Diabetes & Metabolism Journal

Original Articles

Complications
Characterizing the Immune Cell Infiltration in Renal Interstitium and Therapeutic Targets of Drugs in Diabetic Nephropathy by Multiomics Study: Chongbin Liu, Zurong Zhang, Yiyun Xi, Ming Yang, Huafeng Liu, Lin Sun; Received January 6, 2025 Accepted September 20, 2025 Published online January 30, 2026; DOI: https://doi.org/10.4093/dmj.2025.0016 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Immune cell infiltration in the renal interstitium contributes to the progression of diabetic nephropathy (DN), yet the precise mechanisms remain incompletely unclear.
Methods
Public multi-omics datasets were integrated for comprehensive bioinformatic analyses. Interactions between infiltrating immune cells and damaged tubular epithelial cells (TECs) were analyzed with the CellChat, and key regulators were identified by machine learning. DN was modeled in C57BL/6 mice by high-fat diet/streptozotocin. Human kidney 2 (HK-2) cells were exposed to high glucose plus palmitic acid (HGPA). Gene function was validated by Western blotting, real-time quantitative polymerase chain reaction, immunohistochemistry and surface plasmon resonance (SPR).
Results
Renal interstitium from DN patients displayed markedly increased infiltration of M1 macrophages, regulatory T-cells, natural killer cells and other immune subsets, all correlating with indices of renal injury. CellChat analysis indicated that damaged TECs communicated with infiltrating immune cells primarily through chemokine networks centered on C-X-C motif chemokine ligand (CXCL), C-X3-C motif chemokine ligand (CX3CL), and C-C motif chemokine ligand 2 (CCL2). Retinoic acid-induced 2 (RAI2) was upregulated in DN kidneys and showed significant associations with immune infiltration and renal injury via these chemokine pathways. Consistently, RAI2 expression was elevated in kidneys of DN mice and in HGPA-treated HK-2 cells. SPR demonstrated direct, high-affinity binding of resveratrol to human RAI2 protein. Knockdown of RAI2 or treatment with resveratrol attenuated HGPA-induced apoptosis and suppressed CCL2, CXCL, and CX3CL expression levels.
Conclusion
RAI2 is a pivotal mediator of tubule injury and immune cell infiltration in DN, and resveratrol via direct binding to RAI2 and suppressed its function.

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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Abstract PDF Supplementary Material PubReader ePub

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

Citations to this article as recorded by

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
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

Complications
Glycated Albumin Is a More Useful Glycation Index than HbA1c for Reflecting Renal Tubulopathy in Subjects with Early Diabetic Kidney Disease: Ji Hye Huh, Minyoung Lee, So Young Park, Jae Hyeon Kim, Byung-Wan Lee; Diabetes Metab J. 2018;42(3):215-223. Published online May 2, 2018; DOI: https://doi.org/10.4093/dmj.2017.0091

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Abstract PDF PubReader ePub

Background

The aim of this study was to investigate which glycemic parameters better reflect urinary N-acetyl-β-D-glucosaminidase (uNAG) abnormality, a marker for renal tubulopathy, in subjects with type 2 diabetes mellitus (T2DM) subjects with normoalbuminuria and a normal estimated glomerular filtration rate (eGFR).

Methods

We classified 1,061 participants with T2DM into two groups according to uNAG level—normal vs. high (>5.8 U/g creatinine)—and measured their biochemical parameters.

Results

Subjects with high uNAG level had significantly higher levels of fasting and stimulated glucose, glycated albumin (GA), and glycosylated hemoglobin (HbA1c) and lower levels of homeostasis model assessment of β-cell compared with subjects with normal uNAG level. Multiple linear regression analyses showed that uNAG was significantly associated with GA (standardized β coefficient [β]=0.213, P=0.016), but not with HbA1c (β=−0.137, P=0.096) or stimulated glucose (β=0.095, P=0.140) after adjusting confounding factors. In receiver operating characteristic analysis, the value of the area under the curve (AUC) for renal tubular injury of GA was significantly higher (AUC=0.634; 95% confidence interval [CI], 0.646 to 0.899) than those for HbA1c (AUC=0.598; 95% CI, 0.553 to 0.640), stimulated glucose (AUC=0.594; 95% CI, 0.552 to 0.636), or fasting glucose (AUC=0.558; 95% CI, 0.515 to 0.600). The optimal GA cutoff point for renal tubular damage was 17.55% (sensitivity 59%, specificity 62%).

