Diabetes & Metabolism Journal

Original Article

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]

4,206 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

Case Report

A Case of Bartter's Syndrome occurring in Diabetes Mellitus.: Jang Yel Shin, Jeung Rae Cho, Do Young Kim, Joon Kye Lee, Chul Woo Ahn, Jae Hyun Nam, Soo Yon Nam, Young Duk Song, Kyu Hun Choi, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee, Kap Bum Huh, Jai Ho Han, Heun Ju Jung; Korean Diabetes J. 2000;24(1):90-96. Published online January 1, 2001

2,152 View
35 Download

Abstract PDF: Bartter's syndrome is characterized by hypokalemia, metabolic alkalosis, hyperreninemia and secondary hyperaldosteronism without hypertension and edema, Histologically, existing hyperplasia of the juxtaglomerular cell occurs mostly in childhood or adolescence, and initial presentation in patients over 40 years old of age is very rare. It has been recorded that Bartter's syndrome is associated with glucose intolerance, but not with overt diabetes mellitus. Whether this association is coincidental or causal is uncertain, although hypokalemia can cause glucose intolerance. We experienced a case of Bartters syndrome in 44 years old non-insulin dependent diabetic woman. She improved with potassium supplements along with combination of prostaglandin synthetase inhibitor and aldosterona antagonist. We report present case with the review of literature.

First
Prev
Page of 1
Next
Last

Search