Mechanism of JNK signaling in beta cells

β细胞中JNK信号传导机制

基本信息

  • 批准号:
    10907873
  • 负责人:
  • 金额:
    $ 25.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-09-08 至 2024-08-31
  • 项目状态:
    已结题

项目摘要

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.
项目总结

项目成果

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