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

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.