Conclusion

GA is a more useful glycation index than HbA1c for reflecting renal tubulopathy in subjects with T2DM with normoalbuminuria and normal eGFR.

Citations

Citations to this article as recorded by

Diagnostic and therapeutic potential of PCSK9 in diabetic tubulopathy: Evidence from observational and experimental studies
JingJing Quan, Si Li, Bin Yi, Zhijun Huang
International Immunopharmacology.2026; 168: 115907. CrossRef
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Mayura Apte, Girish Kumthekar, Rashmi Santosh Tupe
Biochemical and Biophysical Research Communications.2026; 809: 153479. CrossRef
Albumin does not induce IL-6 release and toll-like receptor activation in vitro: Role of endotoxin contamination and biochemical modifications
Margret Paar, Vera H. Fengler, Martina Schweiger, Christine Rossmann, Christoph Nusshold, Martina Mairold, Doris Payerl, Gerhard Cvirn, Karl Oettl
BBA Advances.2025; 8: 100174. CrossRef
Glucagon-Like Peptide 1 Receptor Agonist Improves Renal Tubular Damage in Mice with Diabetic Kidney Disease
Ran Li, Dunmin She, Zhengqin Ye, Ping Fang, Guannan Zong, Yong Zhao, Kerong Hu, Liya Zhang, Sha Lei, Keqin Zhang, Ying Xue
Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy.2022; Volume 15: 1331. CrossRef
Use of glycated albumin for the identification of diabetes in subjects from northeast China
Guo-Yan Li, Hao-Yu Li, Qiang Li
World Journal of Diabetes.2021; 12(2): 149. CrossRef
Diabetic Kidney Disease, Cardiovascular Disease and Non-Alcoholic Fatty Liver Disease: A New Triumvirate?
Carolina M. Perdomo, Nuria Garcia-Fernandez, Javier Escalada
Journal of Clinical Medicine.2021; 10(9): 2040. CrossRef
Empagliflozin reduces high glucose-induced oxidative stress and miR-21-dependent TRAF3IP2 induction and RECK suppression, and inhibits human renal proximal tubular epithelial cell migration and epithelial-to-mesenchymal transition
Nitin A. Das, Andrea J. Carpenter, Anthony Belenchia, Annayya R. Aroor, Makoto Noda, Ulrich Siebenlist, Bysani Chandrasekar, Vincent G. DeMarco
Cellular Signalling.2020; 68: 109506. CrossRef
Glycated Plasma Proteins as More Sensitive Markers for Glycemic Control in Type 1 Diabetes
Lina Zhang, Qibin Zhang
PROTEOMICS – Clinical Applications.2020;[Epub] CrossRef
Glycated albumin and its variability: Clinical significance, research progress and overall review
Dongjun Dai, Yifei Mo, Jian Zhou
Obesity Medicine.2020; 19: 100256. CrossRef
Hepatic fibrosis is associated with total proteinuria in Korean patients with type 2 diabetes
Eugene Han, Yongin Cho, Kyung-won Kim, Yong-ho Lee, Eun Seok Kang, Bong-Soo Cha, Byung-wan Lee
Medicine.2020; 99(33): e21038. CrossRef
Increasing waist circumference is associated with decreased levels of glycated albumin
Yiting Xu, Xiaojing Ma, Yun Shen, Yufei Wang, Jian Zhou, Yuqian Bao
Clinica Chimica Acta.2019; 495: 118. CrossRef
Glucometabolic characteristics and higher vascular complication risk in Korean patients with type 2 diabetes with non-albumin proteinuria
Yongin Cho, Yong-ho Lee, Eun Seok Kang, Bong-soo Cha, Byung-wan Lee
Journal of Diabetes and its Complications.2019; 33(8): 585. CrossRef
Association of urinary acidification function with the progression of diabetic kidney disease in patients with type 2 diabetes
Huanhuan Zhu, Xi Liu, Chengning Zhang, Qing Li, Xiaofei An, Simeng Liu, Lin Wu, Bo Zhang, Yanggang Yuan, Changying Xing
Journal of Diabetes and its Complications.2019; 33(11): 107419. CrossRef

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