Abstract Rationale Obesity increases asthma risk. Metabolic dysfunction may represent a distinct pathophysiologic pathway contributing to asthma severity and impaired lung function in obese individuals without diabetes. Methods A cross-sectional investigation was conducted in 71 obese (BMI ≥27 kg/m2) adults with uncontrolled (ACQ≥1.5) asthma despite treatment with medium-dose inhaled corticosteroids or greater therapy. Key exclusion criteria included COPD, diabetes, and biologic use. Participants underwent spirometry, induced sputum, blood sampling for differential cell count, glycated hemoglobin (HbA1c) and homeostatic model assessment for Insulin Resistance (HOMA-IR). Data are expressed as mean ±SD for normal and median IQR for non-normal distributed variables. Associations were evaluated using Spearman correlation and linear regression models. Group comparisons were performed with Mann-Whitney test. Results The participants were 47.7±13.7 years of age, 80% females, with BMI of 37.2 32.4-39.7 kg/m2, HbA1c 5.3 5.1-5.7 %, and HOMA-IR 3.8 2.4-5.7. Higher HOMA-IR was associated with worse asthma control (ACQ6; Rs = 0.29, p = 0.01) and reduced lung function (FEV₁% predicted, Rs= -0.25, p = 0.03; FVC% predicted, Rs = -0.30, p = 0.01). Participants with IR (HOMA-IR ≥2.5, n 51) had worse asthma control (ACQ6 of 2.5 vs 2.2, p = 0.008) and tended to have worse lung function (FEV1% predicted 74% vs 84%, p = 0.08), than those without IR (HOMA-IR 2.5). HbA1c inversely correlated with FEV₁% predicted (Rs -0.24, p = 0.04), and FVC% predicted (Rs -0.28, p = 0.01), and positively with daily inhaled corticosteroid exposure (Rs 0.23, p = 0.04), serum periostin (Rs 0.34, p = 0.01), and sputum eosinophils (Rs 0.39, p = 0.001). HbA1c remained positively associated with greater inhaled corticosteroid exposure (β = 257.3, p = 0.01) and serum periostin (β = 43.96, p = 0.003) after adjustment for age, sex, BMI, visceral adipose tissue, and airway eosinophilia. Participants with prediabetic HbA1c levels (≥5.7% and 6.5, n 19) exhibited greater sputum eosinophils (6.9% vs 2%, p = 0.02) and neutrophils (61% vs 55%, p = 0.09) and reduced (13% vs 24%, p = 0.005) macrophages, compared with participants with HbA1c 5.7%. Conclusion Obesity, through metabolic dysfunction, contributes to asthma pathophysiology beyond mechanical effects. Insulin resistance marked an early state of metabolic stress associated with poorer asthma control and reduced lung function. Altered glucose metabolism was independently linked to greater asthma severity, type-2 inflammation, and impaired pulmonary function, suggesting cumulative tissue-level injury and airway remodeling. Identification and targeted management of metabolic dysfunction in patients with asthma may enable mechanism-based interventions to reduce inflammation, preserve lung function, and prevent irreversible airway structural damage. This abstract is funded by: U01 AI155299
Tomasello et al. (Fri,) studied this question.