Diabetes & Metabolism Journal

Original Articles

Genetics
Elucidating the Epigenetic Landscape of Type 2 Diabetes Mellitus: A Multi-Omics Analysis Revealing Novel CpG Sites and Their Association with Cardiometabolic Traits: Ren-Hua Chung, Chun-Chao Wang, Djeane Debora Onthoni, Ben-Yang Liao, Tzu-Sheng Hsu, Eden R. Martin, Chao A. Hsiung, Wayne Huey-Herng Sheu, Hung-Yi Chiou; Diabetes Metab J. 2026;50(1):153-164. Published online October 28, 2025; DOI: https://doi.org/10.4093/dmj.2025.0041

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Background
Type 2 diabetes mellitus (T2DM) is a complex, multifactorial disease with a significant global burden. Although genome-wide association studies (GWAS) have identified many T2DM-associated variants, most lie in non-coding regions, making it difficult to interpret their functional roles.
Methods
We aimed to identify genetically regulated Cytosine–phosphate–Guanine (CpG) sites associated with T2DM by conducting a methylome-wide association study (MWAS), followed by Mendelian randomization (MR) and functional validation using human pancreatic cells and mouse models. MWAS was performed using summary statistics from large-scale GWAS and a DNA methylation (DNAm) prediction model to test associations between genetically predicted DNAm and T2DM.
Results
We identified 111 CpG sites significantly associated with T2DM in Europeans, including 8 novel sites near genes not previously linked to T2DM. These findings were replicated in independent datasets. Many CpGs also showed associations with cardiometabolic traits, highlighting shared epigenetic mechanisms. Trans-ethnic MR analysis confirmed consistent effects for six CpGs in East Asians. Functional analysis revealed that several CpGs regulate gene expression in human pancreatic α- and β-cells. Among them, 2´-5´-oligoadenylate synthetase like (OASL) expression, regulated by a significant CpG, was differentially expressed in α-cells of T2DM cases compared to controls. Supporting evidence from mouse models suggests a role for OASL in glucose regulation.
Conclusion
Our study identifies novel genetically regulated CpG sites associated with T2DM risk and highlights OASL as a potential epigenetic regulator of glucose metabolism in α-cells. These findings provide mechanistic insights into the epigenetic architecture of T2DM and suggest potential targets for cross-ethnic biomarker development and therapeutic intervention.

Citations

Citations to this article as recorded by

Unravelling the molecular mechanisms causal to type 2 diabetes across global populations and disease-relevant tissues
Ozvan Bocher, Ana Luiza Arruda, Satoshi Yoshiji, Chi Zhao, Alicia Huerta-Chagoya, Chen-Yang Su, Xianyong Yin, Davis Cammann, Henry J. Taylor, Jingchun Chen, Ken Suzuki, Ravi Mandla, Ta-Yu Yang, Fumihiko Matsuda, Josep M. Mercader, Jason Flannick, James B.
Nature Metabolism.2026; 8(2): 506. CrossRef

Pharmacotherapy
Acute Hyperinsulinemia during Hyperinsulinemic- Euglycemic Clamp Influences DNA Methylation and Gene Expression in Peripheral Blood Cells of Adult Men: Minjae Joo, Dongseong Shin, Xuan Trong Truong, Seungyoon Nam, Dae Ho Lee; Received January 25, 2025 Accepted July 1, 2025 Published online September 5, 2025; DOI: https://doi.org/10.4093/dmj.2025.0072 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Acute hyperinsulinemia may directly affect blood cells. In this study a hyperinsulinemic-euglycemic clamp (HEC) and multiomics methods were used to explore the epigenetic regulation by hyperinsulinemia in blood cells.
Methods
To assess short-term changes in DNA methylation (within 2 hours), blood samples were collected from five non-diabetic adults before and after HEC. mRNA sequencing (mRNA-seq) and targeted bisulfite sequencing (methyl-seq) were performed. Using mRNA-seq, 697 differentially expressed genes (DEGs) were identified, and methyl-seq was used to select those with changes in promoter or gene body methylation. In vitro validation study was also performed in THP1 and 3T3–L1 cells after acute insulin treatment.
Results
Among the 697 DEGs, 119 (henceforth, ‘methyl-DEGs’) showed methylation changes. Of these 697 DEGs, 45 (‘publictrait- DEGs’) were associated with pathways such as oxidative stress, insulin signaling, inflammation, and carbohydrate metabolism. Interaction networks between methyl-DEGs and public-trait-DEGs revealed that six genes (B3GALNT1, ESR1, FGF4, PER1, PRKAR1B, and TNFSF4) were affected by DNA methylation and linked to insulin response or diabetes. In response to acute insulin treatment, ESR1, PRKAR1B, PER1, and B3GALNT1 expression decreased in THP1 cells. Similar trends were seen in 3T3–L1 cells, except B3GALNT1. PER1 displayed consistent and significant downregulation across the clamp study and the two cell lines, indicating it as a key circadian-responsive gene under acute hyperinsulinemia.
Conclusion
These results provide epigenetic evidence for the role of DNA methylation in CpG regions and gene bodies in hyperinsulinemia- mediated regulation of gene expression in blood cells, which warrants further studies in relation to diabetes-related pathophysiology.

