Role of Sex Hormones in Mediating Adiposity Changes from Weight Loss in People with Type 2 Diabetes: Look AHEAD Sex Hormone Study.

Background: In people with type 2 diabetes (T2D), weight loss impacts sex hormones (testosterone [T], estradiol [E2], sex hormone binding globulin [SHBG]) and reduces fat and lean mass differently in females vs males, but the relationship between sex hormones and adiposity changes due to weight loss is not clear.

Methods: We analyzed data from 2,334 participants (50% female) in the Look AHEAD Sex Hormone Ancillary Study, including a subset of 822 (47.4% female) with dual-energy X-ray absorptiometry scans. Using structural equation modeling, we assessed how changes in E2, T, and SHBG at year 1 (Y1) mediated the effects of intensive lifestyle intervention (ILI) on adiposity measures at year 4 (Y4). We stratified by sex to explore sex differences.

Results: In males, a 14.4% ILI-associated increase in total T at Y1 mediated increases in weight (189g, 95% CI: 65g-317g) and waist circumference (0.135cm, 95% CI: 0.19-0.248cm) at Y4. Additionally, a 24.6% increase in SHBG at Y1 mediated increases in both % trunk fat (0.082%, 95% CI: 0.003%-0.174%) and % whole-body fat (0.068%, 95% CI: 0.001%-0.146%) at Y4. In females, a 21.8% decrease in bioavailable testosterone (BioT) at Y1 mediated decreases in whole-body fat mass (-164g, 95% CI: -326g to -29.3g), whole-body lean mass (-115g, 95% CI: -203.4g to -40g), and trunk lean mass (-97.2g, 95% CI: -156g to -45.5g) at Y4.

Conclusion: The study revealed sex-specific mediating effects of sex hormones due to weight loss from ILI on body composition changes in people with T2D. Further research is needed to explore long-term health outcomes related to sex differences in recommendations for weight loss in people with T2D.