GLUCOSE METABOLISM RESPONSIVE GENES IN PANCREATIC ISLETS

该项目的目标是开始确定和 将胰岛中的非胰岛素基因分类， 通过可代谢的胰岛素促分泌素-特别是通过葡萄糖， 最有效的胰岛素促分泌剂。 胰岛素的独特功能 胰岛β细胞的分泌是， 由促分泌素的代谢调节，而不是由 激动剂与受体的相互作用。 虽然促分泌素 胰岛中的代谢和胰岛素分泌已被充分研究 在这些地区，人们对这些因素的调节知之甚少。 基因表达水平。 胰岛素和其他激素基因 它们已经被很好地描述了，不会被研究。 的基因 参与调节促分泌素代谢和胰岛素 分泌没有被研究得太多，如果有的话，正是这些 我们打算分离和鉴定的基因。 目的是 为了验证对葡萄糖诱导的某些控制的假设， 胰腺β细胞中的胰岛素分泌是在 基因表达水平-按基因的第一近似值 转录。 我们将开始确定具体的信使 在胰岛中丰度增加的RNA， 在促胰岛素葡萄糖存在下培养。cDNA文库 将由大鼠和人胰岛构建， 通过差减杂交进行筛选。 RNA 因此，所识别的特征将关于组织 分布，表达的时间过程，对不同 胰岛素促分泌素、核苷酸和推导的氨基酸 序列的 编码这些RNA的基因将被分离出来 并绘制了它们的调控区域。 将启动研究， 获得关于葡萄糖反应基因如何调节的线索。 的 这个项目的长期目标是了解如何代谢的 葡萄糖和其他促分泌素调节 参与促分泌素代谢和胰岛素释放的基因 胰岛 这些信息可能会被证明是重要的， 基因治疗在胰岛素依赖性疾病治疗中的应用 糖尿病，因为有必要治疗患者 不仅有胰岛素基因， 胰岛素分泌 只有在以下情况下才能刺激胰岛素分泌： 血糖浓度增加并受到抑制， 血糖浓度较低， 不会发生低血糖。

The objective of this project is to begin to identify and catalog non-insulin genes in the pancreatic islet that are induced by metabolizable insulin secretagogues - especially by glucose, the most potent insulin secretagogue. A unique feature of insulin secretion by the beta cell of the pancreatic islet is that it is regulated by metabolism of secretagogues rather than by the interaction of an agonist with a receptor. Although secretagogue metabolism and insulin secretion in the islet are well studied areas, little is known about the regulation of these factors at the level of gene expression. Insulin and other hormone genes have been well-characterized and they will not be studied. The genes involved in the regulation of secretagogue metabolism and insulin secretion have not been studied much, if at all, and it is these genes that we propose to isolate and characterize. The intent is to test the hypothesis that some control over glucose-induced insulin secretion in the pancreatic beta cell is achieved at the level of gene expression - to a first approximation by gene transcription. We will begin by identifying specific messenger RNAs whose abundance increases in pancreatic islets that have been cultured in the presence of insulinotropic glucose. cDNA libraries will be constructed from rat and human pancreatic islets and will be screened by differential land subtraction hybridization. RNA thus identified will be characterized in respect to tissue distribution, time course of expression, response to different insulin secretagogues, and nucleotide and deduced amino acid sequences. The genes that encode these RNAs will then be isolated and their regulatory regions mapped. Studies will be initiated to obtain clues as to how glucose-responsive genes are regulated. The long term goal of this project is to understand how metabolism of glucose and other secretagogues regulate the transcription of the genes involved in secretagogue metabolism and insulin release in pancreatic islets. Such information may prove to be important in the use of gene therapy in the treatment of insulin dependent diabetes mellitus, since it will be necessary to treat patients with not only the insulin gene, but also with genes that regulate insulin secretion. Insulin secretion must be stimulated only when the blood glucose concentration is increasing and suppressed when the blood glucose concentration is low so that hyperglycemia and hypoglycemia do not occur.