The effect of the GLP-1 analogue Liraglutide on intermittent hypoxia-induced systemic insulin resistance in vivo

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Introduction: Intermittent hypoxia (IH) leads to insulin resistance (IR) through visceral adipose tissue inflammation with M1-macrophage polarisation [1]. The GLP-1 receptor agonist, Liraglutide (Lir), not only confers weight loss but has been shown to attenuate macrophage pro-inflammatory responses and adipose tissue inflammation. Here, we tested the hypothesis that Liraglutide counteracts IH-induced systemic IR. Methods: Male C57BL/6 mice were fed a 60% high-fat diet (HFD). Following a run-in time of two weeks mice were randomized to 6 weeks IH (5% inspired oxygen fraction (FiO2) for 30s and 21% FiO2 for 30s, 8 hrs/day) or intermittent air (IA) with or without daily subcutaneous Lir administration (300µg/kg). After 5 weeks, fasting glucose and insulin levels were measured and systemic insulin sensitivity was evaluated via insulin tolerance test (ITT). Following completion of the protocol, insulin-sensitive organs were sampled. Results: The HFD-induced weight gain was significantly attenuated by Lir in both IA and IH-treated mice (IA-PBS 34.4±2.37, vs IA-Lir 27.7±0.94, IH-PBS 29.73±2.7, IH-Lir 27.2±1.6, p=0.001) associated with improvement in fasting glycemia, insulin, and HOMA-IR at 5 weeks IH. As expected, IH decreased insulin sensitivity in comparison to IA control (p=0.034), however, Lir had no further impact with either treatment (p=0.125). Conclusion: Treatment with the GLP-1 analogue Liraglutide did not prevent IH-induced systemic IR. Further experiments will determine the effects of this treatment on IH-mediated adipose tissue inflammation. 1Murphy, A.M., et al Eur Respir J, 2017. 49(4)

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