Obesity, Insulin Resistance, and Asthma

Many pulmonologists, although familiar with the consequences of different respiratory diseases coexisting in the same individual, may be less aware of the potential interactions between those respiratory diseases and metabolic disease (1, 2). In 1976, the forerunner of the Journal published novel work by Schuyler and colleagues showing that young nonsmoking adults with diabetes exhibited lower total lung capacities and poorer elastic recoil (3). Since then, evidence of connections between lung health and diabetes or insulin resistance (IR) has grown (1, 2), including studies linking lower spirometry values to diabetes (4) and to IR in the absence of diabetes (5), even after accounting for coexisting obesity. More recently, IR has been linked to the rate of lung function decline among older individuals (6). A particular role for IR in the “obese asthma” phenotype, which can be challenging to treat, has been suggested by the finding that the relationship between obesity and current asthma is stronger with increasing IR (7). This has stimulated the hypothesis that for some patients, the inflammation driving their asthma may be driven partly by systemic metabolic abnormalities (8). This could result from shared immunological mechanisms that underlie the different disease processes, or from metabolically induced modification of inflammatory responses, raising the possibility that drugs aimed at treating IR may be of benefit to the control of coexisting asthma (8). Analysis of health records has already shown an association between prescription of GLP1R (glucagon-like peptide-1 receptor) agonists for type 2 diabetes and lower asthma exacerbation rates (9). The global rise in obesity, poor metabolic health, and chronic airway disease adds impetus to both understanding their interrelatedness and determining how best to manage or prevent them.

In this issue of the Journal, Peters and colleagues (pp. 1096–1106) explore how IR among subjects with asthma relates to lung function trajectories and lung function responses to β adrenergic agonists and corticosteroids (10). They sampled data from the NHLBI’s Severe Asthma Research Program III, which characterized a cohort of late middle-aged individuals with severe asthma in detail and then followed them longitudinally. A major study strength is the inclusion of reliable biochemical markers of metabolic dysfunction and asthma-related characteristics. Their measure of IR was the homeostatic model assessment of IR (HOMA-IR), calculated by multiplying fasting plasma glucose (mg/dl) by the serum insulin value (mIU/ml) and dividing by 405. One hundred sixty-seven patients without IR had HOMA-IR < 3, 63 with moderate IR had HOMAR-IR between 3 and 5, and 77 patients had severe IR with HOMA-IR > 5. In keeping with prior studies, obesity and IR appeared common among patients with asthma, and IR was associated with lower lung function at enrollment and a steeper rate of FEV₁ decline across 5 years of follow-up. The authors also show a blunting of the bronchodilator and corticosteroid response among those with IR, and these individuals exhibited features of previously described type 2 inflammation, namely, lower sputum eosinophil counts (11). On the basis of these findings, the authors suggest that IR may have led to the cross-sectional decrements and accelerated the longitudinal decline in lung function observed within this asthma cohort.

Although it provides stimulating data, an important caveat of this study is that it shows association, not causation (12). As the authors infer, IR could be driving lung function loss, but it is also possible that this association instead reflects the clustering of susceptibility factors in the same individuals (1). Exposures we encounter across our whole life course, and even prenatally, help shape our respiratory and metabolic health in adulthood. To list some relevant examples, gestational diabetes and obesity appear to be risk factors for the development of childhood asthma, while insulin appears to impair surfactant production, and childhood environmental exposures influence both adult lung function and BMI (2, 13–15). The direction of the relationships underlying the cross-sectional associations observed among lung function, obesity, and IR remains unclear. Similar uncertainty may also apply when interpreting the reported association between IR and lowered type 2 inflammation, evidenced by lower sputum eosinophil percentages. Importantly, cohort participants were not treatment naive or randomly assigned to treatment, and individuals in the insulin-resistant group were more commonly already receiving high-dose inhaled corticosteroid. More common corticosteroid suppression of airway inflammation and sputum eosinophils might therefore partly explain the inflammatory differences observed (16).

Although IR was measured partway through follow-up rather than at enrollment, the association noted between IR and accelerated FEV₁ decline adds to the ongoing debate over this relationship. Many readers may notice that the rate of FEV₁ loss in the non–insulin-resistant reference group (12 ml/yr) is lower than they might expect and lower than the range previously reported among nonsmoking, healthy, middle-aged individuals (17.7–46.4 ml/yr) (17). Further exploration and corroboration of this unexpectedly low rate of decline would be of some interest.

Notwithstanding the caveats regarding assuming causality, this study provides a stimulating argument for further scrutiny of the coexistence of asthma, IR, and obesity to ensure that we are managing affected individuals as effectively as possible. Further population studies, analysis of data sets from prior diabetic drug studies, or new randomized control trials of IR targeting therapies may provide support for the reported relationships and indicate whether there is potential for intervention. By widening our appreciation of the broad spectrum of biochemical pathways that lead to a diagnosis of adult asthma, we might also be able to identify valuable strategies to prevent obesity, IR, and asthma converging in later life.