PUTATIVE MEDIATORS OF INSULIN SECRETION

胰岛β(B)细胞分泌胰岛素，假说 有待检验的是，各种形式的压力会影响B细胞的调节 并以特定的方式分泌，并调用应激反应 它们对B细胞有保护作用。当细胞分泌发生变化时， B细胞对葡萄糖的敏感性降低(脱敏)，如 高血糖和非胰岛素依赖型糖尿病模型的建立 (NIDDM)。B细胞也可能受到其他应激因素的抑制，如 作为细胞因子，如胰岛素分泌减少或缺失，如在 胰岛素依赖型糖尿病(IDDM)模型。长期的 本研究的目标是确定信号转导事件和 参与B细胞发病的代谢过程 脱敏与应激相关事件的进展 反应和B细胞细胞毒作用。在体外胰岛或B细胞模型将 被研究模拟某些体内过程与 各种形式的高血糖/NIDDM或IDDM。目的(L)是为了刻画这部短片 和腺苷环化酶的长期脱敏/下调 胰岛在葡萄糖诱导的脱敏过程中。Adenylyl 将在分离的胰岛中表征环化酶的活性和表达 和胰岛素瘤细胞。目的(2)是定义应激反应细胞 B细胞中的介质。应激源包括：葡萄糖(高或低 浓度)、细胞因子、热休克和氧化应激。压力 待评估的反应包括：热休克蛋白，应激激活 蛋白激酶(SAPKs)、血红素加氧酶诱导、腺苷 一磷酸介导的蛋白激酶(AMPK)和乙酰辅酶A羧基酶 活性和抗氧化酶的诱导/激活。未来 治疗策略将受益于对 与压力相关的特异性B细胞反应。目标(3)是 鉴定肌醇磷脂的活性和表达 B细胞中的磷脂酰胆碱特异性磷脂酶C(PLC) 压力。PLC衍生的二酰甘油可能介导特定的应激反应 B细胞中与髓鞘鞘氨酸酶激活有关的神经酰胺的产生 和核转录事件。这些研究的重要性在于 新的信号转导机制将在B细胞和 关于它们在高血糖和B细胞模型中的作用的特征 细胞毒性。这些研究的结果将增加我们的知识 关于参与病理过程的调节通路 作为与B细胞释放胰岛素相关的生理过程- 细胞，并将导致对糖尿病的更全面的了解 用于未来涉及细胞生物学的治疗干预。

The pancreatic islet beta (B)-cell secretes insulin, and the hypothesis to be tested is that various forms of stress affects B-cell regulation and secretion in specific ways, and that stress responses are invoked which are protective of the B-cell. Secretion is altered when the sensitivity of the B-cell to glucose is reduced (desensitized), as in models of hyperglycemia and non-insulin-dependent diabetes mellitus (NIDDM). The B-cell may also be inhibited by other stress factors, such as cytokines, such that insulin secretion is reduced or absent, as in models of insulin-dependent diabetes mellitus (IDDM). The long-term goals of this study are to determine the signal transduction events and metabolic processes which participate in the onset of B-cell desensitization and the progression of events associated with stress responses and B-cell cytotoxicity. in vitro islet or B-cell models will be studied which mimic certain of the in vivo processes associated with forms of hyperglycemia /NIDDM or IDDM. Aim (l) is to characterize the short and long-term desensitization/down-regulation of adenylyl cyclase in pancreatic islets during glucose-induced desensitization. Adenylyl cyclase activity and expression will be characterized in isolated islets and insulinoma cells. Aim (2) is to define the stress response cellular mediators in B-cells. Stressors include: glucose (high or low concentrations), cytokines, heat shock and oxidative stress. Stress responses to be evaluated include: heat shock proteins, stress-activated protein kinases (SAPKs), heme oxygenase induction, adenosine monophosphate-mediated protein kinase (AMPK) and acetyl-CoA carboxylase activity, and antioxidant enzyme induction/activation. Future therapeutic strategies will benefit from increased awareness of the specific B-cell responses associated with stress. Aim (3) is to characterize the activity and expression of phosphoinositide- and phosphatidylcholine-specific phospholipase C (PLC), during B-cell stress. PLC-derived diacylglycerol may mediate specific stress responses in B-cells related to shingomyelinase activation, ceramide production and nuclear transcription events.The importance of these studies is that novel signal transducing mechanisms will be explored in B-cells and characterized regarding their role in models of hyperglycemia and B-cell cytotoxicity. The results of these studies will increase our knowledge concerning regulatory pathways which participate in pathological as well as physiological processes associated with insulin release from the B- cell, and will lead to more complete understanding of diabetes mellitus for future therapeutic interventions involving cellular biology.