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.

Metabolic Risk/Epidemiology
Association of Remnant Cholesterol Inflammation Index with Cardiovascular Risks and All-Cause Mortality in Individuals with Diabetes or Prediabetes: Qi-Lin Ma, Lei-Lei Du, Jia Peng; Received April 8, 2025 Accepted June 27, 2025 Published online October 2, 2025; DOI: https://doi.org/10.4093/dmj.2025.0305 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Remnant cholesterol (RC) and low-grade inflammation are established contributors to cardiovascular disease (CVD) risks in diabetes. However, their combined prognostic impact remains unclear in dysglycemia. We evaluated the remnant cholesterol inflammation index (RCII), integrating RC and high-sensitivity C-reactive protein (hsCRP), for predicting mortality and CVD risks in diabetes/prediabetes.
Methods
This study included 2206 United States adults with diabetes/prediabetes from National Health and Nutrition Examination Survey 2015–2018. RCII was calculated as [RC (mg/dL)×hsCRP (mg/L)]/10. All-cause mortality was tracked via National Death Index until 2019; CVD risk was assessed cross-sectionally. Cox proportional hazard regression determined the hazard ratio (HR) and 95% confidence intervals (CIs) of RCII for all-cause mortality. Logistic regression models estimated the odds ratio (OR) and 95% CIs of RCII for CVD risks.
Results
For CVD risks, Q4 vs. Q1 demonstrated increased odds (OR, 2.32; 95% CI, 1.23 to 4.37), though per-standard deviation (SD) increments were non-significant (OR, 1.15; 95% CI, 0.98 to 1.35; P=0.083). During a median of 38 months follow-up, higher RCII quartiles showed graded associations with all-cause mortality (Q4 vs. Q1: HR, 2.45; 95% CI, 1.08 to 5.58; per 1-SD increase: HR, 1.21; 95% CI, 1.08 to 1.35). Restricted cubic splines confirmed dose-dependent relationships for CVD risks and all-cause mortality (all P=0.005 for overall). Subgroup analyses revealed consistent mortality associations but sex-specific CVD interactions (P=0.047 for interaction).
Conclusion
Our study found the RCII as a biomarker for predicting all-cause mortality and CVD risks in individuals with prediabetes or diabetes, highlighting the synergistic effects of RC and low-grade inflammation on adverse outcomes in this population and may facilitate early identification of individuals at heightened risk for CVD.

Basic and Translational Research
Inflammatory Milieu by Crosstalk between Glomerulus and Proximal Tubular Cells in Type 2 Diabetes Mellitus Kidney Disease: Peong Gang Park, Juhyeon Hwang, Yongjun Kim, Minki Hong, Donghwan Yun, Haein Yoon, Chaelin Kang, Sohyun Bae, Soo Heon Kwak, Yong Chul Kim, Kyung Chul Moon, Dong-Sup Lee, Yon Su Kim, Hee Gyung Kang, Hyun Je Kim, Seung Seok Han; Diabetes Metab J. 2025;49(5):1024-1039. Published online March 31, 2025; DOI: https://doi.org/10.4093/dmj.2024.0535

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Abstract PDF Supplementary Material PubReader ePub

Background
Due to the limited availability of therapeutic agents for type 2 diabetic kidney disease (T2DKD), there is a need for further knowledge derived from experimental models and innovative techniques. In addressing this issue, single-cell RNA sequencing (scRNA-seq) has been exclusively applied to a genetically modified diabetic kidney disease model, but not to an induced model representing T2DKD. Herein, we analyzed scRNA-seq and other experiments from an induced T2DKD model and validated the results in human-derived biospecimens.
Methods
The model was induced by combining a high-fat diet with streptozotocin to simulate induced T2DKD. scRNA-seq, histological, and flow cytometric analyses were conducted, and the results were compared with control mice. The findings were then applied to human T2DKD kidneys.
Results
Biochemical and histological analyses unveiled early-stage T2DKD features, such as hyperfiltration, increased proteinuria, glomerulomegaly, and interstitial fibrosis. scRNA-seq identified that proximal tubules secreted a variety of chemokines, potentially in response to crosstalk with glomeruli. Notably, C-X-C motif chemokine 12 (CXCL12) emerged as a key player in potentially promoting T-cell recruitment. Flow cytometry substantiated T-cell infiltration into the kidney of the T2DKD model. This finding was further corroborated in human biopsied kidney tissues, showing a correlation between elevated CXCL12 levels and T2DKD progression.
Conclusion
The induced T2DKD model highlights the pivotal role of CXCL12-mediated T-cell infiltration, stemming from the crosstalk between proximal tubules and glomeruli. This data serves as a foundation for future studies, promising a therapeutic target for T2DKD.

