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

Abstract

Background 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. Materials and methods 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. Results 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, independ ent 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/m2 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). Conclusions "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.