Abstract
BACKGROUND: Epigenetic regulation of leptin (LEP) plays a critical role in metabolic disorders, yet its promoter methylation patterns in lean diabetic populations remain poorly characterized. Emerging evidence suggests DNA methylation may precede clinical hyperglycemia, offering potential for early risk stratification. While obesity-associated LEP methylation is well-studied, lean Asian populations who exhibit high diabetes prevalence despite lower adiposity, represent an underexplored cohort. This study hypothesizes that LEP promoter methylation in peripheral leukocytes decreases progressively from normoglycemia to prediabetes and type 2 diabetes mellitus (T2DM), correlating inversely with serum LEP levels in lean Chinese adults [body mass index (BMI) < 24 kg/m(2)]. AIM: To investigate LEP promoter methylation status and its association with serum LEP levels across glycemic states in lean Chinese adults. METHODS: We enrolled 392 participants including 120 normoglycemic controls, 94 prediabetes [44 impaired fasting glucose (IFG)/50 impaired glucose tolerance (IGT)], 178 T2DM aged 40-60 years with BMI < 24 kg/m(2). Genomic DNA from peripheral leukocytes underwent bisulfite conversion followed by methylation-specific PCR to assess CpG methylation in the LEP promoter. Serum LEP was quantified via enzyme-linked immunosorbent assay, with other parameters measured through standard assays. Statistical analyses included analysis of variance, χ² tests, and Pearson correlation (Bonferroni-corrected P value). RESULTS: Methylation frequencies declined progressively: 59.2% (controls) reduced to 43.6% (prediabetes; IFG: 38.6%, IGT: 48%) reduced to 31.5% (T2DM) (all P < 0.05 vs controls; T2DM vs IGT: P = 0.030). Serum LEP levels increased significantly in T2DM (16.94 ± 4.19 μg/L) vs controls (11.33 ± 3.10 μg/L; P = 0.002), with intermediate values in prediabetes (IFG: 13.79 ± 3.32 μg/L; IGT: 12.62 ± 4.81 μg/L). A near-perfect inverse correlation between methylation and LEP levels was observed (r = -0.95, 95%CI: -0.97 to -0.92, P < 0.001), persisting after adjusting for age and BMI (β = -0.91, P < 0.001). CONCLUSION: LEP promoter hypomethylation parallels worsening glycemic status in lean Chinese adults, suggesting its potential as a blood-based epigenetic biomarker for diabetes progression, pending validation in longitudinal cohorts.