成纤维细胞生长因子21对1型糖尿病动物模型的肝糖代谢影响及机制研究

成纤维细胞生长因子(FGF)-21是FGF家族的成员之一.作为近年发现的一种新的糖代谢调节因子,大量研究表明,FGF-21是一种不依赖胰岛素,能够独立降糖的2型糖尿病治疗潜力型药物.但是,能否应用于1型糖尿病的治疗,国内外目前尚无报道.通过改良传统造模方法,诱导小鼠缓慢产生糖耐量异常,研究FGF-21对此类模型的糖代谢影响及肝糖代谢机制.通过检测FGF-21短期注射和长期注射后模型动物血糖的变化,研究FGF-21在模型动物上对血糖的调控效果.采用实时定量PCR检测FGF-21对模型动物肝脏中葡萄糖转运蛋白(GLUT)1、4 mRNA的表达影响.利用蒽酮法检测模型动物肝脏中糖原合成量.实验结果显示,FGF-21能够调节1型糖尿病动物的血糖水平,并呈剂量依赖性.同时,首次在1型糖尿病动物模型上证实了低剂量FGF-21(0.125 mg/kg)与胰岛素的协同作用效果优于相同剂量FGF-21和胰岛素单独注射的效果.治疗结果表明,FGF-21能够维持1型糖尿病动物模型血糖在正常范围,效果优于胰岛素.实时定量PCR结果发现,与胰岛素上调GLUT4 mRNA表达量不同的是,FGF-21作用动物模型8周后,GLUT1 mRNA表达量显著提高,长期的FGF-21与胰岛素协同注射使GLUT1、4 mRNA表达量同时显著提高.长期FGF-21与胰岛素协同注射组和高剂量FGF-21注射均可显著提高模型动物肝糖原的合成.结果表明,FGF-21促进动物模型糖代谢机制与增加GLUT1表达、增加糖原合成作用有关.为临床应用FGF-21治疗1型糖尿病,增加胰岛素敏感性提供了理论依据.

Fibroblast growth factor-21 mediates hepatic glucose metabolism of type 1 diabetes model and its mechanism

Fibroblast growth factor(FGF)-21 is a new member of the fibroblast growth family. Recent studies show that FGF-21 is a novel regulator for glycemic control in various type 2 DM models. However, its potential to treat type 1 diabetes mellitus has not been explored. An evaluation of the function and mechanism of FGF-21 was made in hepatic glucose metabolism of type 1 diabetes mouse model with slow-onset of the impaired glucose tolerance induced by STZ. The mice were administrated with FGF-21, the mRNA expression of GLUT1 and 4 in the liver were detected by the real-time PCR and glycogen synthesis was examined by the anthrone method. The results showed that FGF-21could lower the blood glucose level of the type 1 diabetes model in a dose-depend manner. The blood glucose level of the experimental animals maintained at normal level by injection of the FGF-21 once a day. For the first time, the synergistic effect of FGF-21 with insulin in the animal model was found. Unlike insulin that stimulated GLUT4 expression, FGF-21 could increase the mRNA expression of GLUT1, co-treatment (CT) with insulin and FGF-21 could increase the mRNA expression of both GLUT1 and 4. After long term treatment, the same as insulin, FGF-21 also stimulated glycogen synthesis of the model mice. The results suggested that FGF-21 can regulate glucose metabolism through GLUT1 expression, stimulate glycogen synthesis and improve glucose metabolism in type 1 diabetes model. Moreover, CT administration could increase both GLUT1 and 4 expressions. These data provide the first evidence for clinic application of FGF-21 for treatment of type 1 diabetes patients.