The mediating role of testosterone in the relationship between body fat percentage and diabetes mellitus risk.

BACKGROUND

Obesity is one of the major risk factors for diabetes mellitus (DM), and testosterone plays a pivotal role in metabolic regulation. However, it remains unclear whether testosterone exerts a mediating effect in the association between body fat percentage (BFP) and DM.

METHODS

Clinical data (N = 4433) from Shengjing Hospital were used to assess the BFP-DM association, modeled via restricted cubic spline (RCS). Cross-sectional data from the National Health and Nutrition Examination Survey (NHANES, N = 4772) were then used for observational validation of the mediating pathway and analysis of gender differences. Cross-sectional NHANES data validated the mediating pathway and examined gender differences. Causal relationships of BFP with a mediator (testosterone) and outcomes (blood glucose, T1DM, T2DM) were evaluated using Mendelian randomization (MR), with inverse variance weighting (IVW) as the primary analysis. Sensitivity analyses (MR-Egger, weighted median, MR-PRESSO) assessed pleiotropy and heterogeneity.

RESULTS

Clinical data showed BFP was associated with DM (OR = 2.684, 95% CI 1.981-3.638). NHANES results indicated testosterone may mediate the BFP-DM association, accounting for 6.24% (95% CI 2.84%-10.68%) of the total effect, with significant gender differences: significant in males (14.92%, 95% CI 6.49%-25.29%) but not in females. MR analysis validated these associations: higher BFP may elevate blood glucose (OR = 1.147, 95% CI 1.097-1.200) and T2DM risk (OR = 2.456, 95% CI 2.120-2.845), while reducing testosterone (OR = 0.614, 95% CI 0.521-0.724). Mediation analysis showed testosterone partially mediated BFP's effect on blood glucose (8.63%, 95% CI 2.19%-15.10%) and T2DM risk (3.80%, 95% CI 0.62%-6.98%), but no significant mediation was found for BFP and T1DM.

CONCLUSION

This study speculates that testosterone partially mediates the effect of BFP on DM risk, especially in males. However, further prospective studies are needed to confirm these findings.