Diabetes & Metabolism Journal

Original Articles

Metabolic Risk/Epidemiology
Glucose-Independent Metabolic Signatures of SGLT2 Inhibition in Diabetic Kidney Disease: Integrated Insights from Mendelian Randomization and Transcriptomics: Yang Zhou, Jie Peng, Xuchang Zhou, Yucheng Wang, Guolin Hong, Xinguo Zhuang; Received December 16, 2025 Accepted March 18, 2026 Published online August 7, 2026; DOI: https://doi.org/10.4093/dmj.2025.1273 [Epub ahead of print]

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Abstract PDF: Background
Diabetic kidney disease (DKD) remains a major cause of terminal renal failure, with residual risk remaining unacceptably high despite standard glucose control. Although the sodium-glucose co-transporter 2 (SGLT2) inhibitors have proven reno-protective properties extending beyond that explained by glucose lowering alone, unique glucose-independent molecular mechanisms are still incompletely defined. Unveiling these non-glycemic metabolic pathways is of paramount importance for new therapeutic targets and optimized clinical management.
Methods
A systematic multi-omics triangulation framework integrating Mendelian randomization (MR) with tissue-specific transcriptomics was conducted. Two-sample MR and multivariable Mendelian randomization (MVMR) adjusted for fasting blood glucose were leveraged as a screening tool to detect glucose-independent serum metabolites in humans using large-scale genome-wide association study data. These findings were validated with transcriptomic signatures from both diabetic and non-diabetic mouse kidney models to identify conserved core genes and convergent metabolic pathways.
Results
Genetically proxied SGLT2 inhibition associated with a reduced risk of DKD, with an odds ratio of 0.58, and improved renal function markers. MVMR highlighted 259 glucose-independent metabolites, covering systemic alterations in lipid and amino acid metabolism. A cross-model transcriptomic comparison revealed seven key genes functionally enriched in fatty acid oxidation and ketone body utilization. This convergence supports the concept of a fasting-like metabolic switch and coordinated downregulation of fibrosis-related extracellular matrix pathways irrespective of diabetic status.
Conclusion
This study delineates a systemic-renal metabolic axis whereby SGLT2 inhibition drives renoprotection via metabolic reprogramming and anti-fibrotic mechanisms distinct from blood glucose lowering. These findings provide genetic evidence for specific non-glycemic targets and represent a novel mechanistic insight for precision therapeutic intervention in kidney disease.

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
Novel Insights into the Causal Relationship between Antidiabetic Drugs and Adverse Perinatal Outcomes: A Mendelian Randomization Study: Chang Su, Xueqing He, Xiaona Chang, Juan Tian, Guang Wang, Jia Liu; Diabetes Metab J. 2025;49(6):1242-1251. Published online June 2, 2025; DOI: https://doi.org/10.4093/dmj.2024.0521

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Background
Hyperglycemia during pregnancy increases the risk of adverse perinatal outcomes and birth defects. Evidence regarding the long-term safety of antidiabetic drugs during pregnancy is still lacking.
Methods
A two-sample Mendelian randomization (MR) study was performed to assess the causal association between six antidiabetic drug targets (ABCC8, DPP4, INSR, GLP1R, PPARG, and SLC5A2) and seven adverse perinatal outcomes and five congenital malformation outcomes. Inverse variance weighted (IVW) was adopted as the main MR method, and sensitivity analysis using traditional MR methods was performed to evaluate the robustness of the results.
Results
We observed strong evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors (odds ratio [OR], 0.084; 95% confidence interval [CI], 0.009 to 0.834; P=0.034) reduces the risk of preterm birth; genetic variation in sulfonylurea drug targets (OR, 0.015; 95% CI, 2.50E-04 to 0.919; P=0.045) and genetic variation in thiazolidinedione drug targets (OR, 0.007; 95% CI, 4.16E-04 to 0.121; P=0.001) reduced the risk of eclampsia/preeclampsia; glucagon-like peptide 1 (GLP-1) analogues target (β=–0.549; 95% CI, –0.958 to –0.140; P=0.009) was inversely associated with fetal birth weight; thiazolidinedione target was inversely associated with gestational age (β=–0.952; 95% CI, –1.785 to –0.118; P=0.025); SGLT2 inhibitors reduced the risk of cardiocirculatory malformations (OR, 0.001; 95% CI, 8.75E-06 to 0.126; P=0.005).
Conclusion
Most antidiabetic drugs are safe when used during the perinatal period. Of note, GLP-1 analogues may lead to a risk of low birth weight, while thiazolidinediones may lead to a reduction in fetal gestational age.

