Association between serum dehydroepiandrosterone sulfate and type 2 diabetes in US adults with adiposity as a mediator

Dehydroepiandrosterone sulfate (DHEAS) is the most abundant adrenal androgen in circulation, yet its relationship with type 2 diabetes mellitus (T2DM) and the mediating role of adiposity remain unclear. We analyzed data from 4707 US adults (584 with T2DM, 4123 without diabetes) in the National Health and Nutrition Examination Survey 2021-2023. Serum DHEAS was quantified by isotope dilution LC-MS/MS. Survey-weighted logistic regression assessed the association between DHEAS and T2DM, adjusting sequentially for demographics, sex hormones, and measures of adiposity (body mass index, waist circumference, waist-to-hip ratio, and body roundness index). Restricted cubic splines tested for nonlinear relationships. Mediation analysis quantified the proportion of the DHEAS-T2DM association explained by adiposity. Median serum DHEAS was significantly lower in T2DM than in nondiabetic participants (1.28 vs 2.65 µmol/L; P < .001). Higher DHEAS was associated with reduced odds of T2DM after adjustment for demographics, hormones, and body mass index (per 1 µmol/L: odds ratio 0.87, 95% confidence interval 0.78-0.97). Individuals in the highest DHEAS quartile had lower T2DM odds compared with the lowest quartile (odds ratio 0.44, 95% confidence interval 0.20-0.99). Sex-stratified analysis showed a robust inverse association in men, but not in women. Restricted cubic splines analysis revealed a nonlinear, threshold effect, notably in men. Mediation analysis indicated that adiposity explained 14.4% to 21.8% of the inverse association. In a nationally representative US sample, higher serum DHEAS was independently associated with lower odds of T2DM, particularly among men, with partial mediation by adiposity, highlighting both adiposity-dependent and independent pathways.