A Dietary Intervention to Improve Glucose Tolerance in Adults with Cystic Fibrosis

项目概要/摘要 囊性纤维化（CF）患者的成功治疗使其生存率呈指数级提高。 人口现在迫切需要更好地了解如何促进最佳的长期健康， 这个新的老龄化人群，这是在高风险的发展葡萄糖耐受不良和CF相关的 糖尿病（CFRD）。CFRD在临床和病理生理学上与1型和2型糖尿病不同， 严重损害了生活质量和生存。不幸的是，导致面板堆石坝发生的具体因素 进展仍然未知。我们的初步数据暗示饮食是葡萄糖的一个促发因素 成人CF的不耐受性。体重指数（BMI）和CF生存率之间的历史联系， 鼓励终身处方无限制的高热量，高脂肪饮食，以满足特定的BMI目标。 然而，对卡路里和脂肪数量的关注是以牺牲饮食质量为代价的， 导致过量膳食添加糖的广泛消耗。典型的高附加值的影响 糖，高脂肪CF饮食对葡萄糖耐量的影响尚未得到严格的测试。目前， 现有的研究，使基于证据的饮食建议，关于碳水化合物的质量具体 CF患者。这项研究的目的是确定过量的膳食糖作为 成人CF患者葡萄糖耐受不良的促发因素，并确定潜在的潜在介质。 根据我们的初步数据，我们建议，高添加糖的饮食，通常是消费的， CF患者通过增强胰岛素抵抗和胰岛素抵抗， 内脏脂肪组织（VAT）和其他异位脂肪沉积，并通过促进全身 氨基硫醇向氧化态的氧化还原。我们将使用严格的双盲喂养来测试这一假设 study.具体地说，我们将确定胰岛素分泌和敏感性是否通过联合高血糖评估。 钳夹和葡萄糖增强精氨酸刺激试验（Aim 1），评估VAT和其他异位脂肪沉积 通过磁共振成像（Aim 2），全身氨基硫醇氧化还原（Aim 3）可以改善超过8 通过用低热量的低添加糖，高脂肪的饮食代替典型的高添加糖，高脂肪的CF饮食， 饮食.我们还将评估葡萄糖耐量变化与VAT变化之间的关系， 系统性氧化还原这项研究符合最近的2020-2030年NIH营养研究战略计划目标 在临床环境中使用营养来减轻疾病负担。成功实现我们的目标， 使用严格的饮食干预与黄金标准的代谢测试和成像，将提供新的 对饮食对面板堆石坝发育作用的病理生理学洞察。这些数据将告知 基于证据的设计，与机械支持，饮食方法和其他生活方式或医疗 可能对CF患者的健康和生活质量产生持续影响的干预措施。

PROJECT SUMMARY/ABSTRACT Successes in therapies for individuals with cystic fibrosis (CF) have exponentially improved survival in this population. There is now a critical need for better understanding of how to promote optimal long-term health in this newly aging population, which is at high risk for development of glucose intolerance and CF-related diabetes (CFRD). CFRD is clinically and pathophysiologically distinct from type 1 and type 2 diabetes mellitus, and it drastically impairs quality of life and survival. Unfortunately, specific factors contributing to CFRD onset and progression remain unknown. Our preliminary data implicate diet as a precipitating factor in glucose intolerance in adults with CF. Historical links between body mass index (BMI) and survival in CF have encouraged the life-long prescription of an unrestricted high-calorie, high-fat diet to meet specific BMI goals. However, the focus on the quantity of calories and fat has come at the expense of the quality of the diet, resulting in the widespread consumption of excess dietary added sugars. The impact of the typical high-added sugar, high-fat CF diet on glucose tolerance has not been rigorously tested. Currently, there is insufficient research available to enable evidence-based dietary recommendations regarding carbohydrate quality specific to individuals with CF. The purpose of this study is to determine the extent that excess dietary sugars serve as a precipitating factor in glucose intolerance in adults with CF and to identify potential underlying mediators. Based on our preliminary data, we propose that the high-added sugar diets that are typically consumed by individuals with CF exacerbate a decline in first-phase insulin secretion and insulin resistance by enhancing visceral adipose tissue (VAT) and other ectopic fat deposition and by promoting an imbalance in systemic aminothiol redox towards an oxidized state. We will test this hypothesis using a rigorous, double-blind feeding study. Specifically, we will determine if insulin secretion and sensitivity assessed by a combined hyperglycemic clamp and glucose-potentiated arginine stimulation test (Aim 1), VAT and other ectopic fat deposition assessed by magnetic resonance imaging (Aim 2), and systemic aminothiol redox (Aim 3) can be improved over eight weeks by replacing the typical high-added sugar, high-fat CF diet with a eucaloric low-added sugar, high-fat diet. We will also assess relationships between the changes in glucose tolerance and changes in VAT and systemic redox. This study is in line with the recent 2020-2030 Strategic Plan for NIH Nutrition Research goal of using nutrition to reduce the burden of disease in clinical settings. Successful achievement of our aims, using a rigorous dietary intervention with gold-standard metabolic testing and imaging, will deliver new pathophysiological insight into the role of diet towards the development of CFRD. Such data will inform evidence-based design, with mechanistic support, of dietary approaches and other lifestyle or medical interventions that may have a sustained impact on the health and quality of life of individuals living with CF.