Obesity-related, metabolic asthma: a new role for glucagon-like peptide 1 agonists

Obesity and metabolic syndrome are associated with an increased risk of concurrent asthma. Despite strong epidemiological data linking the two, the underlying mechanisms of this association are complicated and incompletely understood. Chronic inflammation, lipid metabolism, insulin resistance, hormonal changes, and body habitus are proposed as pathogenic links.¹ Other well described abnormalities in obesity and metabolic syndrome, namely alterations in arginine metabolism and accelerated formation of advanced glycation end products (AGEs), could also play a crucial role in asthma pathogenesis and might be modulated by the anti-inflammatory incretin, glucagon-like peptide 1 (GLP-1).^2–5

GLP-1 is a metabolic hormone that interacts with its widely distributed receptor (GLP-1R), triggering insulin production, glucose uptake, systemic effects, such as decreased appetite and gastric emptying, and increased vasodilation.⁶ With the advent of GLP-1R agonists such as liraglutide, this pathway is a notable target for type 2 diabetes and weight loss. GLP-1 receptors are abundant in the lung and might stimulate vasodilation, surfactant production, and bronchodilation.⁷

Results of previous research suggest a prominent role of the GLP-1 pathway in asthma.^8–10 In one murine study,⁸ liraglutide, decreased airway inflammation, mucus secretion, and production of proinflammatory cytokines. These effects were attributed to the activation of protein kinase A (PKA) and inhibition of the proinflammatory transcription factor, NF-kB. Two reports^9,10 that used human tissue to mimic asthmatic conditions ex vivo showed that GLP-1R stimulation improved bronchial hyperresponsiveness and inflammatory changes.

Rogliani and colleagues⁹ showed that the GLP-1R agonist exendin-4 reversed hyperglycaemia and passive sensitisation-induced airway smooth muscle hyperresponsiveness by restoring PKA activity. Furthermore, Mitchell and colleagues¹⁰ showed that GLP-1 inhibited exvivo activation of eosinophils from patients with asthma. These experimental models show that the GLP-1 pathway might counteract some of the cardinal pathogenic components of asthma. With further investigation, GLP-1R agonists could be used as a so-called new class of medications to treat patients with concurrent asthma, obesity, and diabetes.

Additional insights provided by published endocrine studies suggest that arginine metabolism and AGE- mediated inflammation—both attenuated by GLP-1—are important shared mechanisms between obesity and asthma.⁵ L-arginine is a substrate in numerous diverse enzymatic pathways, including the synthesis of nitric oxide (NO), and it stimulates the production of GLP-1. Via NO synthase, arginine might be converted to both beneficial and proinflammatory reactive species of NO. Dysregulation of arginine metabolism occurs in obesity, metabolic syndrome, and asthma, resulting in depletion of L-arginine through increased asymmetric dimethylarginine production and arginase activity.¹¹ A study⁴ of diet-induced metabolic syndrome in mice found asthma-like changes in conjunction with altered arginine metabolism.

AGEs are spontaneously glycated proteins or lipids, with intermediates that can modulate inflammatory responses. While persistent hyperglycaemia, dyslipidaemia, and oxidative stress accelerate AGE production, AGEs can also be consumed directly from food prepared with intense, dry heat.¹² Interactions between AGEs and their receptor (RAGE) can generate oxidative stress and perpetuate inflammation through activation of NF-kB.

Interactions between AGE and RAGE might be central in asthma pathogenesis, as evidenced by increased activity seen in patients with asthma.¹³ Experimentally, RAGE-knockout mice exhibited decreases in airway hypersensitivity, eosinophilic inflammation, airway re-modelling, and inflammatory cytokines.³ Similar findings were seen with pharmacological RAGE inhibition, although no studies have yet evaluated GLP-1 as a RAGE inhibitor in asthma.¹⁴

This GLP-1-arginine–AGE-RAGE axis might be particularly important in advancing the understanding of interactions between obesity, asthma, and lung inflammation. Research into alternative mechanisms of disease and therapies is imperative. By inhibiting RAGE-mediated and arginine-mediated inflammation by the GLP-1 pathway, we might be able to offer a novel therapy in asthma. Currently, the most advanced asthma therapies are aimed at traditional models of allergic inflammation, such as blocking immunoglobulin E or interleukin-5. However, these therapies are expensive and ineffective in non-allergic phenotypes of asthma.

GLP-1R agonists are safe, ready-to-use drugs for both laboratory and clinical research. Results of randomised, controlled trials¹⁵ show reduced cardiovascular complications and death in patients with type 2 diabetes using GLP-1 receptor agonists. Although the cardiovascular implications of diabetes, obesity, and metabolic syndrome are clearly understood and recognised, the consequences to respiratory health are much less appreciated.

Similarly, asthma is a complicated syndrome with many different presentations. By recognising that the lung is only one interactive part of an intricate system, we might be able to draw insight from other disciplines of research to find new treatments. With further investigation, perhaps we will find that by treating the concurrent metabolic syndrome, we might also treat the related metabolic asthma.