二甲双胍对高脂饮食诱导的2型糖尿病小鼠胰岛β细胞功能的改善及机制探讨

发布时间：2018-11-04 12:01

【摘要】：明确二甲双胍对胰岛β细胞的作用并初步考察其作用机制。高脂饮食诱导的2型糖尿病C57BL/6J小鼠,按照空腹血糖、胰岛素耐量实验中40 min时的血糖下降百分数、甘油三酯、胆固醇及体重5个指标分为模型组(model)与二甲双胍组(model+metformin,200 mg·kg~(-1)),连续灌胃给药58天。采用糖耐量实验与高葡萄糖钳夹技术检测胰岛功能,并分析胰腺中与增殖、脂质代谢及内质网应激相关因子的m RNA及蛋白含量变化。与model组相比,二甲双胍可显著降低C57小鼠体重(P0.01)、血中甘油三酯与胆固醇水平(P0.05);减少糖耐量实验中时间-血糖曲线下面积(P0.05);增加C57小鼠高糖钳夹实验中稳态期葡萄糖输注速率(P0.05);降低空腹血清胰岛素(P0.05)。二甲双胍显著上调C57小鼠胰腺中与胰腺增殖相关的胰十二指肠同源框因子-1(Pdx-1,P0.01)及脂质代谢相关的基因肝X受体β(Lxr-β,P0.01)的表达。Western blot结果显示,与model组相比,二甲双胍组小鼠胰腺中PDX-1的蛋白表达显著增加(P0.01);内质网应激相关的PERK通路中的激活转录因子4(ATF4,P0.001)和C/EBP同源蛋白(CHOP,P0.05)蛋白表达量也较model组显著减少。以上结果提示,二甲双胍可改善2型糖尿病C57BL/6J小鼠胰岛素分泌功能。其作用机制可能与促进胰腺增殖、改善脂质代谢并缓解胰腺内质网应激状态相关。
[Abstract]:To investigate the effect of metformin on islet 尾 cells and its mechanism. High fat diet induced type 2 diabetic C57BL/6J mice, according to fasting blood glucose, insulin tolerance test at 40 min blood glucose decreased percentage, triglyceride, Cholesterol and body weight were divided into (model) group and metformin group (model metformin,200 mg kg~ (-1),) by gavage for 58 days. The function of pancreatic islets was measured by glucose tolerance test and hyperglycemic clamp technique. The changes of m RNA and protein contents in pancreas with proliferation, lipid metabolism and endoplasmic reticulum stress-related factors were analyzed. Compared with the model group, metformin significantly decreased the body weight, triglyceride and cholesterol levels of C57 mice (P0.05), decreased the area under the time-glucose curve in glucose tolerance test (P0.05). Increase the glucose infusion rate (P0.05) and decrease fasting serum insulin (P0.05) in C57 mice hyperglycemic clamp test. Metformin upregulated the expression of pancreaticoduodenal homeobox factor-1 (Pdx-1,P0.01) and hepatic X receptor 尾 (Lxr- 尾), which were associated with pancreatic proliferation in C57 mice. Compared with model group, the expression of PDX-1 protein in pancreas of metformin group increased significantly (P0.01). The expression of activator transcription factor 4 (ATF4,P0.001) and C/EBP homologue protein (CHOP,P0.05) in endoplasmic reticulum stress-related PERK pathway was significantly lower than that in model group. These results suggest that metformin can improve insulin secretion in type 2 diabetic C57BL/6J mice. The mechanism may be related to promoting pancreatic proliferation, improving lipid metabolism and relieving stress state of pancreatic endoplasmic reticulum.
【作者单位】：贵州省人民医院中心实验室;中国医学科学院北京协和医学院药物研究所天然药物活性物质与功能国家重点实验室;
【基金】：贵州省人民医院博士基金资助项目(GZSYBS[2016]03) 黔科合院士站([2015]4015) 黔人项目资助(合同(2013)05号,黔科合外G字[2014]7020号)
【分类号】：R965

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