二甲双胍对自发2型糖尿病OLETF大鼠脂肪分解的影响及机制  

Impact of Metformin on lipolysis and mechanisms in relation to the development of diabetes in OLETF rats

作　　者：张婷婷[1] 姚军[1] 段玉敏[2] 何金汗[3] 袁振芳[1] 张俊清[1] 郭晓蕙[1] 

机构地区：[1]北京大学第一医院内分泌科,100034 [2]北京市第六医院内分泌科 [3]四川大学华西医院药剂科

出　　处：《中国糖尿病杂志》2018年第2期144-149,共6页Chinese Journal of Diabetes

基　　金：国家自然科学基金(81000347)

摘　　要：目的研究二甲双胍对不同周龄OLETF大鼠脂肪分解的影响及其机制。方法OLETF大鼠分为OLETF未干预组和二甲双胍干预组,观察不同周龄OGTT(血糖+FIns)和FFA水平的变化。取附睾脂肪组织测定培养液中甘油释放量,Western blot检测脂滴包被蛋白(Perilipin)、磷酸化和总细胞外信号调节激酶(ERK)、激素敏感性脂肪酶(HSL)和脂肪组织甘油三酯水解酶(ATGL)的表达。结果 18周龄时,二甲双胍抑制糖尿病OLETF大鼠附睾脂肪组织增强的脂肪分解达23.96%(P<0.05),28周龄时,二甲双胍失去对脂肪分解的抑制作用。二甲双胍增加OLETF大鼠附睾脂肪组织Perilipin表达并减少ERK磷酸化,但不影响HSL表达,早期增加ATGL表达但后期无明显影响。结论在OLETF大鼠肥胖和糖尿病早期,二甲双胍增加Perilipin表达和减少ERK磷酸化抑制脂肪分解,从而减少FFA释放,改善IR。Objective To investigate the effect of Metformin on the lipolysis of Otsuka Long Evans Tokushima Fatty（OLETF）rats during the development of diabetes and further elucidate the underlying mechanisms, for better understanding of Metformin in the improvement of insulin sensitivity. Methods OLETF rats were divided into untreated group （OLETF group）and treated group （OLETF/Metformin group）with Long-Evans Tokushima Otsuka （LETO）rats as age-matched controls （LETO group）. We measured body weight and epididymal fat weight, and also examined serum free fatty acids （FFAs）, glucose and fasting insulin in oral glucose tolerance test （OGTT）in different weeks. Glycerol released into the medium in 120 minutes served as an index of lipolysis. The protein levels of hormone-sensitive lipase （HSL）, adipose triglyceride lipase （ATGL）, perilipin, phosphorylated extracellular signal-regulated kinase （p-ERK） and total ERK were examined by western blot. Results With the development of obesity, OLETF rats exhibited diabetic phenotypes at 18 weeks. Compared with the age-matched untreated OLETF group, the release of glycerol from epididymal adipose tissues and serum FFAs in OLETF rats pretreated with Metformin were both significantly decreased at 18 weeks by 23.96% and 62.89% （both P〈0.05）, respectively. However, the lipolysis of OLETF rats attenuated at 28 weeks, thus Metformin had no inhibitory effect on it. At 18 weeks and 28 weeks, HSL protein content had no difference in OLETF rats pretreated with Metformin, yet the expression of perilipin was significantly increased（P^0.05）and p-ERK was significantly decreased （P〈0. 05）in Metformin group compared with untreated OLETF group. In addition, the expression of ATGL in Metformin group was up-regulated at 18 weeks, but was not altered at 28 weeks. Conclusion At the early stage of obesity and diabetes in OLETF rats, Metformin attenuates increased lipolysis by suppressing phosphorylation of ERK and upregulating Perilipin, reducing systemic

关 键 词：二甲双胍 脂肪分解 OLETF大鼠 总细胞外信号调节激酶 脂滴包被蛋白 

分 类 号：R587.1[医药卫生—内分泌]