Diabetes & Metabolism Journal

Original Articles

Complications
4-Octyl Itaconate Promotes Diabetic Wound Healing by Enhancing Pro-Resolving Macrophages via the Efferocytosis-MCT1-Lactate-GPR132 Pathway and Macrophage-Independent Synergistic Effects: Mengqin Tu, Xiaoli Zou, Xiaozhen Tan, Yijun Liu, Xinxu Ge, Yu Hu, Qiuyue Peng, Linlin Huang, Yan Zeng, Chunxia Jia, Man Guo, Jiao Chen, Yang Long, Yong Xu; Received September 21, 2024 Accepted July 2, 2025 Published online November 3, 2025; DOI: https://doi.org/10.4093/dmj.2024.0579 [Epub ahead of print]

4,207 View
130 Download
1 Crossref

Abstract PDF Supplementary Material PubReader ePub

Background
Diabetic foot ulcers are a severe diabetic complication causing poor healing. Itaconate, a tricarboxylicacid cycle byproduct, has been shown to improve wound healing. This study investigated the potential of 4-octyl itaconate (4-OI), an esterified derivative of itaconate, to modulate efferocytosis andmacrophage pro-resolving function to promote diabetic wound healing.
Methods
A diabetic mouse wound model was used. For in vitro analysis, RAW264.7 macrophages and apoptotic Jurkat cells were cocultured under high glucose (HG, 30 mM). To further evaluate the roles of macrophages, monocarboxylate transporter 1 (MCT1), and lactate in 4-OI-promoted diabetic wound healing, we used clodronate-liposomes (CLD-Lipo) to deplete macrophages, AZD3965 (an MCT1 inhibitors), telmisartan to validate our hypothesis.
Results
In diabetic mice, impaired apoptotic neutrophils clearance and persistent M1 activation delayed wound healing. 4-OI improved diabetic wound repair by enhancing efferocytosis, shifting macrophages toward M2 pro-resolving phenotype, and boosting angiogenesis. 4-OI showed a protective effect mediated by macrophages, while endothelial cells and neutrophils also played synergistic roles in diabetic wound healing. Moreover, 4-OI upregulated MCT1 which, in turn, increased release of lactate triggered by efferocytosis at the wound site. Lastly, we confirmed that pro-resolving effects of 4-OI onmacrophage function were mediated by promoting pro-resolving macrophage proliferation and polarization via efferocytosis-induced lactate release and subsequent activation of G protein-coupled receptor 132 (GPR132).
Conclusion
4-OI promotes diabetic wound healing through macrophage-dependent/independent mechanisms. Moreover, the protective effect of 4-OI on macrophage was mediated through MCT1-mediated lactate release triggered by efferocytosis and subsequent GRP132 activation.

Citations

Citations to this article as recorded by

Roles of efferocytosis in wound repair: Process, cells, and signals
Yilin Sun, Haiying Guo, Yang Bai, Jin Chen, Yuhong Li
Genes & Diseases.2026; 13(3): 101937. CrossRef

Basic and Translational Research
Abnormally Elevated PKCδ Delays Diabetic Wound Healing by Inhibiting the GAD1-GABA Pathway: Peiliang Qin, Peng Zhou, Yating Huang, Binbin Long, Ruikang Gao, Bingjie Zhu, Yiqing Li, Qin Li; Received August 4, 2024 Accepted May 29, 2025 Published online September 8, 2025; DOI: https://doi.org/10.4093/dmj.2024.0450 [Epub ahead of print]

6,668 View
65 Download

Abstract PDF Supplementary Material PubReader ePub: Background
Diabetic foot ulcer (DFU) represents a challenging complication of diabetes mellitus, characterized by slow healing processes. Protein kinase C delta (PKCδ) has been identified as a significant factor in the pathogenesis of various diabetic complications, including DFU. However, the precise underlying mechanisms remain to be fully elucidated.
Methods
Human umbilical vein endothelial cells (HUVECs) were cultivated under high glucose conditions and PKCδ was knocked down by siRNA. The proliferation, migration, and tube formation of HUVECs were detected. A metabolomics sequencing was done to identify potential metabolites contributing to the changes. HUVECs proliferation, migration, tube formation, and apoptosis were detected after regulating the production of selected metabolite. And finally, the effect of the metabolite on diabetic wound healing was detected.
Results
In vitro, knockdown of PKCδ upregulated glutamate decarboxylase 1 (GAD1) expression and gamma-aminobutyric acid (GABA) levels, which enhanced proliferation, migration, and tube formation and suppressed apoptosis of HUVECs under high glucose conditions. Interestingly, inhibition of GAD1 in normal glucose-treated HUVECs resulted in decreased proliferation, migration, tube formation, and increased apoptosis. Furthermore, in vivo experiments demonstrated that topical administration of GABA accelerated the healing of diabetic wounds in streptozotocin-induced type 2 diabetes mellitus mice, manifested as higher angiogenesis and proliferation.
Conclusion
The inhibition of GAD1-GABA pathway by PKCδ suppresses the proliferation, migration, tube formation and promotes the apoptosis of endothelial cells under high glucose and leads to delayed diabetic wound healing.

