Asthma diagnosis is not associated with reduced beta‐cell function in children and adolescents with obesity

Asthma and obesity frequently co-occur in children and adolescents, yet their combined metabolic implications remain unclear. Obesity is linked to reduced lung function and increased risk of asthma in this age group.1 Research over the past decade has clarified some of the links between the two conditions, where not only mechanical effects are of importance but also immunological aspects as both conditions are associated with systemic inflammation.1 Obesity is commonly associated with hyperinsulinemia and reduced insulin sensitivity. Interestingly, obesity with hyperinsulinemia and reduced insulin sensitivity measured during fasting conditions has been associated with reduced lung function and airway hyperresponsiveness (AHR) in children and adolescents.2-5 Inflammatory pathways are well known to affect insulin sensitivity, but they are also important players in regulating beta-cell function.6 However, whether coincident asthma and obesity in children and adolescents are associated with reduced beta-cell function and different measures of glucose-stimulated insulin secretion is not known. We hypothesized that adolescents with obesity and asthma may differ in beta-cell function when compared to adolescents with an equal degree of obesity but no asthma diagnosis. To test this, we matched children and adolescents (age 10–18 years) with obesity and asthma against children and adolescents with obesity but no asthma in a 1:1 ratio. Matching was done by age (within 6 months), sex, and body mass index (BMI) z-score (within 0.3 units). The individuals were part of the Uppsala Longitudinal Study of Childhood Obesity (ULSCO) cohort with oral glucose tolerance test (OGTT) data available from their first visit within the study. Study visits were between May 2013 and September 2020. Obesity was defined as a BMI z-score of >2 according to the WHO 2007 growth reference. Asthma was defined as having physician-diagnosed asthma and having been prescribed inhaled corticosteroids and/or an oral leukotriene-receptor antagonist for at least 3 months within 12 months before the study visit. With these criteria and matching, we could include 29 individuals in each group. The oral glucose tolerance test was done in the morning after overnight fasting. Subjects ingested 75 g glucose dissolved in water, and blood samples were drawn through a venous catheter at the time points −5, 5, 10, 15, 30, 60, 90, and 120 min from glucose intake. Plasma glucose was quantified by a glucose dehydrogenase method, serum insulin by an electrochemluminescence immunoassay, and plasma HDL-cholesterol and triglycerides were analyzed by a photometric method at the Uppsala University Hospital's central laboratory using an Architect c8000 instrument (Abbott Diagnostics, Solna, Sweden). Area under the curve for glucose and insulin was calculated by the trapezoid method with 0 as baseline. Beta-cell function was estimated by the insulinogenic index (IGI) and the oral disposition index (oDI). The IGI was calculated as (Insulin30min-Insulin−5min)/(Glucose30min-Glucose−5min) and the oDI was calculated as IGI × 1/Insulin−5min. We also assessed insulin sensitivity by the HOMA-IR, calculated as Glucose−5min × Insulin−5min/22.5, and by the single point insulin sensitivity estimator (SPISE), validated for pediatric use, as 600 × HDL-cholesterol0.185/(Triglycerides0.2 × BMI1.338).7 Differences between the asthma and no asthma group in insulin resistance indices, beta-cell function indices, AUCglucose, and AUCinsulin were tested with a two-sided, unpaired bootstrap T-test with 9999 iterations, and are presented below as mean difference (asthma minus no asthma group) with the 95% bootstrap confidence interval of the difference. The average age, BMI z-scores, and sex distribution (66% males) were highly similar in the two groups (Table 1). There was no difference between children and adolescents with and without asthma in: plasma AUCglucose (−32 [−102, 38]) or AUCinsulin (−865 [−6533, 4433]) during the OGTT (Figure 1), IGI (9.9 [−8.7, 28.3]), oDI (0.47 [−0.39, 1.48]), SPISE (−0.04 [−0.55, 0.48]), HOMA-IR (0.17 [−2.2, 2.4]), or fasting insulin (2.6 mU/L [−6.1, 11.0], Table 1). Furthermore, there was no difference in the proportion of impaired to normal glucose tolerance between subjects with and without asthma (34% vs. 38% of subjects). To the best of our knowledge, this is the first study of detailed OGTTs and indices of beta-cell function derived from glucose-stimulated insulin secretion in children and adolescents with obesity with and without asthma. Several previous studies show that low insulin sensitivity is associated with reduced lung function, AHR, and poor asthma control.2-5 However, most,2, 8, 9 although not all,3 studies find that there is no effect of asthma diagnosis per se on the degree of insulin sensitivity. Thus, even though we could not find any association between asthma diagnosis and beta-cell function, it is still quite possible that beta-cell function is associated with asthma outcomes such as lung function and AHR in pediatric obesity. The finding that insulin sensitivity seems to be more closely associated with lung function than with asthma diagnosis per se is in line with the fact that there is loss of lung function associated with obesity also in individuals that have not yet received a diagnosis of asthma.10 Furthermore, one could speculate that beta-cell function could be altered only in poorly controlled asthma with reduced lung function, and the absence of information regarding asthma control is a clear limitation in this study. The absence of information on dose and duration of inhaled corticosteroid treatment is also a limitation of this study, as high doses over long periods of time could interfere with endocrine pathways relevant for the studied outcome. Our study is merely an initial study that should be followed up with studies looking at objective asthma outcomes such as lung function as well as asthma control. An important limitation to the present study is the small groups in the present study, which limits our ability to detect small differences between groups. However, the groups were very well matched with regard to BMI and age, and our estimates point to, if anything, a slightly better beta-cell function in the asthma group. Thus, we believe that despite the statistical limitations, it is unlikely that there is a large and clinically relevant decrease of beta-cell function in asthma. Nevertheless, the results of the present study must be considered preliminary and need to be validated in larger study populations. In conclusion, our study indicates that children and adolescents with obesity and asthma do not have different beta-cell function during oral glucose intake compared to individuals without asthma with equal degree of obesity. Future studies on a larger scale are needed to confirm the absence of an association between asthma and beta-cell function in pediatric obesity. Hannes Manell: Conceptualization; investigation; writing – original draft; methodology; visualization; formal analysis. Rasmus Stenlid: Conceptualization; investigation; methodology; writing – review and editing. Kjell Alving: Funding acquisition; conceptualization; writing – review and editing; supervision; resources; methodology. This research leading to this work was supported by the European Union's Seventh Framework Programme (FP7/2007–2013) under grant agreement number 279153 (Beta-JUDO), the Uppsala-Örebro Regional Research Council, Knut and Alice Wallenberg Foundation, and the Swedish Heart-Lung Foundation. The authors report no conflict of interest related to this work. The study was approved by the Uppsala County regional ethics committee (registration numbers 2009/349, 2010/036 and 2012/318). Written informed consent was obtained from study subjects, and written informed consent was also obtained by the subjects' legal guardians. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/pai.70198.