School of Life Sciences, Chongqing University, Chongqing, 401331, China.
Department of Endocrinology, Translational Research of Diabetes Key Laboratory of Chongqing Education Commission of China, the Second Affiliated Hospital of Army Medical University, Chongqing, 400037, China.
Adv Sci (Weinh). 2024 Oct;11(39):e2405987. doi: 10.1002/advs.202405987. Epub 2024 Aug 19.
Non-healing diabetic wounds and ulcer complications, with persistent cell dysfunction and obstructed cellular processes, are leading causes of disability and death in patients with diabetes. Currently, there is a lack of guideline-recommended hypoglycemic drugs in clinical practice, likely due to limited research and unclear mechanisms. In this study, it is demonstrated that liraglutide significantly accelerates wound closure in diabetic mouse models (db/db mice and streptozotocin-induced mice) by improving re-epithelialization, collagen deposition, and extracellular matrix remodeling, and enhancing the proliferation, migration, and adhesion functions of keratinocytes. However, these effects of improved healing by liraglutide are abrogated in dedicator of cytokinesis 5 (Dock5) keratinocyte-specific knockout mice. Mechanistically, liraglutide induces cellular function through stabilization of unconventional myosin 1c (Myo1c). Liraglutide directly binds to Myo1c at arginine 93, enhancing the Myo1c/Dock5 interaction by targeting Dock5 promoter and thus promoting the proliferation, migration, and adhesion of keratinocytes. Therefore, this study provides insights into liraglutide biology and suggests it may be an effective treatment for diabetic patients with wound-healing pathologies.
非愈合性糖尿病创面和溃疡并发症，伴持续的细胞功能障碍和细胞过程受阻，是糖尿病患者残疾和死亡的主要原因。目前，临床实践中缺乏指南推荐的降血糖药物，这可能是由于研究有限和机制不明确。本研究表明，利拉鲁肽通过改善再上皮化、胶原沉积和细胞外基质重塑，以及增强角质形成细胞的增殖、迁移和黏附功能，显著加速糖尿病小鼠模型（db/db 小鼠和链脲佐菌素诱导的小鼠）创面的闭合。然而，在有丝分裂胞质分裂 5（Dock5）角质形成细胞特异性敲除小鼠中，利拉鲁肽改善愈合的这些作用被消除。在机制上，利拉鲁肽通过稳定非典型肌球蛋白 1c（Myo1c）来诱导细胞功能。利拉鲁肽直接在精氨酸 93 处与 Myo1c 结合，通过靶向 Dock5 启动子增强 Myo1c/Dock5 相互作用，从而促进角质形成细胞的增殖、迁移和黏附。因此，本研究为利拉鲁肽的生物学提供了新的见解，并表明它可能是治疗糖尿病创面愈合病理的有效方法。