Basic Research
Hyperglycemia-Suppressed SMARCA5 Disrupts Transcriptional Homeostasis to Facilitate Endothelial Dysfunction in Diabetes: Ju Wang, Hui Zhou, Jinhua Shao, Shu Zhang, Jing Jin; Diabetes Metab J. 2023;47(3):366-381. Published online March 6, 2023; DOI: https://doi.org/10.4093/dmj.2022.0179

6,575 View
133 Download
4 Web of Science
4 Crossref

Abstract PDF Supplementary Material PubReader ePub

Background
Dysfunction of vascular endothelial cells (ECs) plays a central role in the pathogenesis of cardiovascular complications in diabetes. SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5 (SMARCA5) is a key regulator of chromatin structure and DNA repair, but its role in ECs remains surprisingly unexplored. The current study was designed to elucidate the regulated expression and function of SMARCA5 in diabetic ECs.
Methods
SMARCA5 expression was evaluated in ECs from diabetic mouse and human circulating CD34⁺ cells using quantitative reverse transcription polymerase chain reaction and Western blot. Effects of SMARCA5 manipulation on ECs function were evaluated using cell migration, in vitro tube formation and in vivo wound healing assays. Interaction among oxidative stress, SMARCA5 and transcriptional reprogramming was elucidated using luciferase reporter assay, electrophoretic mobility shift assay and chromatin immunoprecipitation.
Results
Endothelial SMARCA5 expression was significantly decreased in diabetic rodents and humans. Hyperglycemia-suppressed SMARCA5 impaired EC migration and tube formation in vitro, and blunted vasculogenesis in vivo. Contrarily, overexpression of SMARCA5 in situ by a SMARCA5 adenovirus-incorporated hydrogel effectively promoted the rate of wound healing in a dorsal skin punch injury model of diabetic mice. Mechanistically, hyperglycemia-elicited oxidative stress suppressed SMARCA5 transactivation in a signal transducer and activator of transcription 3 (STAT3)-dependent manner. Moreover, SMARCA5 maintained transcriptional homeostasis of several pro-angiogenic factors through both direct and indirect chromatin-remodeling mechanisms. In contrast, depletion of SMARCA5 disrupted transcriptional homeostasis to render ECs unresponsive to established angiogenic factors, which ultimately resulted in endothelial dysfunction in diabetes.
Conclusion
Suppression of endothelial SMARCA5 contributes to, at least in part, multiple aspects of endothelial dysfunction, which may thereby exacerbate cardiovascular complications in diabetes.

Citations

Citations to this article as recorded by

From waste to wonder: exploring the hypoglycemic and anti-oxidant properties of corn processing by−products
Xiaoqian Yang, Yuelong Wang, Jingfeng Li, Yuxing Tai, Kunping Yang, Jingwei Lv, Jiaming Sun, Hui Zhang
Frontiers in Chemistry.2024;[Epub] CrossRef
E3 ubiquitin ligase RNF180 mediates the ALKBH5/SMARCA5 axis to promote colon inflammation and Th17/Treg imbalance in ulcerative colitis mice
Kailing Wang, Fan Liu, Budumu Muchu, Jiawen Deng, Jing Peng, Yan Xu, Fujun Li, Miao Ouyang
Archives of Pharmacal Research.2024; 47(7): 645. CrossRef
USP3 promotes DNA damage response and chemotherapy resistance through stabilizing and deubiquitinating SMARCA5 in prostate cancer
Sheng Li, Situ Xiong, Zhongqi Li, Lin Yang, Hailang Yang, Jing Xiong, Wang Pan, Ju Guo, Songhui Xu, Bin Fu
Cell Death & Disease.2024;[Epub] CrossRef
Overexpression of Chromatin Remodeling Factor SRG3 Down-Regulates IL1β-Expressing M1 Macrophages and IL17-Producing T Cells in Adipose Tissues
Jungmin Jeon, Sung Won Lee, Hyun Jung Park, Yun Hoo Park, Tae-Cheol Kim, Sujin Lee, Seyeong Lee, Luc Van Kaer, Seokmann Hong
International Journal of Molecular Sciences.2024; 25(21): 11681. CrossRef

