PUTATIVE MEDIATORS OF INSULIN SECRETION

胰岛β（B）细胞分泌胰岛素， 各种形式的压力会影响B细胞的调节 和分泌的特定方式，并引发应激反应， 保护B细胞。分泌物改变时， 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 （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，使得胰岛素分泌减少或不存在，如 胰岛素依赖型糖尿病（IDDM）模型。长期 本研究的目的是确定信号转导事件， 参与B细胞发病的代谢过程 脱敏和与压力相关的事件的进展 反应和B细胞毒性。体外胰岛或B细胞模型将 可以研究模拟某些体内过程， 高血糖症/NIDDM或IDDM的形式。目的（1）是表征短 腺苷酸环化酶的长期脱敏/下调 胰岛在葡萄糖诱导的脱敏过程中。腺苷酸 将在分离的胰岛中表征环化酶活性和表达 和胰岛素瘤细胞。目的（2）定义应激反应细胞 B细胞中的介质。压力源包括：葡萄糖（高或低 浓度）、细胞因子、热休克和氧化应激。应力 待评估的反应包括：热休克蛋白，应激激活的 蛋白激酶，血红素加氧酶诱导，腺苷 单磷酸介导的蛋白激酶（AMPK）和乙酰辅酶A羧化酶 活性和抗氧化酶诱导/活化。未来 治疗策略将受益于提高认识， 与压力相关的特定B细胞反应。目标（3）是 表征磷酸肌醇的活性和表达， 磷脂酰胆碱特异性磷脂酶C（PLC），在B细胞 应力PLC衍生的甘油二酯可介导特异性应激反应 在B细胞中，与鞘磷脂酶活化、神经酰胺产生 和核转录事件。这些研究的重要性在于， 将在B细胞中探索新的信号转导机制， 在高血糖症和B细胞 细胞毒这些研究的结果将增加我们的知识 关于参与病理性的调节途径， 作为与胰岛素从B- 细胞，并将导致更完整的了解糖尿病 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.