胰岛衍生因子对肠道胰高糖素样肽-1分泌的调控与信号通路研究

Pancreatic derived factor (PANcreatic DERived factor, PANDER) is a recent discovered cytokine that is highly expressed in the pancreas. PANDER co-localized with insulin in the granules of β cells and secreted from β cells. We have previously demonstrated that over-expression PANDER can induce β cell apoptosis and inhibit β cell function (Diabetes 2003). Studies also have shown that it involves in hepatic glucose and lipids metabolism. Our recent research found that 18F-PANDER highly binds to the intestine of mice. Over-expression of PANDER by tail-vein injection of recombinant Adeno-PANDER induces a significant decrease of Glucagon like peptide -1(GLP-1) level, an anti-diabetes peptide secreted from intestine L cells. This suggests that PANDER plays an important role in the regulation of GLP-1. The purpose of this study is to identify the impact of PANDER on GLP-1 secretion. Using the gene overexpression mice as well as GLP-1 secreting cell line, we will study the impact of PANDER on preglucagon gene expression, GLP-1 secretion in intestinal cells and the active GLP-1 level in mice serum. We expect to identify a new pancreas - intestine feedback axis, to supply important data for further study on the underlying pathways and mechanisms.

胰岛衍生因子（PANDER）主要在胰岛中表达，并在胰岛β细胞分泌。我们曾证实PANDER过表达可至胰岛细胞凋亡，使胰岛功能下降（Diabetes 2003）；它还参与调节肝糖脂代谢。我们最新发现PANDER在肠道有很高的结合，过表达PANDER小鼠肠道降糖激素胰高糖素样肽-1（GLP-1）水平明显下降，提示PANDER对GLP-1存在影响。本课题的目的是阐明PANDER在GLP-1分泌中的作用。拟利用基因过表达小鼠和体外培养GLP-1细胞株，从基因表达、GLP-1分泌、活性GLP-1水平，论证PANDER对GLP-1的调控。研究结果将证实一条新的胰腺-肠道调节轴的存在，为进一步研究PANDER对GLP-1调控的信号通路提供依据。

胰腺衍生因子（PANDER）主要在胰岛中表达，并由胰岛β细胞分泌。我们前期的研究证实脂肪酸可以时间及剂量依赖性地诱导胰岛β细胞PANDER表达量增加，这一作用可被肠道分泌肠促胰岛素胰高素样肽-1（GLP-1）所抑制，我们新近的研究以18F标记PANDER注入小鼠体内以观察PANDER的作用靶点，发现循环中的PANDER不但胰腺、肝脏有很高的结合率，在肠道同样有很高的结合。这些研究表明PANDER可能与肠道分泌的GLP-1存在相互作用，是胰腺-肠道调节轴中的一个重要环节，但其作用方式、部位以及分子机制有待进一步研究。本研究旨在阐明PANDER对GLP-1分泌的影响以及其调控机制和相应的信号通路。研究内容包括：高脂饲料喂养5周龄C57/Bl6雄性小鼠16周后，我们利用重组腺病毒在体内过表达PANDER,并在体外培养GLUTag细胞株,用PANDER多肽处理细胞，检测细胞分泌GLP-1及相关通路蛋白。结果显示，PANDER过表达小鼠结肠glu mRNA表达下调，并且GLP-1分泌降低，这种效应在高脂饲料喂养的小鼠中更为明显。在GluTag细胞株，PANDER可以时间及剂量依赖性地下调glu mRNA表达和GLP-1分泌。并且，PANDER通过抑制胰岛素-Wnt信号通路和cAMP-PKA信号通路而阻断胰岛素、油酰乙醇胺对GLP-1分泌的刺激作用。我们的研究首次证明PANDERA下调肠道L细胞分泌GLP-1，为胰腺-肠道调节轴增添新的理论依据。