PHOSPHOINOSITIDE HYDROLYSIS & BETA CELL SECRETION

磷酸肌醇水解

• 批准号: 3241867
• 负责人: WALTER S. ZAWALICH
• 金额: $ 18.53万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3241867
• 关键词: autoradiography; calcium flux; cholecystokinin; cyclic AMP; diacylglycerols; gel electrophoresis; glucose; hormone regulation /control mechanism; hydrolysis; immunochemistry; insulin; laboratory rat; pancreatic islet function; phosphatidylinositols; phosphorylation; protein kinase C

Phosphoinositide (PI) hydrolysis appears to regulate three separate, but interrelated, temporal phenomena in beta cells of the islets of Langerhans. These include the regulation of second phase insulin secretion in response to various agonists including glucose and cholecystokinin (CCK), the induction of time dependent potentiation (TDP) in response to a variety of agonist including glucose and CCK, and the induction of time independent suppression (TDS) in response to chronic stimulation with high glucose or CCK. The deranged pattern of insulin secretion after the induction of TDS by CCK bears a striking resemblance to that noted in Type II diabetes. Particularly cant is the reduction in first phase insulin secretion. Using isolated islets and isolated beta cells, the involvement of PI-derived second messenger molecules (inositol phosphates, diacylglycerol) and PI-dependent effector systems (C- kinase activity and spatial distribution) on these three insulin secretory response patterns will be assessed. Because our previous studies indicate that the second messenger molecule cAMP regulates the quantitative impact of various agonists on PI hydrolysis, studies will also be conducted to assess the possible ameliorating influence of this nucleotide on TDS of secretion induced by high glucose alone or low glucose plus CCK. Our hypothesis is that the same biochemical and metabolic pathways which regulate beta cell activation (in terms of insulin output) to various agonists also play a pivotal role in the development of aberrant patterns of insulin secretion which develop after chronic stimulation. Biochemical events activated by or associated with cellular increases in PI hydrolysis are implicated in these processes and our goal is to explore these interrelationships.

磷酸肌醇（PI）水解似乎调节三个 独立的，但相互关联的，时间的现象，β细胞的 朗格汉斯岛 其中包括第二阶段的规定 响应包括葡萄糖在内的各种激动剂的胰岛素分泌 和胆囊收缩素（CCK），诱导时间依赖性 增强（TDP）响应于多种激动剂，包括 葡萄糖和CCK，以及诱导非时间依赖性抑制 (TDS)对高葡萄糖或CCK慢性刺激的反应。 胰岛素诱导后胰岛素分泌的紊乱模式 CCK的TDS与II型中所述的TDS有惊人的相似之处， 糖尿病 特别是铁路超高是第一阶段的减少 胰岛素分泌 利用分离的胰岛和β细胞， PI衍生的第二信使分子（肌醇 磷酸盐，二酰基甘油）和PI依赖性效应系统（C- 激酶活性和空间分布）对这三种胰岛素 将评估分泌反应模式。 因为我们之前的 研究表明，第二信使分子cAMP调节 各种激动剂对PI水解的定量影响， 此外，当局亦会进行研究，以评估 这种核苷酸对高浓度诱导分泌物TDS的影响 单独葡萄糖或低葡萄糖加CCK。 我们的假设是 相同的生化和代谢途径调节β细胞 对各种激动剂的激活（就胰岛素输出而言）也 在发展异常模式中起着关键作用， 慢性刺激后产生胰岛素分泌。 由细胞激活或与之相关的生化事件 PI水解的增加与这些过程有关， 我们的目标是探讨这些相互关系。