Citations

Citations to this article as recorded by

Prenatal chemical exposures and fetal growth: a narrative review of gene-environment interactions (2025)
Sumitaka Kobayashi, Fumihiro Sata, Yasuaki Saijo, Reiko Kishi
Pediatric Research.2026;[Epub] CrossRef

Complications
The Causal Relationship and Association between Biomarkers, Dietary Intake, and Diabetic Retinopathy: Insights from Mendelian Randomization and Cross-Sectional Study: Xuehao Cui, Dejia Wen, Jishan Xiao, Xiaorong Li; Diabetes Metab J. 2025;49(5):1087-1105. Published online March 31, 2025; DOI: https://doi.org/10.4093/dmj.2024.0731

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Background
Diabetic retinopathy (DR) is a major cause of vision loss, linked to hyperglycemia, oxidative stress, and inflammation. Despite advancements in DR treatments, approximately 40% of patients do not respond effectively, underscoring the need for novel, noninvasive biomarkers to predict DR risk and progression. This study investigates causal relationships between specific biomarkers, dietary factors, and DR development using Mendelian randomization (MR) and cross-sectional data.
Methods
We conducted a two-phase analysis combining MR and cross-sectional methods. First, MR analysis examined causal associations between 35 biomarkers, 226 dietary factors, and DR progression using data from the UK Biobank and Genome-Wide Association Study (GWAS) datasets. Second, a cross-sectional study with National Health and Nutrition Examination Survey (NHANES) and a clinical cohort from Tianjin Medical University Eye Hospital validated findings and explored biomarkers’ predictive capabilities through a nomogram-based prediction model.
Results
MR analysis identified eight biomarkers (e.g., glycosylated hemoglobin [HbA1c], high-density lipoprotein cholesterol [HDL-C]) with significant causal links to DR. Inflammatory markers and metabolic factors, such as high glucose and HDL-C levels, were strongly associated with DR risk and progression. Specific dietary factors, like cheese intake, exhibited protective roles, while alcohol intake increased DR risk. Validation within NHANES and Tianjin cohorts supported these causal associations.
Conclusion
This study elucidates causal relationships between biomarkers, dietary habits, and DR progression, emphasizing the potential for personalized dietary interventions to prevent or manage DR. Findings support the use of HDL-C, HbA1c, and dietary factors as biomarkers or therapeutics in DR, though further studies are needed for broader applicability.

