Abstract

Cystic Fibrosis (CF)‐Related Diabetes (CFRD) impacts ~50% of adult CF patients. CFRD is associated with abnormally high airway glucose and an accelerated decline in pulmonary function, indicating a failure in the airway epithelial barrier to regulate glucose permeability. Thus, we examined tight junctions of airway cells expressing wild type CF Transmembrane Conductance Regulator (CFTR) to cells expressing mutant ΔF508‐CFTR. Increasing basolateral glucose from 100 to 450 mg/dL compromised tight junctions of ΔF508‐CFTR cells by ~25% vs. control cells which were significantly less affected. Impaired barrier function was associated with decreased expression of claudin‐4 and displacement of junctional ZO‐1. Using a dual‐luciferase‐ based ER stress reporter assay, cells expressing ΔF508‐ CFTR exhibited higher levels of ER stress than control cells. ER stress was further induced upon exposure to high glucose medium. Thus, ER stress amplified by expression of ΔF508‐CFTR impairs the airway glucose barrier and may predispose the lungs of CF patients to the detrimental consequences of systemic diabetes. Support: Emory+Children's Center for CF Research, Emory URC, CFF, NIH‐NIAAA, NIH‐NHLBI.

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