PUTATIVE MEDIATORS OF INSULIN SECRETION

朗格汉斯胰岛β细胞分泌胰岛素是由 第二信使如环磷酸腺苷、环磷酸腺苷、钙、肌醇 三磷酸、二酰甘油和脂肪酸。产生的一氧化氮 由一氧化氮合酶产生的精氨酸是新近发现的一种介质 细胞活跃度。正常情况下，葡萄糖会刺激胰岛素的分泌。然而， 持续的葡萄糖刺激导致β细胞脱敏 分泌性反应。一氧化氮也可能支持胰岛素的释放 正常情况下，但在高浓度时会引起细胞毒性。在……里面 这个项目，新鲜分离的胰岛，和葡萄糖的体外模型- 模拟非胰岛素依赖型糖尿病的诱导β细胞脱敏 糖尿病(NIDDH)和细胞因子诱导的一氧化氮毒性模拟 胰岛素依赖型糖尿病(IDDM)将被调查 特定的第二信使和代谢途径在β细胞中的作用 功能。一氧化氮合酶的特征和各种 为可能的保护活性而调查的药理物质 对抗一氧化氮的细胞毒性。这些研究还将确定 腺苷环化酶异源脱敏是否在一定程度上解释 用于胰岛素释放、胰升糖素敏感性和糖原的脱敏 新陈代谢。腺苷环化酶在β细胞调节中的作用 对心钠素(ANF)受体刺激的反应将是 探索以确定环状GMP和环状AMP的作用。 将对ANF受体的亚型进行表征。肌醇的作用 转运、Na，K-ATPase活性、磷脂酶C和肌醇 三磷酸生产中的葡萄糖脱敏也将被 确定是因为这些细胞活动在 动员和维持细胞内钙水平和分泌。无论是 多元醇途径对肌醇磷脂途径功能和分泌的影响 在脱敏过程中将被确定。加深了对 调控胰岛素分泌的信号转导机制 正常情况下和糖尿病模型中，以及 可能化解细胞毒性事件的药物干预将 提高我们克服糖尿病的知识和能力。

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.