Review

Impaired Wound Healing in Diabetes Mellitus.: Min Jeong Kwon, Jeong Hyun Park; Korean Diabetes J. 2009;33(2):83-90. Published online April 1, 2009; DOI: https://doi.org/10.4093/kdj.2009.33.2.83

5,278 View
112 Download
3 Crossref

Abstract PDF

The normal healing of a cutaneous wound is achieved via well-orchestrated integration of complex biological and molecular events of cell migration, proliferation, extracellular matrix deposition and tissue remodeling. Chronic wounds fail to progress through the normal stages of healing, and enter a state of pathologic inflammation. Complicated diabetic patients show delayed wound healing caused by multiple factors including vascular insufficiency, abnormalities of the biochemical environment and hyperglycemia per se. Novel technologies including growth factor therapy, gene therapy, stem cell technologies, synthetic skins and hyperbaric oxygen treatment are under development. In the near future, these therapeutic strategies will be clinically available.

Citations

Citations to this article as recorded by

Promotion of wound healing through low-fluence ablative fractional laser treatment in diabetic mice
Han Na Lee, Jung Min Bae, Bon Cheol Leo Goo, Young Min Park
Lasers in Medical Science.2019; 34(2): 421. CrossRef
Ethanol Extracts of Chungkookjang Stimulate the Proliferation and Migration of Human Umbilical Vascular Endothelial Cells
Jae Sung Hwang, Dae Il Sung, Whan Myung Lee, Young Shin Chung, Han Bok Kim
The Korean Journal of Microbiology.2014; 50(3): 223. CrossRef
Comparison of Outcome of Trabeculectomy With Mitomycin C and Ahmed Valve Implantation for Uveitic Glaucoma
Joo Yeon Kim, Hyoung Sub Shim, Hwang Ki Kim, Yong Ho Sohn
Journal of the Korean Ophthalmological Society.2010; 51(4): 575. CrossRef

Original Article

Cloning of Novel Epidermal Growth Factor (EGF) Plasmid for Gene Therapy on Diabetic Foot Ulcer.: Hye Sook Chung, Chang Shin Yoon, Min Jeong Kwon, Mi Kyung Kim, Soon Hee Lee, Kyung Soo Ko, Byung Doo Rhee, Jeong Hyun Park; Korean Diabetes J. 2008;32(2):131-140. Published online April 1, 2008; DOI: https://doi.org/10.4093/kdj.2008.32.2.131

3,584 View
75 Download
2 Crossref

Abstract PDF

BACKGROUND
Epidermal Growth Factor (EGF) is one of the important growth factors involved in the epithelialization during cutaneous wound healing. Peptide EGF has been used for the treatment of diabetic foot ulcer. But the inferiority of cost-effectiveness and the inconvenience of daily application might have restricted its wide clinical usage. EGF gene therapy could dramatically improve the efficacy and inconvenience through long-term expression and bypassing the EGF degradation by hostile non-specific proteinases expressed in the wound bed. METHODS: EGF DNAs were amplified via PCR. For the more effective secretion from the transfected cell, we inserted furin cleavage site into EGF plasmids. The efficacy of novel plasmid pbeta-EGF was verified by transfection into the various animal cell lines, and the biologic potency of expressed EGF was confirmed via phosphorylation of PI3K and GSK3beta by Western blotting. RESULTS: We tested various kinds of human EGFs. One of the human EGF isoforms, EGF(828) including a membrane-anchoring domain was successfully released as the mature EGF protein in the cell culture media. Also EGF plasmid including furin cleavage site showed more than 2-fold increased EGF expression compared with the sequence without furin cleavage site. CONCLUSION: In conclusion, these findings suggest that mature EGF could be released easily out of cells by modifying EGF DNA sequence. Our novel EGF plasmid DNA could markedly increase the efficiency of non-viral gene therapy for diabetic foot ulcer.

Citations

Citations to this article as recorded by

Advances in Wound Healing Strategies for Diabetic Foot Ulcers: From Conventional to Regenerative Therapies
Abdullah Alwahbi
Current Diabetes Reviews.2026;[Epub] CrossRef
Effective healing of diabetic skin wounds by using nonviral gene therapy based on minicircle vascular endothelial growth factor DNA and a cationic dendrimer
Min J. Kwon, Songhie An, Sunghyun Choi, Kihoon Nam, Hye S. Jung, Chang S. Yoon, Jung H. Ko, Hye J. Jun, Tae K. Kim, Soo J. Jung, Jeong H. Park, Yan Lee, Jong‐Sang Park
The Journal of Gene Medicine.2012; 14(4): 272. CrossRef

First
Prev
Page of 1
Next
Last

Search