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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Abstract PDF Supplementary Material PubReader ePub

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
Identification and functional validation of EPS15L1 as a key driver of triple-negative breast cancer
Chun-Chao Wang, Sabareeswaran Krishnan, Yen-Hsun Wang, Kai-Chen Hsu, Tzu-Sheng Hsu, Chung-Hsing Chen, Shang-Hung Chen, Ren-Hua Chung
npj Breast Cancer.2026;[Epub] CrossRef

Basic and Translational Research
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; Diabetes Metab J. 2026;50(3):519-534. Published online September 5, 2025; DOI: https://doi.org/10.4093/dmj.2025.0072

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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.

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