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.