Mechanisms of Obesity-related Asthma: Is Insulin Getting on Your Nerves?

To the Editor:

Obesity increases both the incidence and the severity of asthma. Obese asthmatics experience more frequent exacerbations and often respond poorly to currently available asthma medications, which increases healthcare costs and leads to decreased quality of life. Prevention and management of this difficult disease are complicated by the lack of complete understanding of its underlying molecular mechanisms. Although systemic inflammatory mediators, including IL-1β, IL-4, IL-5, and TNF-α (tumor necrosis factor-α), are increased in obesity and metabolic syndrome, their causal role in obesity-related asthma in humans has not been demonstrated (1). Furthermore, increased bronchoconstriction is independent of airway inflammation in obese animals. Clearly, our existing inflammatory paradigms, which have produced significant therapeutic advances for other phenotypes and/or endotypes of asthma, require reexamination in the context of an obesity-related phenotype.

A recent study by Peters and colleagues (2) shows that insulin resistance is independently associated with airflow limitation, blunted treatment responses, and accelerated lung function decline over time in a SARP-3 (Severe Asthma Research Program–3) cohort. Their analysis demonstrates that effects of excess body mass on chest wall mechanics are unlikely to fully explain this association after correcting for body mass index in regression models. Their findings are consistent with those of previous studies, showing that insulin resistance is associated with increased asthma risk. The causal role of insulin resistance in asthma development is suggested by studies showing that insulin resistance frequently precedes the development of asthma symptoms and is associated with worse lung function in humans.

The authors, and an accompanying editorial (3), proposed several potential mechanisms to explain this relationship among insulin resistance, obesity, and asthma. Overlooked in this discussion, however, is the critical role of hyperinsulinemia in development of airway hyperresponsiveness due to nerve dysfunction. Airway parasympathetic nerves, which provide the dominant control of bronchoconstriction through the release of acetylcholine, become hyperresponsive to airway stimulation in the setting of hyperinsulinemia (4), which is usually a compensatory consequence of insulin resistance. Specifically, high concentrations of circulating insulin increase neuronal acetylcholine release by disrupting presynaptic, inhibitory M₂ muscarinic receptor function on parasympathetic nerves. Loss of M₂ receptor function and subsequent increased acetylcholine release increase bronchoconstriction (5). Experimentally, hyperinsulinemia’s effects are attenuated by insulin-lowering agents such as metformin and pioglitazone (4, 6, 7).

Interestingly, in Peters and colleagues’ study (2), the magnitude of insulin’s effect on lung function decline over time in their longitudinal analyses may have been underrepresented because of their use of HOMA-IR (homeostatic model assessment for insulin resistance) only, which is calculated by multiplying fasting plasma glucose (mg/dl) by serum insulin (mIU/ml) and dividing by 405. On the basis of this formula, the main driver of increased HOMA-IR scores may be elevated insulin concentrations during insulin resistance, such as in the prediabetic or early stages of type 2 diabetes, or markedly elevated blood glucose concentrations due to decreased insulin secretion caused by pancreatic decline, as in the late stage of type 2 diabetes. Thus, using HOMA-IR alone in an analysis of the relationship between metabolic disorders and lung function may miss the opportunity to uncover the association between insulin and reduced lung function, which has been shown before in cross-sectional studies and clinical trials. Further exploration and corroboration of insulin concentration and decline of lung function in clinical trials should therefore be of great interest.

Overall, this study has important clinical implications regarding the independent role of insulin resistance in the decline of lung function in obese asthmatics. Results from Peters and colleagues (2) and other relevant investigations (4, 6, 7) provide a strong rationale for designing clinical trials to test whether inhibiting hyperinsulinemia, both alone and in combination with antagonists of nerve-mediated bronchoconstriction (e.g., tiotropium), is an effective treatment for obesity-related asthma.