The Association of Hyperglycemia with Airway Epithelial Cell Ion Channel Dysfunction in Cystic Fibrosis

Abstract

Cystic fibrosis-related diabetes (CFRD) is a common extrapulmonary comorbidity in adults with CF and portends worse outcomes. However, a direct link between hyperglycemia and decline in lung function is unknown. Inflammation related to hyperglycemia is implicated in end-organ damage in those with Diabetes Mellitus and has been shown to be correlated with worse lung function in those with CF. Additionally, preliminary in vitro evidence suggests that hyperglycemia impairs ion channel function in airway epithelial cells thus compromising mucociliary function. To determine if this association was present in those with CF, we conducted a clinical study to measure the correlation between glycemic control measured by continuous glucose monitoring and nasal cell LRRC26 mRNA expression, the γ subunit of the BK channel which is required for its proper function. We enrolled participants with CF and CFRD who underwent continuous glucose monitoring and sampling of their nasal cells. We found that nasal cell expression of LRRC26 mRNA was inversely correlated with hyperglycemic excursions captured on CGM. This finding demonstrates that hyperglycemia impairs BK channel function and suggests that declining lung function in patients with CFRD may be related to BK channel dysfunction.