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3 "Wayne Huey-Herng Sheu"
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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
  • 7,653 View
  • 76 Download
  • 1 Web of Science
  • 1 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   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
Metabolic Risk/Epidemiology
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Predictive Models for Type 2 Diabetes Mellitus in Han Chinese with Insights into Cross-Population Applicability and Demographic Specific Risk Factors
Ying-Erh Chen, Djeane Debora Onthoni, Shao-Yuan Chuang, Guo-Hung Li, Yong-Sheng Zhuang, Hung-Yi Chiou, Wayne Huey-Herng Sheu, Ren-Hua Chung
Diabetes Metab J. 2025;49(6):1272-1286.   Published online May 21, 2025
DOI: https://doi.org/10.4093/dmj.2024.0319
  • 4,038 View
  • 115 Download
  • 2 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
The rising global incidence of type 2 diabetes mellitus (T2DM) underscores the need for predictive models that enhance early detection and prevention across diverse populations. This study aimed to identify predictors of incident T2DM within a Han Chinese population, assess their impact across various age and sex demographics, and explore their applicability to European populations.
Methods
Using data from about 65,000 participants in the Taiwan Biobank (TWB), we developed a predictive model, achieving an area under the receiver operating characteristic curve of 90.58%. Key predictors were identified through LASSO regression within the TWB cohort and validated using over 4 million records from Taiwan’s Adult Preventive Healthcare Services (APHS) program and the UK Biobank (UKB).
Results
Our analysis highlighted 13 significant predictors, including established factors like glycosylated hemoglobin (HbA1c) and blood glucose levels, and less conventionally considered variables such as peak expiratory flow. Notable differences in the effects of HbA1c levels and polygenic risk scores between the TWB and UKB cohorts were observed. Additionally, age and sex-specific impacts of these predictors, detailed through APHS data, revealed significant variances; for instance, waist circumference and diagnosed mixed hyperlipidemia showed greater impacts in younger females than in males, while effects remained uniform across male age groups.
Conclusion
Our findings offer novel insights into the diagnosis and management of diabetes for the Han Chinese and potentially for broader East Asian populations, highlighting the importance of ethnic and demographic diversity in developing predictive models for early detection and personalized intervention strategies.

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  • Plasminogen activator inhibitor-1, vaspin, and dietary inflammatory index in relation to cardiometabolic health in diabetic women
    Sule Kocabas, Nevin Sanlier
    Frontiers in Nutrition.2026;[Epub]     CrossRef
  • The Relationship Between High-Density Lipoprotein (HDL) and Glycated Hemoglobin (HbA1C) in Type 2 Diabetes Mellitus Patients: Implications for Cardiovascular Risk
    Setyoadi Setyoadi, Dina Dewi Sartika Lestari Ismail, Annisa Wuri Kartika, Dewi Purnama Sari, Angel Dwi Septian, Adelina Stefanie Lallo, Rara Kurniasari
    Journal of Rural Community Nursing Practice.2025; 3(2): 234.     CrossRef
Review
Drug/Regimen
Use of SGLT-2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Abdominal Obesity: An Asian Perspective and Expert Recommendations
Wayne Huey-Herng Sheu, Siew Pheng Chan, Bien J. Matawaran, Chaicharn Deerochanawong, Ambrish Mithal, Juliana Chan, Ketut Suastika, Chin Meng Khoo, Huu Man Nguyen, Ji Linong, Andrea Luk, Kun-Ho Yoon
Diabetes Metab J. 2020;44(1):11-32.   Published online February 21, 2020
DOI: https://doi.org/10.4093/dmj.2019.0208
  • 20,366 View
  • 300 Download
  • 45 Web of Science
  • 43 Crossref
AbstractAbstract PDFPubReader   ePub   

The prevalence of obesity in Asia is of epidemic proportions, with an estimated 1 billion overweight/obese individuals in the region. The majority of patients with type 2 diabetes mellitus (T2DM) are overweight/obese, which increases the risk of cardiorenal outcomes in these patients; hence, sustained reductions in body weight and visceral adiposity are important management goals. However, most of the glucose-lowering therapies such as insulin, sulfonylureas, glinides, and thiazolidinediones induce weight gain, which makes the management of overweight/obese T2DM patients challenging. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are the only oral glucose-lowering agents that have been shown to reduce body weight and visceral adiposity. In addition, SGLT-2 inhibitors therapy reduces ectopic fat deposition and improves adipose tissue function and weight-related quality of life. In this article, we aim to consolidate the existing literature on the effects of SGLT-2 inhibitors in Asian patients with T2DM and to produce clinical recommendations on their use in overweight or obese patients with T2DM. Recommendations from international and regional guidelines, as well as published data from clinical trials in Asian populations and cardiovascular outcomes trials are reviewed. Based on the available data, SGLT-2 inhibitors represent an evidence-based therapeutic option for the management of overweight/obese patients with T2DM.

Citations

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    Diabetes & Metabolism Journal.2026; 50(2): 320.     CrossRef
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    Joseph A. M. J. L. Janssen
    International Journal of Molecular Sciences.2026; 27(5): 2150.     CrossRef
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    Mihaela-Simona Popoviciu, Teodor Salmen, Delia Reurean-Pintilei, Vlad Voiculescu, Anca Pantea Stoian
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