A32-02 Imbalance in Circulating Advanced Glycation End-Products With Its Soluble Receptor Associates With Small Airways Dysfunction and Poor Asthma Control

Abstract Rationale Hyperglycemia and diabetes are associated with worse asthma, but the mechanism is unknown. Hyperglycemia promotes production of advanced glycation end-products (AGEs) which, upon binding with its receptor RAGE, induces downstream cellular inflammation and oxidative stress, a pathway implicated in diabetes end-organ diseases. The soluble form of RAGE (sRAGE) experimentally constrains RAGE activity by acting as a decoy receptor. In a local asthma cohort, we previously reported that lower circulating sRAGE associates with hyperglycemia and impaired spirometry independent of obesity and steroid exposure, suggesting that the RAGE axis may connect glucose dysregulation with worse asthma. Thus, we aimed to determine whether N3-carboxymethyllysine (CML), the predominant circulating AGE, and the CML/sRAGE ratio, reflecting balance of AGEs with its counterpart, are associated with asthma outcomes. Methods We analyzed data from 53 adults with physician-diagnosed asthma who were not on medications for dyslipidemia, diabetes, or hypertension. Participants completed asthma control questionnaires and underwent pre-bronchodilator spirometry and oscillometry with percent-predicted values calculated using GLI race-neutral (spirometry) and Oostveen (oscillometry) equations. Serum sRAGE (R Minneapolis, MN) and CML (MBL; Tokyo, Japan) were measured by ELISA, and hemoglobin A1c and fasting glucose were measured by Roche Cobas autoanalyzers. CML and CML/sRAGE ratio were log-transformed for analysis. Robust linear regression models evaluated associations between the CML and CML/sRAGE with spirometry, oscillometry, and asthma control scores, adjusted for BMI and steroid exposure. Analyses were conducted in Stata 18 (StataCorp, TX), and a 2-sided p 0.05 reflected statistical significance. Results The cohort was 77.4% female with a mean age of 39±17 years. Mean sRAGE was 961±429pg/mL and mean CML was 4.43±2.01μg/mL. The CML/sRAGE ratio, but not CML, inversely correlated with glycemic control (for A1c, r = −0.45, p=0.01; for glucose, r = −0.39, p=0.02). After adjustment, a one standard deviation increase in log (CML/sRAGE) was associated with lower percent-predicted FEV1 and FVC and abnormal oscillometry consistent with small airways disease, including higher percent-predicted area of reactance and resonant frequency. Elevated CML/sRAGE ratio was also associated with worse ACQ-6 but not with ACT score. Notably and as previously reported, sRAGE was only associated with lower percent predicted FEV1 and FVC. Conclusions An imbalance in circulating AGE relative to sRAGE, more so than AGE or sRAGE alone, is associated with alteration in lung physiology. These findings suggest that disorders of glucose metabolism may impact small airway function through the RAGE axis, representing a potential therapeutic target for adults with asthma characterized by subclinical hyperglycemia. This abstract is funded by: NIH