A latent metabolic dysfunction phenotype integrating insulin resistance and leptin is associated with disease...

Chronic obstructive pulmonary disease (COPD) is increasingly recognised as a systemic condition in which metabolic dysfunction may influence disease severity and exacerbation risk. The combined effects of insulin resistance and leptin dysregulation on COPD outcomes remain incompletely defined. This study evaluated their associations with exacerbation burden, airflow limitation and patient-reported outcomes, and assessed the discriminative performance of HOMA-IR and serum leptin for identifying advanced disease.

A cross-sectional observational study was conducted at a tertiary care centre in southern Romania, including 96 patients with COPD and 24 healthy controls. Fasting insulin and serum leptin were measured, and insulin resistance was assessed using HOMA-IR. Spirometry and patient-reported outcomes (CAT, mMRC and SGRQ-C) were assessed in COPD patients. Metabolic markers were analysed individually and as a latent metabolic dysfunction phenotype using generalized structural equation modelling (GSEM).

Compared with controls, COPD patients had higher HOMA-IR (+206.9%), insulin (+112.2%) and leptin (+52.8%) levels. Both HOMA-IR and leptin were inversely correlated with spirometric indices, with stronger associations observed for HOMA-IR. Within the COPD cohort, neither individual metabolic markers nor a latent metabolic dysfunction phenotype integrating HOMA-IR, body mass index and leptin was associated with annual exacerbation rate (latent factor IRR = 1.089, 95% CI: 0.841-1.410, p = 0.517). HOMA-IR demonstrated better discrimination of advanced disease than leptin (AUC = 0.769 vs. 0.590, p < 0.001).

Metabolic dysfunction is substantially more pronounced in COPD than in individuals without airflow obstruction and correlates with the degree of airflow limitation, but does not independently predict exacerbation frequency within the COPD population. HOMA-IR outperformed leptin as a marker of disease severity, a finding that requires further validation.