Genetics, glycemic control and the microbiome in cystic fibrosis

囊性纤维化相关糖尿病(CFRD)是最常见的非肺部并发症 囊性纤维化(CF)，影响多达50%的成年人。这一诊断与更多的肺部疾病有关 病情恶化，肺功能恶化，死亡率比无症状者高 CFRD。CFRD患者铜绿假单胞菌和葡萄球菌较多 通过基于微生物培养的分析确定金黄色葡萄球菌肺部感染。然而， CFRD中可见的特定微生物组以及微生物组如何随血糖变化 操纵是不被理解的。CFRD的发展也可能受遗传因素的影响 胰岛素抵抗和β细胞功能的特征，尽管评估这一点的研究有限。 胰岛素是唯一被证明可以改善肺功能的推荐治疗方法。 CFRD的结果；然而，在该患者中很难实现良好的血糖控制 由于高碳水化合物摄入量，频繁的低血糖，以及 糖尿病任务。人工胰腺(Ap)技术是一种很有前途的血液控制方法。 与常规方法相比，该方法具有更高的准确性和易用性。我们有资金来研究 一种AP设备，仿生胰腺(BP)，在受试者中进行的随机平行设计临床试验 CFRD控制不佳(R01DK119699-01，PI：Putman)。这些受试者将被随机安排 常规护理(UC)或血压6个月，评估血压不仅对血糖的影响 不仅影响控制，而且还影响CF的特定结果，包括营养状况和肺功能。 我们将利用这项资助的试验来研究CFRD的新的临床和基因预测因素 并将使用最先进的微生物组分析技术来了解血糖控制 影响林木微生物群落多样性。目标1将比较CFRD受试者的微生物群 参与这项试验，以存储来自非CFRD受试者的样本，并确定如何 基线血糖会影响微生物组。AIM 2将研究遗传和临床 CFRD受试者基线血糖和对BP干预反应的预测因素。目标 3将评估BP实现的严格血糖控制如何影响微生物群多样性 超过6个月，如果血糖改善引起的肺功能改变是中介的 通过微生物群的变化。 总而言之，K23应用程序中提出的研究和指导计划将测试 关于CFRD患者血糖特征和微生物组的创新假说，Will 扩大我们对CFRD的了解，并将提供必要的培训和调查 Brenner博士在临床研究中发展成功、独立的职业生涯的利基。

Cystic fibrosis related diabetes (CFRD) is the most common non-pulmonary complication of cystic fibrosis (CF), affecting up to 50% of adults. This diagnosis is linked to more pulmonary exacerbations, worsening lung function, and increased mortality compared to those without CFRD. Individuals with CFRD have more Pseudomonas Aeruginosa and Staphylococcus Aureus pulmonary infections determined by culture based microbial analysis. However, the specific microbiome seen in CFRD and how the microbiome changes with glycemic manipulation is not understood. The development of CFRD may also be influenced by genetic traits for insulin resistance and beta cell function, though studies evaluating this are limited. Insulin is the only recommended treatment that has been shown to improve pulmonary outcomes in CFRD; however, good glycemic control is difficult to achieve in this patient population due to high carbohydrate intake, frequent hypoglycemia, and the added burden of diabetes tasks. Artificial pancreas (AP) technology is a promising approach to controlling blood glucose with greater accuracy and ease than conventional methods. We have funding to study an AP device, the bionic pancreas (BP), in a randomized parallel design clinical trial in subjects with poorly controlled CFRD (R01DK119699-01, PI:Putman). These subjects will be randomized to usual care (UC) or the BP for 6 months, evaluating the impact of the BP not only on glycemic control but also on CF-specific outcomes including nutritional status and pulmonary function. We will leverage this funded trial to investigate novel clinical and genetic predictors of CFRD and will use state-of-the-art microbiome analytic techniques to understand how glycemic control impacts microbiome diversity in CF. Aim 1 will compare the microbiome in CFRD subjects participating in this trial to biorepository samples from non-CFRD subjects and determine how baseline glycemia influences the microbiome. Aim 2 will investigate genetic and clinical predictors of baseline glycemia and response to the BP intervention in subjects with CFRD. Aim 3 will evaluate how strict glycemic control achieved with the BP impacts microbiome diversity over 6 months, and if the change in lung function seen with improved glycemia is mediated through the change in microbiome. In summary, the research and mentoring plan proposed in this K23 application will test innovative hypotheses about glycemic traits and the microbiome in patients with CFRD, will broaden our understanding of CFRD, and will provide the necessary training and investigational niche for Dr. Brenner to develop a successful, independent career in clinical research.