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

描述（由申请人提供）：CFRD与营养状况恶化、肺功能严重下降和死亡率增加有关。CFRD主要由胰岛素分泌受损引起，传统上认为胰岛素分泌受损是胰腺外分泌组织损伤和纤维化的副产物。最近在2型糖尿病（T2D）领域的发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是T2D的一个特征，也是内质网应激的一个标志，在CF患者的胰岛中发现。全基因组关联研究发现，TCF7L2（一种与肠内分泌功能有关的转录因子）的遗传变异与T2D和CFRD的易感性增加有关。两种肠促胰岛素GLP-1分泌减少和胰岛素分泌对GIP的反应性降低已在T2D中发现，但在CFRD中很少受到关注。此外，对CFRD发展的潜在机制的探索很少。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患者的细胞对葡萄糖的敏感性；2)西格列汀（一种抑制肠促胰岛素分解的T2D治疗）的肠促胰岛素治疗将改善混合膳食中的胰岛素分泌和葡萄糖漂移；3)胰岛素分泌能力，细胞对葡萄糖的敏感性。与野生型TCF7L2等位基因相比，具有t2d风险的TCF7L2等位基因纯合的非糖尿病性CF受试者的肠促胰岛素分泌减少。我们建议进行横断面研究和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青少年和成人将进行葡萄糖增强精氨酸试验（GPA，测量细胞分泌能力和对葡萄糖的敏感性）；这些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。将测试六个月的以肠促胰岛素为基础的治疗（西格列汀）对混合膳食耐量试验期间葡萄糖漂移、肠促胰岛素和胰岛素分泌的影响，以及GPA期间细胞分泌能力和对葡萄糖的敏感性。将在30名非糖尿病儿童和成人中完成类似的TCF7L2等位基因与野生型TCF7L2等位基因纯合的t2d风险研究。我们预计，在CF中，肠促胰岛素分泌紊乱有助于胰岛素分泌受损，肠促胰岛素为基础的治疗可以改善胰岛素分泌，并且t2d赋予基因型与异常的肠促胰岛素调节胰岛素分泌有关。这种复杂的胰岛素和肠促胰岛素分泌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，确定中断进行性胰岛素缺乏的潜在干预措施，并可能发现早期胰岛素分泌紊乱，不仅可以预测CFRD的进展，还可以预测并发肺状况恶化的风险。

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. PUBLIC HEALTH RELEVANCE: The mechanisms underlying development of cystic fibrosis related diabetes (CFRD), a common co-morbidity in cystic fibrosis (CF) associated with increased morbidity and mortality, are poorly understood. This study will explore the role of incretins (hormones secreted by the intestine that can modulate insulin secretion), defects in ¿-cell sensitivity to glucose, and genetics in CFRD. This evidence may serve as the platform upon which to develop new treatment modalities aimed at preserving ¿-cell function.