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Prior studies report slightly lower prostate-specific antigen (PSA) levels among obese men. To understand this effect, we investigated the association between PSA and blood HbA1c, C-peptide, leptin and adiponectin levels in African-American (AA) (n=121) and Caucasian (CA) (n=121) men. Among AA men, PSA levels decreased with increasing C-peptide levels (PSA=0.99, 0.93, 0.75 and 0.53 ng ml(-1) across quartiles of C-peptide, respectively; P(trend)=0.005). Among CA men, PSA levels decreased with increasing HbA1c (PSA=0.84, 0.73, 0.77 and 0.45 ng ml(-1) across quartiles of HbA1c, respectively; P(trend)=0.005). This may suggest that metabolic disturbances related to metabolic syndrome or diabetes affect the ability to detect early-stage prostate cancer.