Insulin resistance is a feature of asthma and underlies barrier dysfunction in primary human bronchial epithelial cells 4260

Abstract Description Asthma and metabolic disorders (obesity, diabetes, metabolic syndrome) are comorbid, but the underlying mechanisms of this association are poorly understood. We previously found that insulin pathway genes are downregulated in asthmatic airway epithelium. Moreover, epidemiological studies have shown that insulin resistance associates with asthma independently of obesity. We hypothesized that insulin dysregulation contributes to asthma pathogenesis by promoting epithelial barrier dysfunction and inflammation. We evaluated this by assessing gene, protein, and metabolic profiles of normal and asthmatic human bronchial epithelium (NHBE; AHBE) at baseline and in insulin-manipulated conditions. We found: (1) AHBE had lower baseline levels of phospho-Akt (Ser473). With insulin restimulation, phospho-Akt (Ser473) and phospho-GSK-3β (Ser9) were decreased in AHBE, confirming AHBE insulin resistance; (2) NHBE barrier dysfunction in insulin-deficient air-liquid interface cultures closely resembled the AHBE phenotype; (3) AHBE had higher levels of GLUT1 glucose transporter and increased anabolic vs. energetic glucose utilization, indicating altered glucose metabolism; and (4) AHBE had a distinct metabolic signature from NHBE, featuring an increase in amino acid metabolism. Our study provides a needed mechanistic framework for understanding the connection between AHBE dysfunction and insulin resistance and provides novel paths for managing comorbid allergic and metabolic disorders. Funding Sources Supported by NIH/NIAID and the Bazley Research Foundation Topic Categories Immune Mechanisms of Human Disease (HUM)