The Potential Therapeutic Role of Glucagon-like peptide (GLP)-1 Receptor Agonist Treatment in Intermittent Hypoxia Induced Metabolic Dysfunction in Obstructive Sleep Apnoea

Background: Obstructive sleep apnoea (OSA) is a highly prevalent disorder, characterised by repeated pharyngeal collapse during sleep and conveys a significant risk for metabolic comorbidities such as insulin resistance (IR) and type 2 diabetes. Intermittent hypoxia (IH) plays a key role in the pathogenesis of metabolic complications in the disorder. Previous work performed in our lab demonstrates that IH induces a pro-inflammatory phenotype of adipose tissue with M1 macrophage polarisation impeding insulin signalling which resembles changes seen in obesity-mediated metabolic perturbations. Continuous positive airway pressure (CPAP) therapy is a treatment of choice for OSA but its benefit on metabolic outcomes is uncertain. While weight loss in combination with CPAP can improve metabolic function in OSA, it is difficult to achieve with conventional measures alone. Liraglutide, which is a glucagon-like peptide-1 (GLP-1) receptor agonist is superior in achieving weight loss than lifestyle changes but has also shown to decrease adipose tissue inflammation and promote anti-inflammatory M2 macrophages. However, its potential benefit on metabolic diseases in OSA is poorly investigated. We hypothesized that Liraglutide attenuates IH-induced inflammation and IR, and thus may resemble a therapeutic strategy for OSA related metabolic dysfunction. Methods: To address the hypothesis we utilized state-of-the art cell culture and murine models of IH evaluating the effects of Liraglutide on IH-mediated pro-inflammatory macrophage polarisation, insulin signalling and systemic insulin sensitivity. Furthermore, we explored potential signalling pathways for Liraglutide in macrophages to elucidate whether it acts dependently or independently of the GLP-1 receptor. Results: In vitro, Liraglutide significantly attenuated IH-induced M1 macrophage polarisation in primary murine macrophages, likely independently of the GLP-1 receptor, but this did not translate to improved insulin sensitivity in adipocytes. Liraglutide significantly attenuated high-fat diet-induced weight gain in vivo but did not improve IH-induced insulin resistance or impact on adipose tissue inflammation. Conclusion: While Liraglutide attenuated IH-induced inflammation in cell culture and promoted weight loss in vivo, the lack of benefit of the intervention on IH-induced IR does not support a role for GLP-1 analogues as a treatment option for metabolic diseases in OSA.