Hyperglycemia, receptor for advanced glycation end products, and small airways dysfunction in asthma.

Salas PS, Villareal DT, Tejwani V, Koirala A, Coarfa C, McCormack MC, Hanania NA, Wu TD. Hyperglycemia, receptor for advanced glycation end products, and small airways dysfunction in asthma. Annals of Allergy, Asthma & Immunology : Official Publication of The American College of Allergy, Asthma, & Immunology. 2026 Feb 1; 136(2):173-179.e3, DOI: 10.1016/j.anai.2025.10.023.

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Abstract:

BACKGROUND: Diabetes and insulin resistance are associated with higher risk of asthma exacerbation and preserved ratio impaired spirometry (PRISm), but the pathophysiology is unclear. These conditions may cause small airways dysfunction (SAD), which is an under-recognized cause of PRISm. OBJECTIVE: To determine whether insulin resistance and poor glucose control associate with SAD and to explore whether proteins prognostic of diabetes end-organ complications predict lung function abnormalities. METHODS: We recruited a prospective cohort of adults with physician-diagnosed asthma. Fasting insulin, glucose, hemoglobin A1c, and concentrations of 13 proteins prognostic of diabetes end-organ complications were measured. Static insulin resistance was calculated by the homeostatic model assessment of insulin resistance. Lung function was measured by spirometry, and SAD was assessed by impulse oscillometry. RESULTS: A total of 65 participants were recruited. Mean body mass index was 32.7 kg/m and 77% were female. There was effect modification by whether participants were taking medications for diabetes, dyslipidemia, or hypertension. Among 53 participants without treated metabolic disease, elevated hemoglobin A1c level was associated with oscillometry abnormalities consistent with SAD and higher odds of PRISm (adjusted odds ratio 5.12; 95% CI 1.15-22.55). Serum soluble receptor for advanced glycation end products, a protein protective of diabetes end-organ complications and which also suppresses airway inflammation in asthma, was associated with lower systemic inflammation, lower hemoglobin A1c level, and improved lung function. CONCLUSION: Hyperglycemia was associated with SAD and PRISm in asthma. Soluble receptor for advanced glycation end products may be a biomarker of hyperglycemia-associated lung dysfunction. Longitudinal study is necessary to validate biomarker relationships and understand structural and physiological consequences.