exenatide and Pulmonary-Disease--Chronic-Obstructive

Goblet cell hyperplasia and metaplasia and excessive mucus are prominent pathologies of chronic airway diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and chronic bronchitis. Chronic infection by respiratory pathogens, including Pseudomonas aeruginosa, exacerbates cyclical proinflammatory responses and mucus hypersecretion. P. aeruginosa and its virulence factor pyocyanin contribute to these pathologies by inhibiting FOXA2, a key transcriptional regulator of mucus homeostasis, through activation of antagonistic signaling pathways EGFR-AKT/ERK1/2 and IL-4/IL-13-STAT6-SPDEF. However, FOXA2-targeted therapy has not been previously explored. Here, we examined the feasibility of repurposing the incretin mimetic Exendin-4 to restore FOXA2-mediated airway mucus homeostasis. We have found that Exendin-4 restored FOXA2 expression, attenuated mucin production in COPD and CF-diseased airway cells, and reduced mucin and P. aeruginosa burden in mouse lungs. Mechanistically, Exendin-4 activated the GLP1R-PKA-PPAR-γ-dependent phosphatases PTEN and PTP1B, which inhibited key kinases within both EGFR and STAT6 signaling cascades. Our results may lead to the repurposing of Exendin-4 and other incretin mimetics to restore FOXA2 function and ultimately regulate excessive mucus in diseased airways.

Topics: Cyclic AMP-Dependent Protein Kinases; Disease Susceptibility; ErbB Receptors; Exenatide; Gene Expression; Glucagon-Like Peptide-1 Receptor; Hepatocyte Nuclear Factor 3-beta; Homeostasis; Humans; Models, Biological; Mucins; PPAR gamma; Protein Binding; Proto-Oncogene Proteins c-akt; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; Signal Transduction; STAT6 Transcription Factor

To assess whether dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists are associated with an increased lung cancer risk among individuals with type 2 diabetes.. We conducted a population-based cohort study using the UK Clinical Practice Research Datalink. We identified 130 340 individuals newly treated with antidiabetes drugs between January 2007 and March 2017, with follow-up until March 2018. We used a time-varying approach to model use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists compared with use of other second- or third-line antidiabetes drugs. We used Cox proportional hazards models to estimate the adjusted hazard ratios, with 95% CIs, of incident lung cancer associated with use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists, separately, by cumulative duration of use, and by time since initiation.. A total of 790 individuals were newly diagnosed with lung cancer (median follow-up 4.6 years, incidence rate 1.5/1000 person-years, 95% CI 1.4-1.6). Compared with use of second-/third-line drugs, use of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists was not associated with an increased lung cancer risk (hazard ratio 1.07, 95% CI 0.87-1.32, and hazard ratio 1.02, 95% CI 0.68-1.54, respectively). There was no evidence of duration-response relationships.. In individuals with type 2 diabetes, use of incretin-based drugs was not associated with increased lung cancer risk.

Topics: Adamantane; Aged; Diabetes Complications; Diabetes Mellitus, Type 2; Dipeptides; Dipeptidyl-Peptidase IV Inhibitors; Exenatide; Female; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Incidence; Incretins; Linagliptin; Liraglutide; Lung Neoplasms; Male; Middle Aged; Proportional Hazards Models; Pulmonary Disease, Chronic Obstructive; Risk Factors; Sitagliptin Phosphate; Smoking