生长分化因子11对db／db糖尿病小鼠胰岛β细胞功能的保护作用及机制研究  

Protective effects of growth differentiation factor 11 on β-cell function in db/db diabetic mice and its possible mechanism

作　　者：李欢[1] 向光大[1] 梅稳[1] 刘敏[2] 向林[2] 董靖[2] 

机构地区：[1]南方医科大学附属武汉临床学院,广州510515 [2]广州军区武汉总医院内分泌科,武汉430070

出　　处：《中华内分泌代谢杂志》2017年第2期123-128,共6页Chinese Journal of Endocrinology and Metabolism

基　　金：国家自然科学基金资助项目（81370896、81570730）

摘　　要：目的探讨生长分化因子11（GDF11）对db／db糖尿病小鼠胰岛功能的影响及机制。方法将20只8周龄雄性db／db小鼠随机分为2组（n=10），分别给予6周GDFll重组蛋白（0．3mg·kg～·day^-1）或等量磷酸盐缓冲液（PBS）腹腔注射，选取10只8周龄db／m小鼠作为正常对照组，用等量PBS干预6周，定期检测各组血糖、体重及摄食量。实验前后行经腹腔葡萄糖耐量试验（IPGTT）并测定胰岛素释放水平，干预6周后，检测血清中HbA1C及三酰甘油（TG）、总胆固醇（TC）、游离脂肪酸（FFA）水平；检测血清及胰腺内胰岛素、胰升糖素水平；RT—PCR分析胰岛Pdx-1、MafA、Nkx6．1、Insulin2基因转录水平；Western印迹法检测胰岛Smad2、P—Smad2表达水平。结果与DM组相比，GDF11组空腹血糖、HbA1C及血脂水平显著降低。而且，GDF11干预后显著改善小鼠糖耐量水平，增加糖负荷前后的胰岛素释放，升高血清及胰腺内胰岛素含量，降低血清中胰升糖素水平。实时荧光定量PCR发现GDFll组胰岛Pdx-1、MafA、Nkx6-1、Insulin2基因表达上调。免疫印迹法发现GDF11干预后胰岛P-Smad2水平升高。结论GDF11可能通过改善脂代谢，减少胰升糖素的释放，上调β细胞重要转录因子的表达，来保护β细胞功能，促进胰岛素的合成及分泌，延缓糖尿病进展。这种保护作用可能与激活胰岛Smad2信号通路有关。Objective To investigate the effects of growth differentiation factor 11 （ GDF11 ） on β-cell function in db/db mice and its possible mechanism. Methods Twenty eight-week-old male db/db mice were randomized to i. p. administration of GDF11 （0.3 mg · kg^-1· day^-1 ） or equivalent PBS （ n = 10） for 6 weeks. 10 agematched male db/m were used as normal control, received equivalent PBS injection for 6 weeks. Blood glucose levels, body weights and food intake were monitored weekly. IPGTF and glucose-stimulated insulin secretion （ GSIS ） were analyzed. After 6 weeks of intervention, serum HbAlc, TG, TC, and FFA were measured respectively. The concentrations of hormones in serum and pancreas were evaluated. The mRNA expression of Pdx-1, MafA, Nkx6.1, and insulin2 were determined by RT-PCR. The expression of phosphorylated Stud2 （ P-Smad2 ） , Smad2 in islet were examined by western blot. Results Compared with NC group, GDFll administration decreased FBG, HbAic, modified lipid profiles. GDF11 improved glucose tolerance and augmented GSIS. Moreover, GDF11 increased serum insulin and pancreatic insulin content, while decreased serum glucagon concentration. The expression of Pdx-1, MafA, Nkx6.1, and Insulin2 were significantly increased in GDF11 group. GDF11 elevated the expression of P- Smad2 in islets. Conclusions GDF11 may preserve β-cell function and facilitate the secretion and production of insulin. Diminishing the metabolic abnormalities, alleviating the secretion of glucagon, as well as maintaining the key transcript factor activation may contribute to the amelioration of β-cell function after GDF11 administration. Smad2 pathway may be related to the protective effects of GDF11.

关 键 词：生长分化因子11 糖尿病 Β细胞功能 

分 类 号：R587.1[医药卫生—内分泌]