Citations

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Exploring potential therapeutic targets for myopia: Causal analysis and biological annotation with gut microbiota
Zixun Wang, Yimeng Sun, Xiaoling Zhang, Luqiang Wang, Desheng Song, Jingtao Yu, Xiaoxue Hu, Weiping Lin, Ruihua Wei
Computational Biology and Chemistry.2026; 120: 108634. CrossRef
Research Status of Diabetic Retinopathy Prediction Models: From Traditional Risk Factors to Artificial Intelligence
银娟李
Journal of Clinical Personalized Medicine.2026; 05(01): 332. CrossRef
Integrative Proteogenomic Analysis Identifies Genetically Supported Plasma Proteins, Metabolites, and Pathways in Glaucoma
Jiajia Yuan, Xuehao Cui, Patrick Yu-Wai-Man, Xuan Xiao
Investigative Ophthalmology & Visual Science.2026; 67(2): 21. CrossRef
Antioxidant vitamin index and risk of age-related macular degeneration: multicenter validation and clinical translation
Xuehao Cui, Jingwen Hui, Zheya Han, Quanhong Han
npj Aging.2026;[Epub] CrossRef
Comprehensive multi-method analysis of blood heavy metals and nutrient intake in myopia and high myopia
Jingwen Hui, Xinyuan Feng, Quanhong Han, Xuehao Cui
Journal of Translational Medicine.2026;[Epub] CrossRef
Exposome-induced dysregulation of glycemic homeostasis: Emerging biomarkers for diabetes risk and progression
Singamoorthy Amalraj, Venkatesan Karthick, Rajkumar Thamarai, Mani Suganya
Environmental Pollution.2026; 397: 128012. CrossRef
Integrated plasma proteomics and metabolomics reveal immunometabolic pathways and predictive signatures for age-related eye diseases
Xuehao Cui, Qiuchen Zhao, Jiajia Yuan, Patrick Yu-Wai-Man
Metabolism.2026; 180: 156624. CrossRef
Association between diabetic retinopathy and suicidal ideation among U.S. adults with diabetes: A cross-sectional NHANES study, 2005–2018
Najuan Huang, Yaru Du, Yan Zheng, Pengfei Wang
Medicine.2026; 105(28): e49694. CrossRef
Associations between dietary nutrient intake and the risk of multiple age-related ocular diseases: evidence from longitudinal analysis
Yuchen Yang, Haidong Zou
The Journal of nutrition, health and aging.2026; 30(9): 100927. CrossRef
Association between weight-adjusted-waist index and retinopathy among American adults: a cross-sectional study and mediation analysis
Junmeng Li, Qianshuo Yin, Jianchen Hao, Ruilin Zhu, Jing Zhang, Yadi Zhang, Xiaopeng Gu, Zihui Wu, Liu Yang
Frontiers in Nutrition.2025;[Epub] CrossRef
Exploring the impact of diet, sleep, and metabolomic pathways on Glaucoma subtypes: insights from Mendelian randomization and cross-sectional analyses
Zhang Shengnan, Wang Tao, Zhang Yanan, Sun Chao
Nutrition & Metabolism.2025;[Epub] CrossRef
Association between endothelial activation and stress index and diabetic retinopathy in patients with diabetic kidney disease: a cross-sectional study based on NHANES database
Jinping Liu, Di’en Yan, Xiaohui Wang, Yinhua Yao, Ling Wang
BMC Endocrine Disorders.2025;[Epub] CrossRef
Hypertriglyceridemic waist phenotype in relation to diabetes mellitus and cardiovascular diseases in the Indonesian and Korean populations: evidence from two national surveys
Fathimah S. Sigit, Sinyoung Cho, Farid Kurniawan, Hye-Ryeong Jeon, Ratu Ayu Dewi Sartika, Dicky L. Tahapary, Hyuktae Kwon
Diabetology & Metabolic Syndrome.2025;[Epub] CrossRef
Non-linear association between Life’s Essential 8 and diabetic retinopathy: mediating role of depression in US adults with diabetes
Long Xie, Yu Qin Peng, Wei Qiang Wei, Xiang Shen
BMC Public Health.2025;[Epub] CrossRef

Basic and Translational Research
Revealing VCAN as a Potential Common Diagnostic Biomarker of Renal Tubules and Glomerulus in Diabetic Kidney Disease Based on Machine Learning, Single-Cell Transcriptome Analysis and Mendelian Randomization: Li Jiang, Jie Jian, Xulin Sai, Xiai Wu; Diabetes Metab J. 2025;49(3):407-420. Published online January 24, 2025; DOI: https://doi.org/10.4093/dmj.2024.0233

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Background
Diabetic kidney disease (DKD) is recognized as a significant complication of diabetes mellitus and categorized into glomerular DKDs and tubular DKDs, each governed by distinct pathological mechanisms and biomarkers.
Methods
Through the identification of common features observed in glomerular and tubular lesions in DKD, numerous differentially expressed gene were identified by the machine learning, single-cell transcriptome and mendelian randomization.
Results
The diagnostic markers versican (VCAN) was identified, offering supplementary options for clinical diagnosis. VCAN significantly highly expressed in glomerular parietal epithelial cell and proximal convoluted tubular cell. It was mainly involved in the up-regulation of immune genes and infiltration of immune cells like mast cell. Mendelian randomization analysis confirmed that serum VCAN protein levels were a risky factor for DKD, while there was no reverse association. It exhibited the good diagnostic potential for estimated glomerular filtration rate and proteinuria in DKD.
Conclusion
VCAN showed the prospects into DKD pathology and clinical indicator.

