The overlooked biochemical pathway: how insulin resistance (HOMA-IR) modulates "metabolic masking" of prostate-specific antigen separately from body mass index

Conventional prostate cancer screening profiles rely heavily on static serum prostate-specific antigen (PSA) thresholds, consistently overlooking the confounding impacts of the modern metabolic syndrome epidemic. This study aimed to isolate and quantify the long-term longitudinal impact of insulin resistance (HOMA-IR) and Body Mass Index (BMI) on serum PSA levels. We retrospectively evaluated 9095 routine annual screening records from 5,846 asymptomatic male subjects (2016–2026) with concurrent clinical data for PSA, HOMA-IR, BMI, and total testosterone. Linear Mixed-Effects Models with subject-specific random intercepts were constructed to rigorously account for intra-subject correlations across consecutive annual follow-up visits. Multi-variable longitudinal analysis demonstrated that while BMI exhibited a strong downward trend on baseline biomarkers (per-unit decrease of 0.018 ng/mL ( p = 0.057), elevated HOMA-IR served as a statistically significant, independent biochemical marker inversely associated with serum PSA ( p = 0.042). Crucially, categorical stratification revealed a highly significant, non-linear biomarker collapse: subjects in the highest cumulative metabolic burden quadrant (concurrent BMI ≽35 kg/m 2 and HOMA-IR > 3.0) exhibited a profound 34.8% reduction in age-adjusted serum PSA concentrations compared to metabolically healthy, normal-weight counterparts ( p < 0.001). "Metabolic masking" of serum PSA is a complex, two-pronged process characterized by physical hemodilution via tissue mass and cellular transcription-level suppression via chronic hyperinsulinemia. Transitioning away from simplistic weight-based corrections in clinical preventive screening guidelines along with systematic integration of insulin resistance profiles into individualized urological risk stratification may help eliminate this critical diagnostic blind spot.