Sex Differences in the Association Between Insulin Resistance and Systemic Inflammation Below the HbA1c Prediabetes Threshold: NHANES 2015–March 2020

Insulin resistance and systemic inflammation are closely linked, but their association may differ by sex even before conventional glycemic thresholds for prediabetes are reached. This study examined whether sex modifies the association between insulin resistance, assessed using the homeostatic model assessment of insulin resistance (HOMA-IR), and systemic inflammation, assessed using high-sensitivity C-reactive protein (hsCRP), among U.S. adults aged 20 years or older without diagnosed diabetes and with HbA1c <5.7%. Using nationally representative NHANES 2015–March 2020 pre-pandemic data and survey-weighted regression, we identified evidence of a sex difference in the adjusted HOMA-IR–hsCRP association. The association was more positive among women than men in the primary analysis. This contrast was robust across alternative HOMA-IR transformations, upper-tail restrictions, adiposity specifications, and targeted sensitivity analyses addressing smoking, statin use, renal and hepatic measures, alcohol use, and pregnancy. However, restricting the analysis to participants with hsCRP ≤10 mg/L attenuated the estimated sex difference by approximately 51%, indicating that the observed heterogeneity is partly sensitive to the upper range of hsCRP. This Zenodo record contains the manuscript, supplementary material, and the archived v1.0.0 computational repository supporting the study. The repository includes reproducible Python analysis code, aggregate analysis outputs, sensitivity analyses and diagnostics, figures, documentation, and independent R validation of the primary interaction model. Raw NHANES data and participant-level derived datasets are not redistributed; the source NHANES data are publicly available from the National Center for Health Statistics.