Review

Pathophysiology
Protein Arginine Methyltransferases: Emerging Targets in Cardiovascular and Metabolic Disease: Yan Zhang, Shibo Wei, Eun-Ju Jin, Yunju Jo, Chang-Myung Oh, Gyu-Un Bae, Jong-Sun Kang, Dongryeol Ryu; Diabetes Metab J. 2024;48(4):487-502. Published online July 24, 2024; DOI: https://doi.org/10.4093/dmj.2023.0362

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Cardiovascular diseases (CVDs) and metabolic disorders stand as formidable challenges that significantly impact the clinical outcomes and living quality for afflicted individuals. An intricate comprehension of the underlying mechanisms is paramount for the development of efficacious therapeutic strategies. Protein arginine methyltransferases (PRMTs), a class of enzymes responsible for the precise regulation of protein methylation, have ascended to pivotal roles and emerged as crucial regulators within the intrinsic pathophysiology of these diseases. Herein, we review recent advancements in research elucidating on the multifaceted involvements of PRMTs in cardiovascular system and metabolic diseases, contributing significantly to deepen our understanding of the pathogenesis and progression of these maladies. In addition, this review provides a comprehensive analysis to unveil the distinctive roles of PRMTs across diverse cell types implicated in cardiovascular and metabolic disorders, which holds great potential to reveal novel therapeutic interventions targeting PRMTs, thus presenting promising perspectives to effectively address the substantial global burden imposed by CVDs and metabolic disorders.

Citations

Citations to this article as recorded by

Protein Arginine Methyltransferase 1: A Multi-Purpose Player in the Development of Cancer and Metabolic Disease
Daphne de Korte, Menno Hoekstra
Biomolecules.2025; 15(2): 185. CrossRef
Arginine Methylation by PRMT1 Affects ADAMTS13 Secretion and Enzymatic Activity
Szumam Liu, Min Ma, Jun Qu, Joshua Muia, Zhijian Wu, Quintijn Bonnez, Karen Vanhoorelbeke, Liang Zheng, Xinyang Zhao, X. Long Zheng
Arteriosclerosis, Thrombosis, and Vascular Biology.2025; 45(4): 506. CrossRef
Protein Arginine N‐Methyltransferase 4 Activation Contributes to Glucose‐Induced Skeletal Muscle Atrophy
Pawan Kumar, Farah Gulzar, Nikita Chhikara, Arvind K. Maurya, Sushmita Singh, Ishbal Ahmad, Sanjeev Kanojiya, Akhilesh K. Tamrakar
The FASEB Journal.2025;[Epub] CrossRef
PRMT1 in Health and Disease: Emerging Perspectives From Molecular Mechanisms to Therapeutic Strategies
Yanqun Luo, Ying Gao, Xiaoliang Deng, Lei Wang, Tao Wu
MedComm.2025;[Epub] CrossRef

Original Article

Basic Research
N⁶-Methyladenosine Methyltransferase METTL3 Alleviates Diabetes-Induced Testicular Damage through Modulating TUG1/Clusterin Axis: Yuan Tian, Yue-Hai Xiao, Chao Sun, Bei Liu, Fa Sun; Diabetes Metab J. 2023;47(2):287-300. Published online January 19, 2023; DOI: https://doi.org/10.4093/dmj.2021.0306

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Background
The present study investigated the regulatory effects of N6-methyladenosine (m6A) methyltransferase like-3 (METTL3) in diabetes-induced testicular damage.
Methods
In vivo diabetic mice and high glucose (HG) treated GC-1 spg cells were established. The mRNA and protein expressions were determined by real-time quantitative polymerase chain reaction, Western blot, immunofluorescence and immunohistochemistry staining. Levels of testosterone, blood glucose, cell viability, and apoptosis were detected by enzyme-linked immunosorbent assay, MTT, and flow cytometry, respectively. Molecular interactions were verified by RNA immunoprecipitation and RNA pull-down assay. Histopathological staining was performed to evaluate testicular injury.
Results
METTL3 and long non-coding RNA taurine up-regulated 1 (lncRNA TUG1) were downregulated in testicular tissues of diabetic mice and HG-treated GC-1 spg cells. METTL3 overexpression could reduce the blood glucose level, oxidative stress and testicular damage but enhance testosterone secretion in diabetic mouse model and HG-stimulated GC-1 spg cells. Mechanically, METTL3-mediated m6A methylation enhanced the stability of TUG1, then stabilizing the clusterin mRNA via recruiting serine and arginine rich splicing factor 1. Moreover, inhibition of TUG1/clusterin signaling markedly reversed the protective impacts of METTL3 overexpression on HG-stimulated GC-1 spg cells.
Conclusion
This study demonstrated that METTL3 ameliorated diabetes-induced testicular damage by upregulating the TUG1/clusterin signaling. These data further elucidate the potential regulatory mechanisms of m6A modification on diabetes-induced testicular injury.

