Liu Hao, Tian Faming, Hu Yunpeng, Ping Shaohua, Zhang Liu
Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, Hebei, People's Republic of China.
Department of Orthopedic Syrgery, The Affiliated Hospital, North China University of Science and Technology, Tangshan, Hebei, People's Republic of China.
Diabetes Metab Syndr Obes. 2023 Apr 29;16:1235-1245. doi: 10.2147/DMSO.S404392. eCollection 2023.
Fractures in patients with type 2 diabetes mellitus are at a high risk of delayed union or non-union. Previous studies have shown a protective effect of liraglutide on bone. In the present study, we aimed to investigate the effects of a combination of liraglutide and insulin on fracture healing in a rat model of diabetes and the mechanisms involved.
Closed femoral mid-shaft fractures were established in male Sprague-Dawley rats with or without diabetes mellitus, and the diabetic rats were administered insulin and/or liraglutide. Six weeks after femoral fracture, the femoral callus was evaluated by immunohistochemistry, histology, and micro-computed tomography. Additionally, the effects of liraglutide on high-glucose-stimulated MC3T3-E1 cells were analyzed by Western blotting.
Micro-computed tomography and safranin O/fast green staining showed that fracture healing was delayed in the diabetic rats, and this was accompanied by much lower expression of osteogenic markers and greater osteoclast activity. However, treatment with insulin and/or liraglutide prevented these changes. Liraglutide in combination with insulin treatment resulted in lower blood glucose concentrations and significantly higher osteocalcin (OCN) and collagen I (Col I) expression six weeks following fracture. Western blot analysis showed that liraglutide prevented the low expression of the bone morphogenetic protein-2, osterix/SP7, OCN, Col I, and β-catenin in high-glucose-stimulated MC3T3-E1 cells.
These results demonstrate that insulin and/or liraglutide promotes bone fracture healing in the DF model. The combination was more effective than either single treatment, which may be because of the two drugs' additive effects on the osteogenic ability of osteoblast precursors.
2型糖尿病患者的骨折发生延迟愈合或不愈合的风险较高。既往研究显示利拉鲁肽对骨骼具有保护作用。在本研究中，我们旨在探讨利拉鲁肽与胰岛素联合应用对糖尿病大鼠骨折愈合的影响及其相关机制。
对雄性斯普拉格-道利大鼠制造有无糖尿病的闭合性股骨干中段骨折，并对糖尿病大鼠给予胰岛素和/或利拉鲁肽。股骨骨折六周后，通过免疫组织化学、组织学和微型计算机断层扫描对股骨骨痂进行评估。此外，通过蛋白质印迹法分析利拉鲁肽对高糖刺激的MC3T3-E1细胞的影响。
微型计算机断层扫描和番红O/固绿染色显示糖尿病大鼠骨折愈合延迟，同时伴有成骨标志物表达降低和破骨细胞活性增强。然而，胰岛素和/或利拉鲁肽治疗可防止这些变化。利拉鲁肽与胰岛素联合治疗导致骨折六周后血糖浓度降低，骨钙素（OCN）和I型胶原蛋白（Col I）表达显著升高。蛋白质印迹分析显示，利拉鲁肽可防止高糖刺激的MC3T3-E1细胞中骨形态发生蛋白-2、osterix/SP7、OCN、Col I和β-连环蛋白的低表达。
这些结果表明胰岛素和/或利拉鲁肽可促进糖尿病骨折模型中的骨折愈合。联合治疗比单一治疗更有效，这可能是由于两种药物对成骨细胞前体成骨能力的相加作用。