Citations

Citations to this article as recorded by

Inflammation and Diabetic Kidney Disease
Rong Mei Zhang, Maria Luiza Caramori
International Journal of Molecular Sciences.2026; 27(2): 1097. CrossRef
Aging Mediates Inflammatory Transformation of Kidney-Resident Macrophages via Thrombospondin-1 Signaling
Chaelin Kang, Donghwan Yun, Boyoun Jang, Yongjun Kim, Minki Hong, Juhyeon Hwang, Haein Yoon, Jeongmin Oh, Hyun Mu Shin, Kyung Chul Moon, Dong-Sup Lee, Yon Su Kim, Hyun Je Kim, Seung Seok Han
Immune Network.2025;[Epub] CrossRef

Basic and Translational Research
Macrophage-Specific Progranulin Deficiency Prevents Diet-Induced Obesity through the Inhibition of Hypothalamic and Adipose Tissue Inflammation: Chan Hee Lee, Chae Beom Park, Hyun-Kyong Kim, Won Hee Jang, Se Hee Min, Jae Bum Kim, Min-Seon Kim; Diabetes Metab J. 2025;49(4):784-797. Published online March 11, 2025; DOI: https://doi.org/10.4093/dmj.2024.0486

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Abstract PDF Supplementary Material PubReader ePub

Background
Chronic low-grade inflammation in multiple metabolic organs contributes to the development of insulin resistance induced by obesity. Progranulin (PGRN) is an evolutionarily-conserved secretory protein implicated in immune modulation. The generalized deletion of the PGRN-encoded Grn gene improves insulin resistance and glucose intolerance in obese mice fed a high-fat diet (HFD). However, it remains unclear which cells or organs are responsible for the beneficial metabolic effect of Grn depletion.
Methods
Considering the critical role of macrophages in HFD-induced obesity and inflammation, we generated mice with a macrophage-specific Grn depletion (Grn-MΦKO mice) by mating lysozyme M (LysM)-Cre and Grn-floxed mice. Body weight, food intake, energy expenditure, and glucose and insulin tolerance were compared between Grn-MΦKO mice and their wildtype (WT) controls under normal chow diet (NCD)- or HFD-fed conditions. We also examined macrophage activation and inflammation- related gene expression in the visceral adipose tissue and hypothalamus along with insulin and leptin signaling.
Results
Grn-MΦKO mice showed no alteration in metabolic phenotypes under NCD-fed conditions. However, upon HFD feeding, these mice exhibited less weight gain and improved glucose and insulin tolerance compared to WT mice. Moreover, HFD-induced macrophage activation and proinflammatory cytokine expression were significantly reduced in both the adipose tissue and hypothalamus of Grn-MΦKO mice, while HFD-induced impairments in leptin and insulin signaling showed improvement.
Conclusion
Macrophage-derived PGRN and possibly other Grn products play a critical role in the development of HFD-induced obesity, tissue inflammation, and impaired hormonal signaling in both central and peripheral metabolic organs.

