阿托伐他汀对大鼠胰岛功能影响的量效和时效关系

目的 观察阿托伐他汀对Wistar大鼠胰岛功能及糖耐量的影响,研究其效应与剂量、时间的相关性.方法 将60只8周龄正常Wistar大鼠采用随机数字表法分为正常对照组(生理盐水2 ml/d,n=10)、低剂量阿托伐他汀组(阿托伐他汀5 mg· kg-1·d-1,n=1O)、中剂量阿托伐他汀组(阿托伐他汀25 mg·kg-1·d-1,n=10)和高剂量阿托伐他汀组(阿托伐他汀50 mg·kg-1·d-1,n=30).于干预第0、4、8周分别行口服葡萄糖耐量试验(OGTr),测定血糖、血清胰岛素,计算稳态模型评估-β细胞功能指数(HOMA-β)、第一时相胰岛素分泌指数(△I30/△G30)、稳态模型评估-胰岛素抵抗指数(HOMA-IR)、胰岛素曲线下面积(AUCi)、葡萄糖曲线下面积(AUCg)和处置指数.然后将高剂量阿托伐他汀组部分大鼠采用随机数字表法分为两组,继续给药组仍给予高剂量阿托伐他汀灌胃,洗脱组改为生理盐水灌胃,4周后再次行OGTT检测.并取血行甘油三酯、总胆固醇检测.结果 干预8周后高剂量阿托伐他汀组OGTT 0、15、30、60、120 min的胰岛素水平及HOMA-β、△I30/△G30、AUCi、AUCg、HOMA-IR均低于正常对照组(F=4.168 ～ 306.493,P均＜0.05);干预4周时各组及干预8周时中、低剂量阿托伐他汀组均未见相似效应(P均＞0.05).经4周药物洗脱期后,洗脱组的OGTT0、15、30、60、120 min胰岛素水平(F=4.64 ～ 15.58,P均＜0.05)及上述指标均高于继续给药组(t=29.044、4.433、4.429、2.964,P均＜0.05).但各剂量阿托伐他汀组间血糖和处置指数均未见明显影响(P均＞0.05).HOMA-β、△I30/△G30、AUCi随阿托伐他汀剂量的增加和时间的延长,均逐渐降低,具有剂量及时间依赖关系(F=213.970、63.839、18.222,P均＜0.01).HOMA-IR、AUCg随阿托伐他汀剂量的增加逐渐降低,随着时间的延长逐渐升高,也呈剂量及时间依赖关系(F=214.437,P ＜O.01;F=9.33,P ＜O.05).结论 阿托伐他汀可抑制大鼠胰岛β细胞胰岛素分泌,改善胰岛素敏感性,并与给药剂量和时间有关,但对血糖影响不明显.

Dose-effects and time-effects of atorvastatin on islet function of rats

Objective To study the effects of atorvastatin on islet function and glucose tolerance,investigate the dose-effects and time-effects of atorvastatin in Wistar rats.Methods Sixty eight-week-old healthy Wistar rats were divided into normal control group(physiological saline 2 ml/d,n =10),low-dose atorvastatin group (atorvastatin 5 mg · kg-1 · d-1,n =10),middle-dose atorvastatin group (atorvastatin 25 mg· kg-1.d 1,n =10) and high-dose atorvastatin group (atorvastatin 50 mg · kg-1 · d-1,n =30) by random number table method.An oral glucose tolerance test(OGTT)was carried out at O,4th,8th week,and the levels of blood glucose and serum insulin were measured.Homeostasis model assessment-β function (HOMA-β),first-phase insulin secretion (△I30/△ G30),homeostasis model assessment-insulin resistance (HOMA-IR),area under the curve of blood insulin (AUCi),area under the curve of blood glucose(AUCg) and simple glucose disposition index (DI) were calculated.Some rats in high-dose atorvastatin group were further divided into atorvastatin-continued administration group (fed with high dose atorvastatin)and atorvas tatin-elution group (fed with saline) by random number table method.OGTT was carried out in these two groups after 4 weeks.The serum were collected to measure triglyceride and total cholesterol.Results After 8 weeks of intervention,compared with normal control group,the level of serum insulin at any time point (0,15,30,60,120 min) during OGTT,△I30//△G30,AUCi,AUCg,HOMA-IR were decreased in high-dose atorvastatin group (F =4.168-306.493,all P ＜ 0.05).No similar effects were observed after 4 weeks of in tervention in any atorvastain group,or after 8 weeks in the middle-dose or low-dose atorvastatin group (all P ＞ 0.05).After 4 weeks atorvastatin elution,compared with atorvastatin-eontinued administration group,the level of serum insulin at any time point (0,15,30,60,120 main) during OGTT were higher in atorvas tatin-elution group (F =4.64-15.58,all P ＜ 0.05),and other index mentioned above were higher in atorvastatin-elution group too (t =29.044,4.433,4.429,2.964 respectively,all P ＜ 0.05).But atorvastatin at any dose group showed no obvious difference in blood glucose level and DI (all P ＞ 0.05).HOMA-β,/△I30//△G30 and AUCi decreased gradually with the increase of atorvastatin dose and the prolongation of the experimental time,and had a dose-and time-dependent manner (F =213.970,63.839,18.222,all P ＜ 0.01).HOMA-IR and AUCg decreased gradually with the increase of atorvastatin dose,and increased grad ually with the prolongation of the experimental time,also in a dose-and time-dependent manner (F =214.437,P ＜ 0.01;F =9.33,P ＜0.05).Conclusion Atorvastatin inhibits insulin secretion and increases insulin sensitivity in dose and time-response manner,without obvious effects on blood glucose.