Citations

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GALNT3-mediated AKT1 glycosylation activates the AKT1/CREB signaling pathway to inhibit high glucose-induced spermatogenic cell apoptosis and mitochondrial dysfunction
Yong Zhao, Jia Luo, Lu Wu
Biochemical and Biophysical Research Communications.2026; 802: 153329. CrossRef
Targeting lncRNA-mediated networks to overcome doxorubicin resistance in cancer
Mengru Qiu, Zhaoting Wang, Yuanyin Teng, Mengxi Li, Fan Wu, Yu Tian
Critical Reviews in Oncology/Hematology.2026; 221: 105214. CrossRef
Rbbp6-Mediated Bmal1 Ubiquitination Inhibits YAP1 Signaling Pathway to Promote Ferroptosis in Diabetes-Induced Testicular Damage
Yuan Tian, Zhiqiang Zhu, Jun Qiao, Bei Liu, Yuehai Xiao
Diabetes & Metabolism Journal.2025; 49(2): 210. CrossRef
METTL3 promotes podocyte pyroptosis in diabetic nephropathy through N 6 -methyladenosine modification of TRIM29 mRNA
Xiaohong Xu, Xiaolin Huang, Ce Zhang, Xia Mi, Chi Zhang, Fei Hua, Liexiang Zhang
Renal Failure.2025;[Epub] CrossRef
The m6A transferase METTL3 regulates high glucose-induced proliferation and apoptosis of human lens epithelial cells through the lncRNA TUG1/KHSRP/p38MAPK signaling axis
Yuxuan Li, Ziyi Yao, Xiaoqin Gao, Yaxin Niu, Ziqing Gao, Shengqun Jiang
Experimental Eye Research.2025; 258: 110492. CrossRef
METTL3 alleviates renal tubular mitochondrial dysfunction by regulating the TUG1/PGC-1a axis in an IGF2BP2-dependent manner in diabetic nephropathy
Tong Chen, Juan Wang, Yanyan Xu, Yonghong Zhu, Ying Jin, Qiuling Fan
Renal Failure.2025;[Epub] CrossRef
m6A modification of non‑coding RNA: Mechanisms, functions and potential values in human diseases (Review)
Qian Yi, Yi Liao, Wei Sun, Jiachen Li, Dahang Yang, Hongxi Shang, Weichao Sun
International Journal of Molecular Medicine.2025; 56(4): 1. CrossRef
The role of m6A methyltransferase METTL3 in metabolism-related diseases: Mechanism and clinical implications
Libao Cui, Wang Jun, Yan Ying, Hengrong Fang
Pharmacological Research.2025; 221: 107962. CrossRef
Regulation of m6A methylation in the immune microenvironment in the development of diabetes mellitus
Haoyue Deng, Qiang Liu, Yanning Gong, Yue Qiu
Journal of Translational Medicine.2025;[Epub] CrossRef
Mechanism of the traditional Chinese medicine SMBJ alleviates diabetes mellitus-induced Leydig cell dysfunction in rats testes
Wenxiu Zhang, Yuanyuan Liu, Li Tong, Yihan Jin, Chao Gao, Yugui Cui, Baofang Jin, Dalin Sun
Scientific Reports.2025;[Epub] CrossRef
Negative Regulation of LINC01013 by METTL3 and YTHDF2 Enhances the Osteogenic Differentiation of Senescent Pre‐Osteoblast Cells Induced by Hydrogen Peroxide
Jiaxin Song, Yuejun Wang, Zhao Zhu, Wanqing Wang, Haoqing Yang, Zhaochen Shan
Advanced Biology.2024;[Epub] CrossRef
Diabetes and diabetic associative diseases: An overview of epigenetic regulations of TUG1
Mohammed Ageeli Hakami
Saudi Journal of Biological Sciences.2024; 31(5): 103976. CrossRef
BRD7 facilitates ferroptosis via modulating clusterin promoter hypermethylation and suppressing AMPK signaling in diabetes-induced testicular damage
Yuehai Xiao, Zongjian Liang, Jun Qiao, Zhiqiang Zhu, Bei Liu, Yuan Tian
Molecular Medicine.2024;[Epub] CrossRef
Roles of m6A modification in regulating PPER pathway in cadmium-induced pancreatic β cell death
Yifei Sun, Rongxian Li, Wenhong Li, Nan Zhang, Guofen Liu, Bo Zhao, Zongqin Mei, Shiyan Gu, Zuoshun He
Ecotoxicology and Environmental Safety.2024; 282: 116672. CrossRef
METTL14-Mediated m6A Modification of TUG1 Represses Ferroptosis in Alzheimer's Disease via Inhibiting GDF15 Ubiquitination
Xunhu Gu, Yuanqing Song, Xu Liu, Zhijuan Cheng, Jun Min, Yangbo Zhang
Frontiers in Bioscience-Landmark.2024;[Epub] CrossRef

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