PUTATIVE MEDIATORS OF INSULIN SECRETION

胰岛β细胞的胰岛素分泌是由 第二信使如环AMP、环CMP、钙、肌醇 三磷酸盐、二酰基甘油和脂肪酸。产生的一氧化氮 一氧化氮合酶从L-精氨酸合成的一氧化氮是最近发现的介质 细胞活动。正常情况下，葡萄糖刺激胰岛素分泌。然而，在这方面， 持续葡萄糖刺激导致β细胞脱敏 分泌反应一氧化氮也可以支持胰岛素的释放， 正常条件下，但在高浓度下诱导细胞毒性。在 这个项目，新鲜分离的胰岛，和体外模型的葡萄糖- 模拟非胰岛素依赖型糖尿病的诱导β细胞脱敏 NIDDH），和马槟榔诱导的一氧化氮毒性模拟 胰岛素依赖型糖尿病（IDDM）将被研究， 特定第二信使和代谢途径在β细胞中的作用 功能一氧化氮合酶将被表征和各种 研究可能的保护活性的药理学药物 对抗一氧化氮的细胞毒性。这些研究也将决定 腺苷酸环化酶的异源脱敏是否部分地解释了 用于胰岛素释放、胰高血糖素敏感性和糖原的脱敏 新陈代谢.腺苷酸环化酶在β细胞介导中的作用 对心房利钠因子（ANF）受体刺激的反应将是 探索以确定环GMP和环AMP的作用。 ANF受体的亚型将被表征。肌醇的作用 Na+，K+-ATP酶活性，磷脂酶C和肌醇 葡萄糖脱敏中三磷酸盐的产生也将 由于这些细胞活动在细胞生长中起着重要作用， 动员和维持细胞Ca 2+水平和分泌。是否 多元醇途径影响磷酸肌醇途径的功能和分泌 将确定是否进行脱敏。进一步了解如何 调节胰岛素分泌的信号转导机制 正常条件下和糖尿病模型中，以及 可能缓解细胞毒性事件的药物干预， 提高我们对糖尿病的认识和战胜糖尿病的能力。

Insulin secretion from beta cells of islets of Langerhans is mediated by second messengers such as cyclic AMP, cyclic CMP, calcium, inositol trisphosphate, diacylglycerol, and fatty acids. Nitric oxide generated from L-arginine by nitric oxide synthase is a recently identified mediator of cell activity. Normally, glucose stimulates insulin secretion. However, continuous glucose stimulation leads to a desensitization of the beta cell secretory response. Nitric oxide may also support insulin release under normal conditions, but in high concentrations induces cytotoxicity. In this project, freshly isolated islets, and in vitro models of glucose- induced beta cell desensitization mimicking non-insulin dependent diabetes mellitus (NIDDH), and cytokine-induced nitric oxide toxicity mimicking insulin -dependent diabetes mellitus (IDDM) will be investigated for the role of specific second messengers and metabolic pathways in beta cell function. Nitric oxide synthases will be characterized and various pharmacological agents investigated for possible protective activity against nitric oxide cytotoxicity. These studies will also determine whether heterologous desensitization of adenylate cyclase accounts in part for desensitization of insulin release, glucagon sensitivity and glycogen metabolism. The role of adenylate cyclase in mediating the beta cell responses to atrial natriuretic factor (ANF) receptor stimulation will be explored in order to define the role of cyclic GMP and cyclic AMP. Subtypes of ANF receptors will be characterized. The role of myo-inositol transport, Na+,K+-ATPase activity, phospholipase C and inositol trisphosphate production in glucose desensitization will also be determined since these cell activities play an important role in mobilizing and maintaining cellular Ca2+ levels and secretion. Whether the polyol pathway affects phosphoinositide pathway function and secretion during desensitization will be determined. Increased understanding of the signal-transduction mechanisms which modulate insulin secretion under normal conditions and in models of diabetes mellitus, and of the pharmacological interventions which may defuse cytotoxic events, will increase our knowledge of and ability to overcome diabetes mellitus.