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、更严重的肺功能下降和更高的死亡率有关。CFRD的主要原因是胰岛素分泌受损--传统上被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(T2D)领域的最新发展推动了对这一基本解释的重新审视。例如，胰岛细胞淀粉样蛋白是T2D的一个特征，也是内质网应激的标志，在CF的胰岛中发现。全基因组关联研究发现，TCF7L2基因变异与T2D和CFRD的易感性增加有关，TCF7L2是一种与肠道内分泌功能有关的转录因子。GLP-1的分泌减少和胰岛素分泌对GIP的反应性降低，这两种胰岛素都在T2D中被发现，但在CFRD中得到的关注很少。此外，对CFRD开发的基础机制也进行了最低限度的探索。我们假设：1)急性胰岛素暴露和长期基于胰岛素的治疗将改善早期血糖异常患者和CFRD患者的细胞对葡萄糖的敏感性；2)使用西格列汀(一种抑制胰岛素分解的T2D疗法)基于胰岛素的治疗将改善混合膳食中的胰岛素分泌和葡萄糖漂移；3)非糖尿病CF患者的胰岛素分泌能力、细胞对葡萄糖的敏感性和胰岛素分泌减少。我们提出了横断面和为期6个月的干预研究来检验这些假设。45名患有不确定糖耐量、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测试(GPA，衡量细胞分泌能力和对葡萄糖的敏感性)；这些测试将在存在和不存在急性胰岛素(GIP或GLP-1)暴露的情况下进行。将测试为期6个月的以胰岛素为基础的治疗(西格列汀)对混合餐耐量试验期间血糖漂移、胰岛素和胰岛素分泌的影响，以及在GPA期间细胞分泌能力和对葡萄糖的敏感性。类似的研究将在30名非糖尿病儿童和成人中完成，这些纯合子携带T2D风险的TCF7L2等位基因与野生型TCF7L2等位基因。我们预计，在CF中，胰岛素分泌紊乱导致胰岛素分泌受损，基于胰岛素的治疗可以改善胰岛素分泌，并且T2D相关基因与异常的胰岛素调节胰岛素分泌有关。胰岛素和胰岛素分泌的如此复杂的表型以前从未进行过。所获得的知识将更好地确定导致CFRD中胰岛素分泌缺陷的机制，确定潜在的干预措施来阻断进行性胰岛素缺乏，并可能发现早期的胰岛素分泌障碍，这些障碍不仅可以预测CFRD的进展，还可以预测同时存在肺状况恶化的风险。

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 ¿-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, ¿-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 ¿-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 ¿-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.