Cystic Fibrosis (CF) is a lethal inherited disease that primarily affects the lungs but also confers a high risk of diabetes, with up to 40-50% of adults experiencing CF-related diabetes (CFRD). CFRD is associated with an accelerated decline in lung function, nutritional status and survival and despite treatment mortality in patients with CFRD remains high. Airway inflammation and susceptibility to infections caused by hyperglycemia, and the catabolic effect of insulin deficiency are posited mechanisms of CFRD-associated morbidity. Respiratory failure caused by airway disease is well known but the contribution of respiratory muscle dysfunction may be critical. In Type 2 Diabetes Mellitus (T2DM) glucose and insulin defects are closely correlated with muscle function. The pulmonary muscles are crucial to respiration and airway clearance in CF. Muscle function is dependent on its mass, composition, and energy metabolism. Lean body mass (LBM) deficits are present in CF and improvement in LBM improves pulmonary function. Using T2DM as a model for muscle dysfunction, my hypothesis is that glucose intolerance exacerbates LBM deficits, negatively affects muscle composition, and alters muscle metabolism leading to respiratory muscle dysfunction and a decline in pulmonary function. Through the proposed K23, I will investigate the links between glucose abnormalities and the aforementioned elements critical to muscle function as well as explore improvements in these on insulin therapy in CFRD. These goals of this application are to [1] advance our understanding of muscle abnormalities in CF, especially with relation to glucose abnormalities which are common, and to [2] apply physiologic insights to develop rational, targeted, and effective therapeutic interventions to improve pulmonary health. These goals will be advanced through the pursuit of 3 overarching training and career development objectives: First, I will acquire didactic and technical knowledge critical for the successful design and execution of patient- oriented research. Second, I will accrue new expertise in the assessment of peripheral muscle function through novel functional imaging techniques. Third, I will transition to independence as an investigator gaining necessary expertise through completion of the proposed study, and securing subsequent R01 funding. The strategies proposed in this award will test our central hypotheses that: [1] CF people have lower LBM, altered energy metabolism, and poor muscle composition, reflected in intramyocellular lipid accumulation (IMCL), [2] glucose abnormalities exacerbate these factors and [3] insulin treatment improves muscle function. To test these hypotheses, we will examine peripheral muscle mass, IMCL accumulation and metabolism in [1] CF subjects and matched non-CF controls, [2] CF subjects over the spectrum of glucose tolerance and [3] newly diagnosed CFRD subjects as they receive insulin therapy. While we infer that respiratory muscles experience similar alterations in muscle function, I will extend the expertise acquired to directly examine respiratory muscles and their impact on pulmonary decline in CF and specifically in CFRD. This project employs the many unique resources at the Children's Hospital of Philadelphia and University of Pennsylvania, including state of the art facilities, excellent mentorship and collaboration with experts in radiology and muscle metabolism. This work will allow me to establish a solid background from which to pursue future, independently-funded studies on the role of muscles in CF and other pulmonary diseases.

Public Health Relevance

Cystic Fibrosis related diabetes (CFRD) is an exceedingly common complication in Cystic Fibrosis (CF) that despite treatment is associated with poor pulmonary outcomes and increased mortality. Muscle dysfunction from glucose and insulin abnormalities as seen in Type 2 Diabetes Mellitus may be operative in CFRD, and may increase the risk of respiratory failure. Identifying the specific muscle elements that underlie glucose mediated muscle dysfunction and culminate in respiratory failure may direct novel treatment strategies to effectively treat these complications and improve care and outcomes in CF individuals.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mentored Patient-Oriented Research Career Development Award (K23)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Spain, Lisa M
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Children's Hospital of Philadelphia
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