B22-02 Glucagon-like Peptide-1 Receptor Agonists as Dual Therapeutics for Obesity-related Asthma and Metabolic Dysfunction

Rationale Obesity-related asthma represents a heterogenous phenotype that accounts for a disproportionate burden of severe and difficult-to control asthma cases in the United States. Clinical observations have shown that individuals with concurrent asthma and type 2 diabetes mellitus (T2DM) treated with glucagon-like peptide-1 receptor agonists (GLP-1RAs) exhibit fewer asthma exacerbations, reduced asthma-related hospitalizations, and improved symptom control. Despite these promising findings, the molecular mechanisms underlying GLP-1RA mediated improvement in airway function remain poorly understood. Our prior work demonstrated that insulin pretreatment diminished intracellular cyclic adenosine monophosphate (cAMP) levels in a dose-dependent manner, indicating heterologous desensitization of the β2-adrenergic receptor (β2AR) pathway. Here, we hypothesize that GLP-1RAs promote airway smooth muscle relaxation through enhanced cAMP production and protein kinase A (PKA) activation. Methods To model insulin-induced β2AR dysfunction, precision-cut lung slices (PCLS) from BALB/C mice were incubated with insulin and subsequently assessed for airway contractility and relaxation responses. Methacholine was used to induce airway constriction, followed by albuterol challenge to assess β2AR-mediated relaxation. To evaluate potential therapeutic rescue, human airway smooth muscle cells (HASMCs) expressing the AKAR3 biosensor were treated with semaglutide to monitor real-time PKA activation. In parallel, PCLS were precontracted with methacholine and treated ex-vivo with liraglutide to assess bronchodilator responses, alone or in combination with salbutamol to determine maximal dilation capacity. Results Insulin-treated PCLS displayed a 30% reduction in albuterol-induced relaxation and a 30% increase in methacholine-induced contraction, confirming insulin-mediated airway hyperreactivity. In HASMCs, semaglutide treatment induced a robust increase in PKA activity, comparable to isoproterenol (ISO) stimulation, indicating restoration of downstream β2AR signaling via cAMP and PKA activation. Similarly, liraglutide administration in methacholine-precontracted PCLS produced a marked acute bronchodilator effect. Collectively, these findings demonstrate that GLP-1RAs directly modulate ASM tone through cAMP and PKA signaling, independent of canonical β2AR activation. Conclusion Our findings reveal a novel immunometabolic mechanism by which insulin impairs β2AR-mediated relaxation in airway smooth muscle and identify GLP-1RAs as potent modulators of airway tone via cAMP and PKA signaling. This mechanism provides a molecular basis for the clinical benefits of GLP-1RAs observed in patients with obesity-related asthma and T2DM. Given the escalating global prevalence of both obesity and diabetes, these results highlight GLP-1RAs as promising dual-action therapeutics targeting intertwined metabolic and respiratory dysfunction.