Citations

Citations to this article as recorded by

Tissue-specific immune and MAPK signatures in models of reduced Progranulin and Western diet
Andrea R. Merchak, Maria Elizabeth de Sousa Rodrigues, Cassandra Cole, Noelle Neighbarger, Nilay Bhavsar, Rebecca L. Wallings, Valerie Joers, Jianjun Chang, Sean D. Kelly, Timothy R. Sampson, Malú Gámez Tansey
Neurobiology of Disease.2026; 220: 107287. CrossRef
Role of Macrophage-Derived Progranulin in Energy and Glucose Metabolism
Do Kyeong Song
Diabetes & Metabolism Journal.2025; 49(4): 580. CrossRef
The Adipokine Hypothesis of Heart Failure With a Preserved Ejection Fraction
Milton Packer
JACC.2025; 86(16): 1269. CrossRef
Serum Granulin Concentrations Are Elevated in Prediabetes and Newly Diagnosed Diabetes: A Cross-Sectional Study
Yu-Hsuan Chou, Yuan Kao, Ka Chon Chan, Hsuan-Wen Chou, Yu-Cheng Liang, Hung-Tsung Wu, Horng-Yih Ou
Journal of Clinical Medicine.2025; 14(18): 6566. CrossRef
TNFR2 signaling in musculoskeletal diseases: Implications for rheumatoid arthritis and osteoarthritis
Emily Qian, Ryan S MacLeod, Chuan-Ju Liu
Journal of Leukocyte Biology.2025;[Epub] CrossRef

Basic and Translational Research
Ras Guanine Nucleotide-Releasing Protein-4 Inhibits Erythropoietin Production in Diabetic Mice with Kidney Disease by Degrading HIF2A: Junmei Wang, Shuai Huang, Li Zhang, Yixian He, Xian Shao, A-Shan-Jiang A-Ni-Wan, Yan Kong, Xuying Meng, Pei Yu, Saijun Zhou; Diabetes Metab J. 2025;49(3):421-435. Published online January 23, 2025; DOI: https://doi.org/10.4093/dmj.2024.0398

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Abstract PDF Supplementary Material PubReader ePub

Background
In acute and chronic renal inflammatory diseases, the activation of inflammatory cells is involved in the defect of erythropoietin (EPO) production. Ras guanine nucleotide-releasing protein-4 (RasGRP4) promotes renal inflammatory injury in type 2 diabetes mellitus (T2DM). Our study aimed to investigate the role and mechanism of RasGRP4 in the production of renal EPO in diabetes.
Methods
The degree of tissue injury was observed by pathological staining. Inflammatory cell infiltration was analyzed by immunohistochemical staining. Serum EPO levels were detected by enzyme-linked immunosorbent assay, and EPO production and renal interstitial fibrosis were analyzed by immunofluorescence. Quantitative real-time polymerase chain reaction and Western blotting were used to detect the expression of key inflammatory factors and the activation of signaling pathways. In vitro, the interaction between peripheral blood mononuclear cells (PBMCs) and C3H10T1/2 cells was investigated via cell coculture experiments.
Results
RasGRP4 decreased the expression of hypoxia-inducible factor 2-alpha (HIF2A) via the ubiquitination–proteasome degradation pathway and promoted myofibroblastic transformation by activating critical inflammatory pathways, consequently reducing the production of EPO in T2DM mice.
Conclusion
RasGRP4 participates in the production of renal EPO in diabetic mice by affecting the secretion of proinflammatory cytokines in PBMCs, degrading HIF2A, and promoting the myofibroblastic transformation of C3H10T1/2 cells.

Citations

Citations to this article as recorded by

Differential effects of prophylactic iron supplementation on physiological gestational anemia and post-IDA gestational anemia: a study based on a rat model
Zelin Zhang, Limin Lai, Ziping Liu, Sili Liu, Liping Qu, Wenjun Zou
Frontiers in Nutrition.2025;[Epub] CrossRef

Review

Basic Research
Roles of Histone Deacetylase 4 in the Inflammatory and Metabolic Processes: Hyunju Kang, Young-Ki Park, Ji-Young Lee, Minkyung Bae; Diabetes Metab J. 2024;48(3):340-353. Published online March 22, 2024; DOI: https://doi.org/10.4093/dmj.2023.0174

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