PUTATIVE MEDIATORS OF INSULIN SECRETION

该项目的目的是确定作用机制 胰岛素分泌的特异性假定介质 鼠的胰岛。 核心假设是， 分泌的特定介质，如磷脂和脂肪酸， 酸、环GMP和环AMP，以及包括钙在内的阳离子 和钠，在胰岛素调节中具有协调作用 分泌物 一个具体的目的是阐明转导 调节α-2肾上腺素受体作用的机制 刺激胰岛素释放，并发生远端的变化 环腺苷酸的生产。 α-2肾上腺素受体的作用 总葡萄糖利用和磷酸戊糖分流激动剂 活性、葡萄糖转运和磷酸化以及磷脂 将测定分离的胰岛中的周转。 此外，本发明还提供了一种方法， 用培养的人肝癌细胞和RINm 5 F进行的研究 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其他肾上腺素受体所特有的或共同的。 组织，以及在胰岛中观察到的效应是否发生 尤其是β细胞 环鸟苷酸的拮抗作用， α-2肾上腺素受体的毒蕈碱受体激动剂 对分泌和碳水化合物代谢的抑制作用 进行调查，以确定是否与 环腺苷酸特异性影响葡萄糖代谢途径 并介导受体刺激。 Na+/H+的作用 细胞内Ca 2+水平的变化，以及花生四烯酸 α-2肾上腺素受体介导的抑制的酸代谢 还将研究胰岛分泌反应。 另一 本建议的目的是确定以下方面的相互关系： 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，和 蛋白激酶C对环核苷酸生物合成的活性将 下定决心。 相反，环核苷酸对 将研究磷脂酶活性。 第三个目标是 一个项目是确定一种特定的磷脂酰胆碱 生物合成途径有助于脂质库， 花生四烯酸被动员来介导β细胞的作用， 刺激。 激发胰岛素分泌的新方法可能是 从更好地理解刺激分泌 耦合机制，这可能是负责受损 糖尿病患者胰岛素释放。

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.