GLUCOSE METABOLISM RESPONSIVE GENES IN PANCREATIC ISLETS

该项目的目标是开始确定和 对胰岛中被诱导的非胰岛素基因进行分类 通过可代谢的胰岛素分泌剂--尤其是通过葡萄糖， 最有效的胰岛素促分泌剂。胰岛素的一个独特特征 胰岛的β细胞分泌的是它是 受促分泌素新陈代谢调节，而不是由 激动剂与受体的相互作用。虽然喜欢偷偷摸摸 胰岛的新陈代谢和胰岛素分泌得到了很好的研究。 对于这些因素的调控，人们知之甚少 基因表达水平。胰岛素和其他激素基因有 已经被很好地定性了，他们将不会被研究。基因 参与促分泌素代谢和胰岛素的调节 对分泌物的研究还不多，如果有的话，就是这些 我们计划分离和鉴定的基因。其意图是 来检验这样一种假设，即对葡萄糖的某种控制会导致 胰岛β细胞的胰岛素分泌是在 基因表达水平--基因的第一近似值 抄写。我们将从识别特定的信使开始 其丰度在胰岛中增加的RNA 在含有促胰岛素的葡萄糖的情况下培养。CDNA文库 将由大鼠和人的胰岛和Will构建 通过差异陆地消减杂交进行筛选。核糖核酸 由此确定的将关于组织的特征 分布、表达的时间进程、对不同 胰岛素促分泌剂、核苷酸和推导的氨基酸 序列。编码这些RNA的基因随后将被分离 并绘制了它们的监管区域。将启动研究，以 获取有关葡萄糖反应基因如何调控的线索。这个 这个项目的长期目标是了解新陈代谢是如何 葡萄糖和其他促分泌剂调节细胞的转录 与促分泌素代谢和胰岛素释放有关的基因 胰岛。这些信息可能被证明是重要的 基因治疗在胰岛素依赖型糖尿病治疗中的应用 糖尿病，因为治疗病人是必要的 不仅与胰岛素基因有关，而且与调节 胰岛素分泌。只有在以下情况下才能刺激胰岛素分泌 血糖浓度在以下情况下升高和抑制 血糖浓度低，使高血糖和 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.