PUTATIVE MEDIATORS OF INSULIN SECRETION

这个项目的目的是确定作用机制。 分离的胰岛素分泌的特异性介体 大鼠的朗格汉斯胰岛。中心假设是 特定的分泌介质，如磷脂和脂肪 酸、环GMP和环AMP以及包括钙在内的阳离子 和钠，在调节胰岛素方面有协同作用 分泌物。一个特定的目的是阐明转导 介导α-2肾上腺素能受体作用的机制(S) 对胰岛素释放的刺激，发生在变化的远端 在环状AMP生产中。α-2肾上腺素能受体的作用 总葡萄糖利用和磷酸戊糖分流的激动剂 活性、葡萄糖转运和磷酸化，以及磷脂 将确定孤立小岛的周转率。此外, 培养的鲁伯肝癌细胞和RINm5F的研究 胰岛素瘤细胞和血小板将决定α-2 胰岛中的肾上腺素受体效应是独一无二的，也是其他 组织，以及在胰岛中观察到的效应是否发生 尤其是在β细胞中。环鸟苷酸和环磷酰胺拮抗 α-2肾上腺素能受体激动剂 对分泌和碳水化合物代谢的抑制作用 被调查以确定环状GMP是否与 环磷酸腺苷特异性影响糖代谢途径 并调节受体的刺激。钠/氢的作用 交换、细胞内钙水平的变化与花生四烯酸 α2肾上腺素能受体介导的抑制作用中的酸代谢 胰岛分泌反应也将被调查。另一个 这项建议的目的是确定 脂质和环核苷酸在胰岛素调节中的作用 分泌物。游离脂肪酸、脂氧合酶和 环氧合酶衍生的花生四烯酸代谢物，以及 蛋白激酶C在环核苷酸生物合成中的活性将 要下定决心。反之，环核苷酸对细胞周期的影响 将对磷脂酶活性进行调查。这样做的第三个目的是 项目是确定一种特定的磷脂酰胆碱 生物合成途径有助于形成一个脂水池， 花生四烯酸被动员来介导β细胞的活动 刺激物。激发胰岛素分泌的新方法可能是 是由对刺激分泌的更好理解决定的 可能导致损伤的耦合机制 糖尿病患者的胰岛素释放。

The aim of this project is to determine the mechanisms of action of specific putative mediators of insulin secretion in isolated islets of Langerhans of the rat. The central hypothesis is that specific mediators of secretion, such as phospholipids and fatty acids, cyclic GMP and cyclic AMP, and cations including calcium and sodium, have coordinate actions in the regulation of insulin secretion. A specific aim is to elucidate the transduction mechanism(s) which mediate the effects of alpha-2 adrenoceptor stimulation on insulin release, and which occur distal to changes in cyclic AMP production. The effects of alpha-2 adrenoceptor agonists on total glucose utilization and pentose phosphate shunt activity, glucose transport and phosphorylation, and phospholipid turnover in isolated islets will be determined. In addition, studies with cultured Reuber hepatoma cells and RINm5F insulinoma cells, and platelets, will determine if alpha-2 adrenoceptor effects in the islet are unique or common to other tissues, and whether the effects observed in the islet occur specifically in the beta cell. Antagonism by cyclic GMP and muscarinic receptor agonists of the alpha-2 adrenoceptor inhibitory effects on secretion and carbohydrate metabolism will be investigated to determine if cyclic GMP as compared to cyclic AMP specifically affects pathways of glucose metabolism and mediates receptor stimulation. The role of Na+/H+ exchange, changes in intracellular Ca2+ levels, and arachidonic acid metabolism in alpha-2 adrenoceptor-mediated inhibition of the islet secretory response will also be investigated. Another aim of this proposal is to determine the interrelationship of lipids and cyclic nucleotides in the regulation of insulin secretion. The effects of free fatty acids, lipoxygenase- and cyclooxygenase--derived arachidonic acid metabolites, and protein kinase C activity on cyclic nucleotide biosynthesis will be determined. Conversely, effects of cyclic nucleotides on phospholipase activities will be investigated. A third aim of this project is to determine if a specific phosphatidylcholine biosynthetic pathway contributes to a lipid pool from which arachidonic acid is mobilized to mediate the actions of beta cell stimuli. New ways of evoking insulin secretion may be determined from a better understanding of stimulus-secretion coupling mechanisms which may be responsible for impaired insulin release in diabetes mellitus.