目的:评估和比较利拉鲁肽的疗效,Tirzepatide,在db/db小鼠中治疗糖尿病肾病(DKD)。
方法:Db/db小鼠腹腔注射利拉鲁肽(10nmol/kg),Tirzepatide(10nmol/kg),和瑞特鲁肽(10nmol/kg)持续10周。随后,我们评估了这三种药物控制血糖水平的有效性,减轻体重,改善血清生化指标和DKD。此外,我们测量并比较了肾脏炎症和纤维化指标。同时,比较了肠道代谢产物丁酸盐的含量,以反映这三种药物对肠道微生物群的调节作用。
结果:与利拉鲁肽和替西平肽相比,在降低db/db小鼠体重和改善肾功能方面表现出优异的效果。此外,它显著抑制促炎细胞因子(TNF-α,caspase-1和NLRP3)和促纤维化因子(纤连蛋白,α-SMA,和小鼠肾脏中的胶原蛋白I)。此外,瑞特鲁肽显著增强肝功能,降低甘油三酯水平,胆固醇水平,低密度脂蛋白胆固醇,高密度脂蛋白胆固醇升高,与其他两种药物相比,增加了db/db小鼠肠道代谢产物丁酸盐的含量。不幸的是,尽管它有降低血糖水平的能力,Retatrutide并未优于其他两种药物。相比之下,Tirzepatide有较好的降血糖效果,减肥,降脂,与利拉鲁肽相比,DKD有所改善。
结论:Retatrutide和Tirzepatide在改善DKD方面有显著疗效,控制血糖和体重。瑞特鲁肽在改善DKD和体重方面最有效,而替西帕肽在控制血糖方面最有效。抑制炎症因子和纤维化介质的表达以及调节肠道菌群可能是这两种药物延缓DKD进展的潜在机制。
OBJECTIVE: To assess and compare the therapeutic efficacy of Liraglutide, Tirzepatide, and Retatrutide in treating diabetic kidney disease (DKD) in db/db mice.
METHODS: Db/db mice were administered intraperitoneal injections of Liraglutide (10 nmol/kg), Tirzepatide (10 nmol/kg), and Retatrutide (10 nmol/kg) for 10 weeks. Subsequently, we assessed the effectiveness of these three drugs in controlling blood glucose levels, reducing weight, and improving serum biochemical indicators and DKD. Additionally, we measured and compared the renal inflammation and fibrosis indexes. Meanwhile, the content of intestinal metabolite butyrate was compared to reflect the regulatory effects of these three drugs on gut microbiota.
RESULTS: Retatrutide demonstrated superior effectiveness in reducing weight and improving renal function in db/db mice compared to Liraglutide and Tirzepatide. Additionally, it markedly suppressed the expression of pro-inflammatory cytokines (TNF-α, caspase-1, and NLRP3) and pro-fibrotic factors (fibronectin, α-SMA, and collagen I) in the kidneys of mice. Furthermore, Retatrutide substantially enhanced liver function, reduced triglyceride levels, cholesterol levels, low-density lipoprotein cholesterol, elevated high-density lipoprotein cholesterol, and increased the content of intestinal metabolite butyrate in db/db mice when compared to the other two drugs. Unfortunately, despite its ability to lower blood glucose levels, Retatrutide did not outperform the other two drugs. In contrast, Tirzepatide exhibited better effects on lowering blood glucose, weight loss, lipid reduction, and improvement of DKD compared to Liraglutide.
CONCLUSIONS: Retatrutide and Tirzepatide were significantly effective in improving DKD, controlling blood glucose and body weight. Retatrutide was the most effective in improving DKD and body weight, while Tirzepatide was the most effective in controlling blood glucose. Inhibiting the expression of inflammatory factors and fibrosis mediators and regulating intestinal microbiota may be the potential mechanisms of these two drugs to delay the progression of DKD.