摘要
目的考察阿托伐他汀对糖耐量异常KKAy小鼠胰岛功能的影响并探讨可能作用机制。方法选择糖耐量异常的KKAy雌性小鼠模型。随机分为模型组和阿托伐他汀组(30 mg·kg-1·d-1),连续灌胃给药46 d,考察其对糖脂代谢及胰岛功能相关指标的影响。结果阿托伐他汀可显著降低KKAy小鼠血清脂质水平、血清胰岛素及胰岛素抵抗指数(P<0.05);阿托伐他汀亦可显著降低口服糖耐量实验中药时曲线下面积(P<0.001),增加胰腺重量指数(P<0.01);阿托伐他汀组胰岛中的炎性细胞浸润及脂肪空泡有一定程度减少,且β细胞阳性颗粒增多;阿托伐他汀可显著上调胰腺Bcl-2与SREBP2基因的表达水平(P<0.01,P<0.05),并显著降低了Chop蛋白的表达水平(P<0.01)。结论阿托伐他汀可改善糖耐量异常KKAy小鼠的胰岛素敏感性和胰岛功能,可能与其改善机体糖脂代谢紊乱、调控胰腺中抗凋亡和内质网应激相关因子有关。
Objective To evaluate the effects of the atorvastatin（ Ator）on β cell function in KKAy mice with impaired glucose tolerance（ IGT-KKAy）. Methods Female KKAy mice selected by insulin tolerance test（ ITT） were divided into two groups. Model group was orally administered by gavage with water,Ator group at a dose of 30 mg·kg^- 1·d^- 1for about 46 days. Normal C57 mice were recruited as Nor group. ITT,glucose tolerance tests（ OGTT） and fasting plasma lipids and insulin levels were determined. Pancreas weight index was tested. Pancreas morphology changes and β cell mass were evaluated by hematoxylin- eosin and gomori- aldehyde fuchsin stainning. The changes of gene and protein expression in the pancreas were also analyzed by Real- time- PCR and Western bolt. Results Ator significantly improved glucose intolerance and insulin resistance in IGT- KKAy mice. Lipid profiles such as triglyceride（ TG）,total cholesterol（ CHO）,free fatty acid（ FFA） and low density lipoprotein cholesterol（ LDL- C） were all significantly diminished after Ator treatment. Fasting plasma insulin levels and homeostatic model assessment- insulin resistance（ HOMA- IR） index were also decreased after treatment. In addition,Ator markedly increased pancreas weight index,improved islets periphery and recovered β cell mass.It was showed that Ator up- regulated the pancreatic gene expression of anti- apoptotic Bcl-2 and cholesterol metabolism related SREBP2（ P〈0. 01,P〈0. 05）. Moreover,the protein expression of ER stress related Chop is decreased in Ator group（ P0.01）. Conclusion These results indicated that chronic administration of Ator improved dyslipidemia and glucose homeostasis in IGT- KKAy mice,which is related to up- regulation of genes involved in lipid metabolism and anti- apoptosis.The findings of the present study indicate that Ator might have a potential role for protecting β cell function.
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2014年第9期783-787,共5页
The Chinese Journal of Clinical Pharmacology
基金
重大新药创制国家科技重大专项基金资助项目(2012ZX09301002-004)
关键词
阿托伐他汀
KKAY小鼠
糖脂代谢
胰岛功能
凋亡
内质网应激
atorvastatin
IGT-KKAy mice
glucose and lipid metabolism
β-cell function
apoptosis
endoplasmic reticulum stress
