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Introduction The prevalence of type 2 diabetes (T2D) has surged, yet body mass index (BMI) fails to explain the 30%–40% of cases that occur in individuals with a healthy weight. Emerging evidence suggests that regional fat distribution differentially impacts glucose metabolism, independent of total adiposity. This study investigated the independent association between regional body composition and T2D risk using BMI-matched National Health and Nutrition Examination Survey (NHANES) data to identify sex-specific effects and the mediating role of insulin resistance.Research design and methods Our study employed data from the 2011–2018 cycles of NHANES. Participants were classified into a high-risk T2D group if they met one or more of the following criteria: fasting blood glucose≥6.1 mmol/L, 2-hour blood glucose≥7.8 mmol/L following an oral glucose tolerance test or self-reported physician’s diagnosis of diabetes or pre-diabetes. Body composition data were assessed via dual-energy X-ray absorptiometry, which provides a precise assessment of regional fat and muscle mass distribution.Results Participants at high T2D risk exhibited significantly reduced lower limb fat mass compared with healthy controls (p <0.001), with higher amounts of lower limb fat serving as a protective factor against both diabetes and insulin resistance. Notably, this protective effect of lower-limb fat (OR 0.86 (0.76–0.97), p=0.01) along with the detrimental impact of visceral fat (OR 7.35 (1.57–34.4), p=0.01) was particularly pronounced in male subjects. Additionally, 36.18% of the protective effect of lower limb fat on diabetes is mediated by improved insulin sensitivity.Conclusions This study delineates a protective role for lower-body fat in diabetes pathogenesis, mediated substantially through ameliorating insulin resistance. The sex-specific associations underscore the protective effect of lower-body fat and the detrimental impact of visceral adiposity in men after controlling for BMI.