Sun SQ, Liang SZ, Huang Q, Sun JZ. Methylation status of leptin gene promoter in relatively lean Chinese adults with prediabetes and type 2 diabetes mellitus. World J Diabetes 2025; 16(12): 112789 [DOI: 10.4239/wjd.v16.i12.112789]
Corresponding Author of This Article
Jia-Zhong Sun, Chief, Professor, Department of Endocrinology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan 430071, Hubei Province, China. sjz300@163.com
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Endocrinology & Metabolism
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Basic Study
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Dec 15, 2025 (publication date) through Dec 15, 2025
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World Journal of Diabetes
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1948-9358
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Sun SQ, Liang SZ, Huang Q, Sun JZ. Methylation status of leptin gene promoter in relatively lean Chinese adults with prediabetes and type 2 diabetes mellitus. World J Diabetes 2025; 16(12): 112789 [DOI: 10.4239/wjd.v16.i12.112789]
World J Diabetes. Dec 15, 2025; 16(12): 112789 Published online Dec 15, 2025. doi: 10.4239/wjd.v16.i12.112789
Methylation status of leptin gene promoter in relatively lean Chinese adults with prediabetes and type 2 diabetes mellitus
Shi-Qi Sun, Sheng-Ze Liang, Qi Huang, Jia-Zhong Sun
Shi-Qi Sun, Sheng-Ze Liang, Clinical Laboratory, The Sixth Hospital of Wuhan (Affiliated Hospital of Jianghan University), Wuhan 430014, Hubei Province, China
Qi Huang, Jia-Zhong Sun, Department of Endocrinology, Zhongnan Hospital of Wuhan University, Wuhan 430071, Hubei Province, China
Author contributions: Sun SQ designed the study and performed methylation experiments and statistical analysis; Liang SZ collected clinical samples and conducted enzyme-linked immunosorbent assay and data curation; Huang Q assisted in molecular assays and manuscript drafting; Sun JZ as corresponding author supervised the project, secured funding, revised the manuscript critically, and approved the final version; all authors reviewed and approved the manuscript.
Institutional review board statement: This study was conducted following the ethical standards outlined in the Declaration of Helsinki. Ethical clearance was obtained from the Institutional Review Board of Zhongnan Hospital of Wuhan University (No. 2025054KJ).
Conflict-of-interest statement: The authors declare that they have no competing interests. All stages of the study, including data analysis and interpretation, were performed independently and were free from any external financial, professional, or institutional influence.
Data sharing statement: The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jia-Zhong Sun, Chief, Professor, Department of Endocrinology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuhan 430071, Hubei Province, China. sjz300@163.com
Received: August 6, 2025 Revised: September 29, 2025 Accepted: October 29, 2025 Published online: December 15, 2025 Processing time: 131 Days and 12.1 Hours
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/m2].
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/m2. 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.
Core Tip: This study reveals progressive hypomethylation of the leptin (LEP) gene promoter in peripheral leukocytes of relatively lean Chinese adults (body mass index < 24 kg/m2) across glycemic states: (1) Normoglycemia (59.2%); (2) Prediabetes (43.6%); and (3) Type 2 diabetes mellitus (31.5%). The methylation decline correlated inversely with serum LEP levels (r = -0.95, P < 0.001), suggesting epigenetic dysregulation precedes metabolic dysfunction independent of obesity. These findings position LEP promoter methylation as a potential blood-based biomarker for early diabetes risk stratification in lean populations, highlighting its clinical utility for preventive strategies.
