Discussion
By meticulously matching participants for age, sex, and BMI, we minimized the confounding effects of these variables, thereby isolating the unique contribution of regional fat and muscle to diabetes pathogenesis. Our study provides novel insights into the sex-specific associations between body composition and diabetes risk.
The negative association between lower limb fat mass and diabetes risk, particularly in men, aligns with emerging evidence.11 39 40 Unlike visceral fat, which releases proinflammatory cytokines and free fatty acids that impair insulin signaling, lower body adiposity possibly acts as a ‘metabolic sink’, sequestering excess lipids and reducing ectopic fat deposition in organs such as the liver and pancreas.12 Our mediation analysis further supports this hypothesis, demonstrating that 36.18% of the protective effect of lower limb fat mass on diabetes is mediated by improved insulin sensitivity (HOMA-IR).
Our subgroup sex-specific results showed the robust protective effect of lower limb fat mass against diabetes in men and its non-significance in women, coupled with the male-specific detrimental impact of visceral adiposity. This may be attributed to the significant effects of sex hormones on fat mass and distribution. Estrogen promotes the storage of subcutaneous adiposity instead of visceral adiposity, primarily in the gluteal and femoral regions, resulting in greater lower-body fat accumulation in women compared with men.41 Androgens promote VAT accumulation, predisposing to central obesity and impairment of insulin sensitivity.42 43 VAT in men exhibits heightened secretion of proinflammatory cytokines (interleukin 6, tumor necrosis factor-α), while the ‘metabolic buffering’ capacity of lower-body fat assumes greater physiological significance in male individuals.44 45
To our knowledge, this study provides the first evidence that lower-body fat influences diabetes risk through the mediating effect of insulin resistance in BMI-matched individuals. Current reliance on BMI obscures critical variations in fat distribution, lower-body fat distribution, particularly for men with normal BMI but adverse fat distribution (higher visceral adiposity combined with lower limb fat mass), may serve as a novel protective marker against T2D, partially mediated by ameliorating insulin resistance. For men, interventions specifically targeting visceral fat reduction—such as high-intensity interval training, resistance exercise, and dietary modifications focused on reducing refined carbohydrates—may yield greater metabolic benefits than general weight loss approaches alone. Clinical interventions targeting fat redistribution, particularly those combining aerobic exercise, resistance training, and nutritional strategies, warrant further exploration in sex-specific diabetes prevention strategies. While challenging, such targeted approaches are becoming increasingly feasible through personalized exercise prescriptions and nutritional interventions that account for sex-specific metabolic responses.
Our investigation did not find a significant association between muscle mass and T2D risk, challenging the conventional view of muscle mass as uniformly protective. It may suggest that assessing muscle mass in combination with functional parameters (such as handgrip strength) or fat infiltration provides a more comprehensive evaluation of the muscle’s impact on glucose metabolism than using individual metrics alone.46–48 In addition, participants in our study are younger than 60 years of age, who have not totally experienced age-related muscle mass declines. Furthermore, myosteatosis (pathological fat infiltration within muscle tissue) may counteract the beneficial effects of muscle mass, necessitating assessment via CT/MRI imaging modalities to quantify muscle fat infiltration.49 50
Moreover, several limitations warrant acknowledgment. Our sample’s demographic scope may limit generalizability, and unmeasured confounders like dietary patterns could influence associations. In addition, we prioritized reporting unadjusted p values in this exploratory analysis to avoid overcorrection and a potential loss of statistical power for identifying novel associations. The findings regarding the sex-specific protective role of lower limb fat require confirmation in future confirmatory studies. Future research should combine advanced imaging (CT, DXA/MRI) with omics profiling to unravel molecular pathways linking regional adiposity to insulin sensitivity.
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