GLUCAGON BIOSYNTHESIS AND METABOLISM

胰高血糖素，一种29个氨基酸的肽，调节葡萄糖和 氨基酸代谢，是一个大家庭的成员， 结构相关肽在胃肠道中表达 和神经系统。 目标是了解 这些复杂基因的生物学功能。 期间 在过去的资助期内，我们分离并测序了 编码大鼠前胰高血糖素原，以及两个相应的 不同的琵琶鱼cDNA。 胰高血糖素原是多聚蛋白 含有多种胰高血糖素相关肽。 鱼 胰高血糖素原编码一个和大鼠两个额外的胰高血糖素样 缩氨酸 胰高血糖素原的加工过程在以下方面明显不同： 胰腺与肠导致形成三种不同的 胰高血糖素样肽I，胰高血糖素样肽II，和胰高血糖素样肽I， 酰胺化插入肽。 胰高血糖素样肽I（7-37） 具有有效的促胰岛素作用， 似乎是生长因子 我们有 开发了来自大鼠胰岛的克隆细胞系， 不同的产酶表型，并启动了 增强子、沉默子和代谢反应元件的研究 参与基因的细胞特异性和代谢调节。 细胞特异性增强子序列和蛋白激酶C反应 元件似乎位于5'侧翼的一个内切酶内， 基因的区域。 我们的目标是：（1）分离和结构 并在功能上表征顺式作用DNA元件， 控制细胞特异性的反式作用DNA结合蛋白 胰高血糖素基因的表达，（2）鉴定抗血清， GLP和GLP结构的放射免疫测定 （3）确定胰高血糖素样肽的生物学功能 肽和（4）表征新的胰高血糖素相关肽 和大脑中表达的基因。 这些调查 与理解细胞分化的潜在相关性 和糖尿病的发病机制。

Glucagon, a 29 amino acid peptide, that regulates glucose and amino acid metabolism, is a member of a large family of structurally-related peptides expressed in the gastro-intestinal and nervous systems. The goals are to gain an understanding of the biologic functions of this complex set of genes. During the past grant period we isolated and sequenced the cDNAs and genes encoding the rat pre-proglucagon, as well as two corresponding distinct angler fish cDNAs. The proglucagons are polyproteins that contain multiple glucagon-related peptides. The fish proglucagon encodes one and the rat two additional glucagon-like peptides. The processing of proglucagon differs markedly in pancreas vs. intestine resulting in the formation of three different glucagon-like peptide I's, glucagon-like peptide II, and an amidated intervening peptide. The glucagon-like peptide I(7-37) has potent insulinotropic actions and the other peptides derived from the proglucagon appear to be growth factors. We have developed clonal cell lines derived from rat islets that have different hormone-producing phenotypes and have initiated studies of the enhancer, silencer and metabolic-response elements involved in cell-specific and metabolic regulation of the gene. Cell-specific enhancer sequences and protein Kinase C-response elements appear to reside within one kilobase of the 5' flanking region of the gene. Our aims are to: (1) isolate and structurally and functionally characterize the cis-acting DNA elements and the trans-acting DNA-binding proteins that govern cell-specific expression of the glucagon gene, (2) Characterize the antisera and radioimmunoassays for the GLP's and the structures of the GLP peptides, (3) determine the biologic functions of the glucagon-like peptides and (4) characterize the new glucagon-related peptides and genes expresed in the brain. These investigations have potential relevance to an understanding of cellular differentiation and the pathogenesis of diabetes mellitus.