Chen Zhuangsen, Zhou Zhongyu, Wang Lin, Zhang Yanrong, Huang Caiyan, Wang Cong, Huang Ying, Wang Shanshan, Yan Dewen, Feng Kun
Department of Endocrinology, Pingshan District People's Hospital of Shenzhen, Shenzhen, Guangdong Province, China.
Department of Endocrinology, Pingshan Hospital of Southern Medical University, Shenzhen, Guangdong Province, China.
J Diabetes Investig. 2025 Apr;16(4):715-727. doi: 10.1111/jdi.14373. Epub 2024 Dec 9.
Polyethylene glycol loxenatide (PEG-Loxe) is applied in treating type 2 diabetes mellitus. Nevertheless, the effect and mechanism of PEG-Loxe on lipid metabolism disorder and insulin resistance in type 2 diabetes mellitus are not fully understood.
Type 2 diabetes mellitus rats developed by high-fat diet/streptozotocin injection were treated with PEG-Loxe (0.3 or 1 mg/kg). Insulin resistance was evaluated by fasting blood glucose (FBG), oral glucose tolerance test, fasting insulin, homeostasis model of assessment for insulin resistance and for insulin sensitivity. Immunohistochemistry, hematoxylin and eosin staining, and biochemistry measurements were performed to assess lipid metabolism. Inflammatory response and oxidative stress were assessed by inflammatory cytokines and reactive oxygen species. Genes' expressions were tested using RT-qPCR, western blot, and in situ hybridization. Relationships of molecules were validated by pull-down assay and RNA immunoprecipitation. mRNA stability was examined by actinomycin D assay.
High-PEG-Loxe decreased FBG and ameliorated glucose tolerance, hyperinsulinemia, and insulin resistance. Low-PEG-Loxe partly while high-PEG-Loxe apparently relieved hepatocyte injury, reduced lipase I, triglyceride, total cholesterol and leptin, and increased adiponectin in type 2 diabetes mellitus rats. PEG-Loxe mitigated inflammatory response and oxidative stress. High-PEG-Loxe reduced RhoA and Rho-associated coiled-coil kinase 2 (ROCK2) in liver tissues of type 2 diabetes mellitus rats, while both doses of PEG-Loxe decreased steroid receptor RNA activator (SRA). SRA overexpression reversed the protective functions of high-PEG-Loxe. SRA cooperated with cellular nucleic acid binding protein (CNBP) to enhance ROCK2 mRNA stability.
High-PEG-Loxe relieves insulin resistance and lipid metabolism disorder in type 2 diabetes mellitus through SRA/CNBP/ROCK2 axis. This research provides a molecular mechanism of PEG-Loxe for treating type 2 diabetes mellitus.
聚乙二醇洛塞那肽（PEG-Loxe）用于治疗2型糖尿病。然而，PEG-Loxe对2型糖尿病脂质代谢紊乱和胰岛素抵抗的作用及机制尚未完全明确。
采用高脂饮食/链脲佐菌素注射诱导的2型糖尿病大鼠，给予PEG-Loxe（0.3或1mg/kg）治疗。通过空腹血糖（FBG）、口服葡萄糖耐量试验、空腹胰岛素、胰岛素抵抗及胰岛素敏感性稳态模型评估胰岛素抵抗。进行免疫组织化学、苏木精-伊红染色及生化检测以评估脂质代谢。通过炎症细胞因子和活性氧评估炎症反应和氧化应激。采用逆转录定量聚合酶链反应（RT-qPCR）、蛋白质免疫印迹法和原位杂交检测基因表达。通过下拉试验和RNA免疫沉淀验证分子间关系。用放线菌素D试验检测mRNA稳定性。
高剂量PEG-Loxe降低FBG，改善葡萄糖耐量、高胰岛素血症和胰岛素抵抗。低剂量PEG-Loxe部分缓解，高剂量PEG-Loxe明显减轻2型糖尿病大鼠的肝细胞损伤，降低脂肪酶I、甘油三酯、总胆固醇和瘦素水平，并增加脂联素水平。PEG-Loxe减轻炎症反应和氧化应激。高剂量PEG-Loxe降低2型糖尿病大鼠肝组织中的RhoA和Rho相关卷曲螺旋蛋白激酶2（ROCK2），而两种剂量的PEG-Loxe均降低类固醇受体RNA激活剂（SRA）。SRA过表达逆转了高剂量PEG-Loxe的保护作用。SRA与细胞核酸结合蛋白（CNBP）协同增强ROCK2 mRNA稳定性。
高剂量PEG-Loxe通过SRA/CNBP/ROCK2轴缓解2型糖尿病的胰岛素抵抗和脂质代谢紊乱。本研究为PEG-Loxe治疗2型糖尿病提供了分子机制。
