单纯高脂饮食诱导2型糖尿病小鼠模型的构建及病理改变的评价

Construction of a mouse model of type 2 diabetes induced by high fat diet alone and evaluation of pathological changes

本文旨在研究单纯高脂饮食(high fat diet,HFD)诱导2型糖尿病(type 2 diabetes mellitus,T2DM)小鼠模型的成模时间以及HFD对糖脂代谢相关器官的病理和功能影响。给予C57BL/6小鼠正常饮食(NC组)或HFD(HFD组)0、4、8、12、16和20周,通过检测体重、空腹血糖和葡萄糖耐量,评估T2DM建模成功的时间;通过胰岛素耐量、血脂、血管功能检测以及胰腺、肝脏HE染色评估糖脂代谢相关器官的功能和病理改变。结果显示,与NC组相比,HFD组在HFD 8周后体重开始显著升高;在HFD 16周时,HFD组出现空腹糖耐量受损;在HFD 20周时,HFD组小鼠达到糖尿病状态,出现葡萄糖耐量受损和胰岛素抵抗,胰岛体积缩小、胰岛发生空泡变性等病理改变,肝细胞出现大量脂滴,肝脏组织AMPK磷酸化水平显著升高,胸主动脉存在内皮依赖性舒张功能障碍;和NC组相比,HFD组小鼠尿蛋白水平显著增加。上述结果提示,单纯HFD诱导20周可成功建立T2DM小鼠模型,该模型的特征为胰岛素抵抗、脂肪肝、高脂血症、血管功能异常、肾功能损害以及胰岛和肝细胞的病理改变等,与T2DM患者相似,可作为理想的T2DM动物研究模型。

The purpose of the present study was to investigate the modeling time of type 2 diabetes mellitus(T2DM)mouse model induced by high fat diet(HFD)alone and the effects of HFD on the pathology and function of organs related to glucose and lipid metabolism.C57BL/6 mice were fed with normal diet(NC group)or HFD(HFD group).The time of successful T2DM modeling was evaluated by measuring body weight,fasting blood glucose and glucose tolerance at time points of 0,4,8,12,16 and 20 weeks.The functional and pathological changes of glucose and lipid metabolism related organs were evaluated by detecting insulin tolerance,plasma lipid levels,vascular function,as well as HE staining of pancreas and liver.The results showed that compared with the NC group,the HFD group had significantly increased body weight after 8 weeks of HFD.After 16 weeks of HFD,the HFD group exhibited impaired fasting glucose tolerance.After 20 weeks of HFD,the HFD group mice reached diabetic state,showing impaired glucose tolerance and insulin resistance,islet volume reduction and vacuolar degeneration;Large number of lipid droplets appeared in liver cells,and the level of AMPK phosphorylation in liver tissue was significantly increased in the HFD groups,compared with the NC group;There was endothelial dependent diastolic dysfunction in the thoracic aorta of the HFD group;Compared with the NC group,the HFD group mice showed a significant increase in urinary protein levels.These results suggest that T2DM mouse model can be successfully established by HFD induction alone for 20 weeks.The model is characterized by insulin resistance,fatty liver,hyperlipidemia,vascular dysfunction,renal dysfunction and pathological changes of islet and liver cells,which are similar to those of T2DM patients.Therefore it can be used as an ideal animal model for T2DM research.