胰腺外分泌调节胰岛内分泌功能及其细胞信号传导系统的探索

项目名称： 胰腺外分泌调节胰岛内分泌功能及其细胞信号传导系统的探索

项目编号： No.30871187

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 轻工业、手工业

项目作者： 杨金奎

作者单位： 首都医科大学

项目金额： 30万元

中文摘要： 传统观念认为胰腺内、外分泌系统在组织学和功能上各自独立。但新近研究发现：胰腺导管与胰岛之间在组织学上存在紧密联系；外分泌功能不足的病人发生糖尿病的风险增加。课题组研究发现外分泌因子HCO3-对胰岛素分泌有剂量依赖新调节作用。我们研究了囊性纤维化跨膜通道调节因子（CFTR）通过外碳酸氢根离子（HCO-3）介导的胰岛β#32454;胞分泌胰岛素,发现高HCO3-浓度导致MIN6细胞的胰岛素分泌显着减少，呈剂量依赖的相关性，而细胞存活率没有显着差异。 CFTR的mRNA和CFTR蛋白在MIN6β32454;胞表达，CFTR的主要是位于细胞膜。 CFTR的mRNA表达水平呈与细胞外的HCO3-的治疗浓度正相关。在25mM的HCO3-，CFTR的抑制剂-CFTRinh-172促进胰岛素分泌。结果表明HCO3-的负调节胰岛素分泌是CFTR介导的。新近，我们通过模片钳技术分析CFTR对细胞内HCO3－离子的影响及pH值变化，进一步研究其对胰岛细胞功能的作用。调节胰腺导管细胞分泌功能可能成为糖尿病药物治疗新的靶点。

中文关键词： 胰岛素;Na+-HCO3-共同转运体;胰腺导管上皮细胞

英文摘要： We commonly believed that the endocrine and exocrine systen of the pancreas were indepent in histology and function. However, recent studies have found: between the pancreatic ducts and islets there is a close contact; patients with exocrine insufficiency are accompanied with increased risk of diabetes; our research group found exocrine factes like HCO3- had a stimulating effect on insulin secretion. We found that increasing HCO3- concentrations led to significant decreases in insulin secretion by MIN6 cells, in a dose-dependent correlation, although there were no significant differences in cell viability over the range of treatment concentrations. CFTR mRNA and CFTR protein were expressed in MIN6 βells, and CFTR was primarily located in the cell membrane. CFTR mRNA levels were positively correlated with extracellular HCO3- treatment concentrations. At 25 mM HCO3-, the addition of the CFTR inhibitor CFTR(inh)-172 promoted insulin secretion compared to levels without the inhibitor. These results indicated that extracellular HCO3- negatively regulated insulin secretion, and this inhibitory effect was mediated by CFTR. Recently, we analyzed the effects of CFTR on HCO3- and intracellular pH changes through the patch-clamp technique to further study the role of CFTR on islet cell function. Regulating the function of pancreatic duct cell secreation may become a new target for drug treatment of diabetes.

英文关键词： Insulin; Na+-HCO3-co-transporter; pancreatic ductal cells