岛素分泌对GIP（两种肠促胰岛素）的反应性降低已在T2 D中发现，但在CFRD中很少受到关注。此外，对面板堆石坝开发的机制探讨甚少。我们假设：1）急性肠促胰岛素暴露和慢性肠促胰岛素治疗将改善早期血糖异常患者和CFRD患者的胰岛β细胞对葡萄糖的敏感性，2）西格列汀的肠促胰岛素治疗（抑制肠促胰岛素分解的T2 D疗法）将改善混合餐期间的胰岛素分泌和葡萄糖波动，和3）胰岛素分泌能力，β细胞对葡萄糖的敏感性，与野生型TCF 7 L2等位基因相比，T2 D风险赋予TCF 7 L2等位基因纯合子的非糖尿病CF受试者中肠促胰岛素分泌减少。我们建议进行横断面研究和为期6个月的干预研究来验证这些假设。45名患有不确定葡萄糖耐量、葡萄糖耐量受损和CFRD的CF青少年和成人将接受葡萄糖增强精氨酸试验（GPA，测量胰岛细胞分泌能力和对葡萄糖的敏感性）;这些试验将在存在和不存在急性肠促胰岛素（GIP或GLP-1）暴露的情况下进行。将检测6个月基于肠促胰岛素的治疗（西格列汀）对混合餐耐量试验期间葡萄糖波动以及肠促胰岛素和胰岛素分泌的影响，以及GPA期间胰岛细胞分泌能力和对葡萄糖的敏感性。将在30名T2 D风险相关TCF 7 L2等位基因与野生型TCF 7 L2等位基因纯合子的非糖尿病儿童和成人中完成类似研究。我们预计，在CF肠促胰岛素分泌紊乱有助于受损的胰岛素分泌，肠促胰岛素为基础的治疗可以改善胰岛素分泌，T2 D赋予基因型与肠促胰岛素调节的胰岛素分泌异常。胰岛素和肠促胰岛素分泌的这种复杂的表型以前没有进行过。所获得的知识将更好地定义CF中胰岛素分泌缺陷的机制，确定潜在的干预措施来中断进行性胰岛素缺乏，并可能发现早期胰岛素分泌紊乱，这不仅可以预测进展为CFRD，还可以预测肺功能恶化的并发风险。

DESCRIPTION (provided by applicant): CFRD is associated with worse nutritional status, greater pulmonary function decline, and increased mortality. CFRD arises primarily from compromised insulin secretion--traditionally considered a by- product of pancreatic exocrine tissue damage and fibrosis. Recent developments in the field of type 2 diabetes (T2D) are propelling a re-examination of this basic explanation. For example, islet cell amyloid, a feature of T2D and a marker of endoplasmic reticulum stress, is found in pancreatic islets in CF. Genome-wide association studies have associated genetic variants in TCF7L2, a transcription factor implicated in enteroendocrine function, with increased susceptibility to T2D and CFRD. Decreased secretion of GLP-1 and decreased responsiveness of insulin secretion to GIP, both incretins, have been identified in T2D, but have received minimal attention in CFRD. Moreover, the mechanisms underlying CFRD development have been minimally explored. We hypothesize that 1) acute incretin exposure and chronic incretin-based therapy will improve ß-cell sensitivity to glucose in patients with early glucose abnormalities and in patients with CFRD, 2) incretin-based therapy with sitagliptin (a T2D therapy that inhibits breakdown of incretins) will improve insulin secretion and glucose excursion during a mixed meal, and 3) insulin secretory capacity, ß-cell sensitivity to glucose, and incretin secretion are decreased in non-diabetic CF subjects homozygous for the T2D-risk conferring TCF7L2 allele vs the wildtype TCF7L2 allele. We propose cross sectional and 6-month intervention studies to test these hypotheses. Forty-five CF adolescents and adults with Indeterminate glucose tolerance, impaired glucose tolerance, and CFRD will undergo Glucose Potentiated Arginine Tests (GPA, which measures ß-cell secretory capacity and sensitivity to glucose); these will be performed in the presence and absence of acute incretin (GIP or GLP-1) exposure. The impact of six months of incretin-based therapy (sitagliptin) upon glucose excursion and incretin and insulin secretion during the Mixed Meal Tolerance Test, and ß-cell secretory capacity and sensitivity to glucose during the GPA will be tested. Similar studies will be completed in thirty non-diabetic children and adults homozygous for the T2D-risk conferring TCF7L2 allele vs the wildtype TCF7L2 allele. We anticipate that in CF disturbed incretin secretion contributes to impaired insulin secretion, that incretin-based therapy can improve insulin secretion, and that the T2D-conferring genotype is associated with aberrant incretin regulated insulin secretion. Such sophisticated phenotyping of insulin and incretin secretion has not previously been undertaken. The knowledge gained will better define the mechanisms responsible for insulin secretion defects in CF, identify potential interventions to interrupt progressive insulin deficiency, and may uncover early insulin secretion disturbances that will predict not only progression to CFRD but concurrent risk of worsening pulmonary status.