Citations

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Transient versican expression is required for β1-integrin accumulation during podocyte layer morphogenesis in amphibian developing kidney
Isabelle Buisson, Jean-François Riou, Muriel Umbhauer, Ronan Le Bouffant, Valérie Bello
Cells & Development.2026; 185: 204062. CrossRef
m6A Modified VCAN Promotes Glomerular Endothelial Cells Injury and Diabetic Nephropathy by SHH Pathway
Jie Jiang, Jicheng Zhang, Chao Wang, Feng Wang
Applied Biochemistry and Biotechnology.2026; 198(5): 3461. CrossRef
Pathology-Anchored Biomarker Research Progress for the Early Diagnosis of Diabetic Kidney Disease: From Pathological Association to Early Validation
Qiu Li, Mei Yang, Yingyu Luo, Nannan Zhang
Biomedicines.2026; 14(7): 1643. CrossRef
Multi-omics and machine learning identify FN1 and ALDH2 as diagnostic biomarkers and therapeutic targets in early and late diabetic kidney disease
Jingwei Lin, Yingying Zheng, Diman Mai, Fuxiang Fang, Zhuokun Wei, Mengyu Liu, Trung Hieu Pham, Ming Li, Jiawen Zhao
Renal Failure.2025;[Epub] CrossRef

Metabolic Risk/Epidemiology
Longitudinal Association of Changes in Metabolic Syndrome with Cognitive Function: 12-Year Follow-up of the Guangzhou Biobank Cohort Study: Yu Meng Tian, Wei Sen Zhang, Chao Qiang Jiang, Feng Zhu, Ya Li Jin, Shiu Lun Au Yeung, Jiao Wang, Kar Keung Cheng, Tai Hing Lam, Lin Xu; Diabetes Metab J. 2025;49(1):60-79. Published online October 29, 2024; DOI: https://doi.org/10.4093/dmj.2024.0117

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Background
The association of changes in metabolic syndrome (MetS) with cognitive function remains unclear. We explored this association using prospective and Mendelian randomization (MR) studies.
Methods
MetS components including high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), waist circumference (WC), fasting plasma glucose (FPG), and triglycerides were measured at baseline and two follow-ups, constructing a MetS index. Immediate, delayed memory recall, and cognitive function along with its dimensions were assessed by immediate 10- word recall test (IWRT) and delayed 10-word recall test (DWRT), and mini-mental state examination (MMSE), respectively, at baseline and follow-ups. Linear mixed-effect model was used. Additionally, the genome-wide association study (GWAS) of MetS was conducted and one-sample MR was performed to assess the causality between MetS and cognitive function.
Results
Elevated MetS index was associated with decreasing annual change rates (decrease) in DWRT and MMSE scores, and with decreases in attention, calculation and recall dimensions. HDL-C was positively associated with an increase in DWRT scores, while SBP and FPG were negatively associated. HDL-C showed a positive association, whereas WC was negatively associated with increases in MMSE scores, including attention, calculation and recall dimensions. Interaction analysis indicated that the association of MetS index on cognitive decline was predominantly observed in low family income group. The GWAS of MetS identified some genetic variants. MR results showed a non-significant causality between MetS and decrease in DWRT, IWRT, nor MMSE scores.
Conclusion
Our study indicated a significant association of MetS and its components with declines in memory and cognitive function, especially in delayed memory recall.

Citations

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Modifying Role of Sustainable Diets on the Association Between Particulate Matter and Biological Aging: The Guangzhou Biobank Cohort Study
Rui Qiang Li, Shou Xin Peng, Rui Hang Zhang, Ting Yu Lu, Wei Sen Zhang, Jiao Wang, Ying Wang, Lin Yang, Shiu Lun Ryan Au Yeung, Tai Hing Lam, Kar Keung Cheng, Lin Xu
Aging Cell.2026;[Epub] CrossRef
Association of metabolic syndrome severity with cognitive decline among Chinese older adults: evidence from two prospective cohort studies
Ming Chen, Lu Liu, Na Liu, Ji-Wen Che, Yuan-Yuan Peng, Yan Zeng
Frontiers in Neuroscience.2026;[Epub] CrossRef
Association of body mass index, waist circumference, (abdominal) overweight and obesity with sex- and age-specific cognitive function over time—the Doetinchem Cohort Study
Femke te Hoonte, M. Liset Rietman, Kirsten E. J. Wesenhagen, H. Susan J. Picavet, W. M. Monique Verschuren
International Journal of Obesity.2026; 50(5): 1150. CrossRef

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