GLP-1-AMPK信号在DJB手术治疗T2DM中的作用及分子机制的实验研究

项目名称： GLP-1-AMPK信号在DJB手术治疗T2DM中的作用及分子机制的实验研究

项目编号： No.31671208

项目类型： 面上项目

立项/批准年度： 2017

项目学科： 生物科学

项目作者： 高志芹

作者单位： 潍坊医学院

项目金额： 25万元

中文摘要： 胃肠手术治疗2型糖尿病(T2DM)疗效确切机制不清。我们前期研究发现十二指肠空肠旷置(DJB)手术后T2DM大鼠胰腺GLP-1R、肝脏InsR 的表达明显升高，血清GLP-1分泌增加等。有文献报道GLP-1激活肝组织AMPK降低其脂肪合成；二甲双胍治疗T2DM与十二指肠组织AMPK激活有关。我们提出：DJB手术治疗T2DM的关键在“前肠”，使GLP-1分泌增加，激活小肠和肝组织AMPK，减少小肠葡萄糖吸收和调节肝组织葡萄糖代谢。本研究拟采用DJB手术干预T2DM大鼠，十二指肠肠壁注射AMPK拮抗剂或激动剂，检测分析AMPK活性变化及其与GLP-1的关系；采用HepG2胰岛素抵抗细胞模型，验证GLP-1能够激活AMPK并提高肝细胞葡萄糖代谢调节能力。明确GLP-1-AMPK信号在T2DM治疗中的作用和分子机制，为选择适合的外科术式治疗T2DM和针对AMPK的降糖药物的研发提供理论依据。

中文关键词： 2型糖尿病；十二指肠空肠旷置手术；AMP依赖蛋白激酶；胰高血糖素样肽1；葡萄糖代谢

英文摘要： Gastric bypass surgery becoming a new way for type 2 diabetes (T2DM) treatment with the mechanism remains unclear.. Our previous studies showed the significantly increased secretion of GLP-1 after DJB, and increasing expression of GLP-1R in pancreas cells and increasing expression of insulin receptor in liver cells which showed the increasing the insulin sensitive of the liver. Together with the studies of the other groups that Glucagon-like peptide-1(GLP-1) reduces hepatic lipogenesis by the activation of AMP-activated protein kinase (AMPK) and antidiabetic drug metformin treating T2DM was associated with AMPK activation in duodenum, we hypothesis that foregut plays the important role in the mechanism of DJB treatment of T2DM. The increasing secretion of GLP-1 by DJB could activate AMPK in duodenum and liver.. In this study, we sought to investigate the role of AMPK activation in the proximal gut on glucose homeostasis by measuring insulin sensitivity, GLP-1 levels after DJB surgery. By in vivo duodenal intestine injections or in vitro using HepG2 insulin resistance cell model of AMPK antagonists or agonist, study the effect of AMPK activity with the ability of intestine absorption and liver glucose metabolic regulation. The Confirmation of the important role of GLP-1-AMPK signal in the treatment of T2DM, giving us the better choice of surgical procedure in T2DM treatment and providing clue for new drugs targeting AMPK for the T2DM medicine treatment.

英文关键词： Type 2 Diabetes Mellitus;T2DM;Duodenal Jejunal Bypass; DJB;AMP-activated protein kinase;Glucagon-Likepeptide1;GLP-1;Glycometabolism