Abstract
BACKGROUND AND PURPOSE: Observational studies suggest an association between insulin resistance (IR) and chronic obstructive pulmonary disease (COPD), but this link is susceptible to confounding and reverse causality. This study integrated cross-sectional analysis with Mendelian Randomization (MR) to systematically evaluate their potential causal relationship. METHODS: Using NHANES data, we employed complex sampling weighting and multivariable logistic regression to assess the observational association between IR (measured by HOMA-IR) and COPD. For genetic analysis, genetic variants strongly associated with IR were selected as instrumental variables from GWAS summary data. Two-sample MR analyses were conducted using inverse-variance weighted (IVW), weighted median, and MR-Egger regression, with rigorous testing for pleiotropy and heterogeneity. RESULTS: Observational analysis showed no significant association before confounder adjustment (P=0.166). After adjustment, moderate IR levels (third quintile) were associated with increased COPD risk (OR=2.24, 95% CI: 1.15-4.37, P=0.018). MR analysis revealed inconsistent estimates: IVW suggested a weak risk effect (OR=1.009, P<0.001), while MR-Egger indicated a protective effect (OR=0.998, P=1.54e-05). The MR-Egger intercept test detected significant horizontal pleiotropy (P<2e-16), indicating that genetic instruments influence COPD through pathways independent of IR, violating a key MR assumption. The genetic effect sizes were extremely small and not clinically meaningful. CONCLUSION: This integrated analysis does not support an independent causal role of IR in COPD. The observational association is confounded and non-linear, while genetic evidence is undermined by substantial pleiotropy. Therefore, IR should be regarded as a comorbid risk marker reflecting a systemic metabolic-inflammatory state rather than a direct causal target. For COPD patients with comorbid IR, clinical management should shift from targeting a single metabolic parameter toward a comprehensive strategy grounded in smoking cessation and pulmonary rehabilitation, alongside active management of obesity and dyslipidemia. Future research should prioritize elucidating the common upstream mechanisms linking metabolic dysregulation and lung function decline.