Diabetes & Metabolism Journal

Original Article

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; Diabetes Metab J. 2026;50(4):688-706. Published online September 8, 2025; DOI: https://doi.org/10.4093/dmj.2024.0450

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Background
Diabetic foot ulcer (DFU) is a challenging complication of diabetes mellitus, characterized by delayed wound healing. Protein kinase C delta (PKCδ) has been identified as an important factor in the pathogenesis of various diabetic complications, including DFU. However, the precise underlying mechanisms remain incompletely elucidated.
Methods
Human umbilical vein endothelial cells (HUVECs) were cultured under high-glucose conditions, and PKCδ was knocked down using siRNA. The proliferation, migration, and tube formation of HUVECs were assessed. Metabolomic sequencing was performed to identify potential metabolites contributing to these changes. HUVEC proliferation, migration, tube formation, and apoptosis were then assessed after regulation of the selected metabolite. Finally, the effect of the metabolite on diabetic wound healing was evaluated.
Results
In vitro, PKCδ knockdown 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 decreased proliferation, migration, and 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, as manifested by increased angiogenesis and proliferation.
Conclusion
PKCδ-mediated inhibition of the GAD1-GABA pathway suppresses endothelial cell proliferation, migration, and tube formation and promotes apoptosis under high-glucose conditions, thereby delaying diabetic wound healing.

Citations

Citations to this article as recorded by

Integrated multi-technology exploration of the mechanism by which Badushengji San regulates core targets in diabetic foot ulcer
Yifan Cai, Aizhen Lin, Junyi Shen, Xiaoyu Zhang, Jinbo Zhou, Yuanzhi Rang, Xiaoyin Chen
Molecular Genetics and Genomics.2026;[Epub] CrossRef

Short Communication

Basic Research
GPR40 Agonism Modulates Inflammatory Reactions in Vascular Endothelial Cells: Joo Won Kim, Eun Roh, Kyung Mook Choi, Hye Jin Yoo, Hwan-Jin Hwang, Sei Hyun Baik; Diabetes Metab J. 2022;46(3):506-511. Published online January 24, 2022; DOI: https://doi.org/10.4093/dmj.2021.0092

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Endothelial dysfunction is strongly linked with inflammatory responses, which can impact cardiovascular disease. Recently, G protein-coupled receptor 40 (GPR40) has been investigated as a modulator of metabolic stress; however, the function of GPR40 in vascular endothelial cells has not been reported. We analyzed whether treatment of GPR40-specific agonists modulated the inflammatory responses in human umbilical vein endothelial cells (HUVECs). Treatment with LY2922470, a GPR40 agonist, significantly reduced lipopolysaccharide (LPS)-mediated nuclear factor-kappa B (NF-κB) phosphorylation and movement into the nucleus from the cytosol. However, treatment with another GPR40 agonist, TAK875, did not inhibit LPS-induced NF-κB activation. LPS treatment induced expression of adhesion molecules vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) and attachment of THP-1 cells to HUVECs, which were all decreased by LY2922470 but not TAK875. Our results showed that ligand-dependent agonism of GPR40 is a promising therapeutic target for overcoming inflammatory reactions in the endothelium.

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