Mechanism of JNK signaling in beta cells

项目摘要 糖尿病是一个严重的世界性健康问题。糖尿病的患病率是 预计将从2017年的4.51亿人增加到2045年的6.93亿人。超过90%的人 2型糖尿病患者的饮食习惯2型糖尿病的发病机制与肥胖密切相关， 与胰岛素抵抗、慢性高血糖和高脂血症相关的代谢综合征， 促进进行性B细胞功能障碍和B细胞衰竭。目前有几种药物正在开发中， 包括改善B细胞功能和存活的方法。尽管如此， 开发有效和安全的治疗方法。因此，药物开发新靶点的鉴定 需要我们了解代谢功能障碍的B细胞的生理和病理生理。 营养过剩可导致代谢功能障碍和B细胞应激。最近的研究已经确定c-Jun NH 2-末端激酶（JNK）信号通路作为代谢应激反应的介质。消耗 高脂饮食（HFD）导致JNK活性增加，并促进代谢综合征的发展， 肥胖、高血糖和胰岛素抵抗。JNK在代谢组织中的作用已经使用 细胞类型特异性JNK敲除小鼠。这些研究表明，外周代谢中JNK缺乏， 组织抑制HFD诱导的高血糖症和高胰岛素血症。然而，虽然JNK在这些方面的作用 外周组织已被广泛研究，B细胞JNK在生理和发病机制中的作用 仍不清楚然而，已经报道JNK抑制增加胰岛素分泌并保护胰岛素抵抗。 体外抗苦参碱诱导的B细胞凋亡。然而，JNK在B细胞生理学中的作用尚未被阐明。 使用具有B细胞特异性Jnk基因消除的体内模型进行研究。我们的初步数据显示，B中的JNK 细胞在调节小鼠B细胞质量、胰岛素分泌和葡萄糖稳态中起重要作用 喂了一只HFD因此，JNK在代谢应激诱导的B细胞发病机制中起关键作用。 了解HFD诱导的B细胞功能障碍的机制是重要的，因为胰岛素可能 抵抗可能促进高血糖、高胰岛素血症和随后的B细胞衰竭， 代谢综合征与2型糖尿病旨在检查JNK依赖性B细胞机制的研究 因此，由HFD消费引起的功能障碍是重要的，因为获得的知识可能是 可用于设计治疗和预防2型糖尿病的新治疗策略。 我们将使用B细胞特异性切除JNK基因的小鼠来研究JNK信号传导的作用， 确定控制B细胞功能的JNK依赖性调节机制。实现我们的目标将 增加对代谢应激信号如何促进B细胞生理学和病理生理学的理解。我们 我预计，这项研究计划的成功完成将导致识别机制 调节B细胞的稳态。

Project Summary Diabetes mellitus represents a serious world-wide health problem. The prevalence of diabetes mellitus is predicted to increase from 451 million people in 2017 to 693 million people in 2045. More than 90% of individuals with diabetes mellitus have type 2 diabetes. The pathogenesis of type 2 diabetes is closely linked to obesity and metabolic syndrome that are associated with insulin resistance, chronic hyperglycemia, and hyperlipidemia that promote progressive b cell dysfunction and b cell failure. Several medications are currently under development, including approaches to improve b cell function and survival. Nevertheless, there is an unmet need for the development of effective and safe therapies. Therefore, the identification of novel targets for drug development requires that we gain an understanding the physiology and pathophysiology of b cells with metabolic dysfunction. Nutrient excess can result in metabolic dysfunction and b cell stress. Recent studies have identified the c-Jun NH2-terminal kinase (JNK) signaling pathway as a mediator of metabolic stress responses. Consumption of a high-fat diet (HFD) causes increased JNK activity and promotes the development of metabolic syndrome, such as obesity, hyperglycemia, and insulin resistance. The role of JNK in metabolic tissues has been studied using cell type-specific JNK knockout mice. These studies demonstrate that JNK deficiency in peripheral metabolic tissues suppresses HFD-induced hyperglycemia and hyperinsulinemia. However, while the role of JNK in these peripheral tissues has been extensively studied, the function of b cell JNK in physiology and pathogenesis remains unclear. Nevertheless, it has been reported that JNK inhibition increases insulin secretion and protects against cytokine-induced b cell apoptosis in vitro. However, the role of JNK in b cell physiology has not been studied using an in vivo model with b cell-specific Jnk gene ablation. Our preliminary data show that JNK in b cells plays an important role in the regulation of b cell mass, insulin secretion, and glucose homeostasis in mice fed a HFD. Therefore, JNK plays a critical role in metabolic stress-induced b cell pathogenesis. Knowledge of the mechanism of HFD-induced b cell dysfunction is important because it is likely that insulin resistance may promote hyperglycemia, hyperinsulinemia and subsequent b cell failure during progression from metabolic syndrome to type 2 diabetes. Studies designed to examine the mechanism of JNK-dependent b cell dysfunction caused by consumption of a HFD are therefore significant because the knowledge obtained may be useful for the design new therapeutic strategies for the treatment and prevention of type 2 diabetes. We will examine the role of JNK signaling using mice with b cell-specific ablation of the Jnk genes and we will identify the JNK-dependent regulatory mechanisms that control b cell function. Achievement of our goals will increase understanding of how metabolic stress signaling contributes b cell physiology and pathophysiology. We anticipate that the successful completion of this research program will lead to the identification of mechanisms that regulates b cell homeostasis.