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

项目摘要/摘要 囊性纤维化(CF)患者的成功治疗已经成倍地提高了患者的存活率 人口。现在迫切需要更好地了解如何在以下方面促进最佳长期健康 这一新的老龄化人口是发展为糖耐量异常和CF相关疾病的高危人群 糖尿病(CFRD)。CFRD在临床和病理生理上不同于1型和2型糖尿病， 它极大地损害了生活质量和生存。不幸的是，导致CFRD发病的特定因素 进展如何仍不得而知。我们的初步数据表明饮食是血糖的一个沉淀因素 成人CF患者的耐受性。体重指数(BMI)与慢性阻塞性肺疾病存活率之间的历史联系 鼓励终身处方不受限制的高热量、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， 导致人们普遍摄入过量的膳食添加糖。典型的高附加值的影响 糖、高脂肪的CF饮食对糖耐量的影响还没有得到严格的测试。目前，还没有足够的 可用于支持关于碳水化合物质量特定的循证饮食建议的研究 对于患有慢性阻塞性肺疾病的个人。这项研究的目的是确定过量膳食糖在多大程度上起到了 本研究旨在探讨成人CF患者糖耐量异常的诱因，并找出潜在的潜在影响因素。 根据我们的初步数据，我们认为，通常由 CF患者通过增强胰岛素分泌第一时相和胰岛素抵抗而加重 内脏脂肪组织(VAT)和其他异位脂肪沉积并通过促进全身失衡 氨基硫醇氧化还原到氧化态。我们将使用严格的双盲喂养来检验这一假设 学习。具体地说，我们将确定是否通过联合高血糖来评估胰岛素分泌和敏感性 钳夹和葡萄糖增强精氨酸刺激试验(目标1)，评估VAT和其他异位脂肪沉积 通过磁共振成像(目标2)和全身氨硫醇氧化还原(目标3)可以改善8 通过将典型的高添加糖、高脂肪的CF饮食替换为高热量的低添加糖、高脂肪的饮食 节食。我们还将评估糖耐量变化和增值税变化之间的关系 全身性氧化还原。这项研究符合最近的2020-2030年美国国立卫生研究院营养研究战略计划的目标 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和黄金标准的新陈代谢测试和成像，将提供新的 饮食在CFRD发展中的作用的病理生理学洞察。这样的数据将会告诉我们 基于证据的设计，有机械的支持，饮食方法和其他生活方式或医疗 可能对慢性纤维性心脏病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.