不同维持剂量聚乙二醇修饰的FGF-21在Ⅰ型糖尿病小鼠中降糖作用的研究

Hypoglycemic effect of different maintaining dose of PEGylated FGF-21 in mice with typeⅠdiabetes

成纤维细胞生长因子21(FGF-21)是一种具有调节血糖功能的蛋白,且FGF-21聚乙二醇化可增加其半衰期、降低其免疫原性,有望成为临床治疗糖尿病新药。为推进聚乙二醇化FGF-21(pFGF-21)临床应用,在I型糖尿病小鼠模型上探索使用剂量。研究以1 mg·kg^(-1)pFGF-21作为启动剂量治疗小鼠15 d;后降低治疗剂量,分别以0.25、0.5 mg·kg^(-1)pFGF-21作为维持剂量持续治疗30 d。试验期间检测小鼠血糖、口服葡萄糖耐受量(OGTT)、糖化血红蛋白(HbA1c)、血清功能及肝脏糖代谢相关基因mRNA表达水平。结果发现,试验方法对Ⅰ型糖尿病治疗效果显著;此外,通过生化指标对比显示经pFGF-21治疗后,可显著改善肝脏功能和脂代谢紊乱(P<0.01)。结果证明,1 mg·kg^(-1)pFGF-21启动后,以0.25和0.5 mg·kg^(-1)作为维持剂量,即高剂量启动,低剂量维持,治疗效果良好,对pFGF-21临床应用具有重要意义。

Fibroblast growth factor 21（FGF-21） is a kind of protein that can regulate hyper- glycemia. And PEGylated FGF-21 can increase its half-life period, reduce its immunogenicity. It is expected to become a new drug treatment of diabetes. In order to better promote the clinical application of pFGF-21, we explored its application dosage in type I diabetes. Firstly, the pFGF-21 1 rag. kg1 was used as the initial dose for 15 d in type I diabetes mice, then the dose was reduced. Respectively, pFGF-21 of the 0.25, 0.5 rag. kg1 as maintenance dose of 30 d was executed in continuous treatment. During the experiment, blood glucose, OGTT, HbAlc, serum index, mRNA expression level of hepatic glucose metabolism related genes were measured. We found that the type I diabetes mice showed a good therapeutic effect. Furthermore, we found pFGF-21 can significantly ameliorate the hepatic function and the lipid metabolism disorder through the biochemical index （P〈0.01）. In all, the results showed that the initial dose of pFGF-21 of 1 mg. kg1 and maintenance dose of 0.25 and 0.5 mgo kg1 can act a good therapeutic effect and which is of great importance to the future clinical application of pFGF-21.