Redox Biology and Muscle Insulin Sensitivity

描述（由申请方提供）：导致骨骼肌中饮食诱导胰岛素抵抗发生的潜在机制尚未解决。胰岛素敏感性降低是2型糖尿病病因学中的关键因素，因此，确定胰岛素抵抗的潜在机制对于设计适当的预防和治疗策略至关重要。最近的证据表明，高膳食脂肪摄入增加了肌肉中线粒体过氧化氢的产生和排放，使细胞内氧化还原环境转变为更氧化的状态。通过使用线粒体靶向抗氧化剂阻断过氧化氢释放可防止细胞氧化还原环境的转变并保持胰岛素敏感性，从而提供线粒体呼吸系统感知并启动对细胞营养过载的平衡反应的证据。该项目的长期目标是确定调节线粒体过氧化氢产生/排放的潜在生物能量学机制，确定对细胞氧化还原系统的影响和整合，并破译氧化还原信号网络与胰岛素敏感性控制相关的机制。本项目的具体目标是确定通过氧化的通量是否是控制线粒体过氧化氢排放、细胞氧化还原状态和胰岛素敏感性的主要因素;确定丙酮酸脱氢酶复合物调节过氧化氢产生/排放的机制;并确定过氧化氢诱导的磷酸酶活性的氧化还原调节作为饮食的潜在介质的潜在作用-诱导胰岛素抵抗。将采用最先进的线粒体功能分析以及功能获得和丧失小鼠模型来解决这些目标。预计这些研究将揭示有关代谢失衡导致骨骼肌胰岛素抵抗的潜在机制的新见解，为设计适当的靶向预防和/或治疗策略提供框架。

DESCRIPTION (provided by applicant): The underlying mechanism responsible for the development of diet-induced insulin resistance in skeletal muscle remains unresolved. Decreased insulin sensitivity is a key factor in the etiology of type 2 diabetes and, as such, identifying the underlying mechanism of insulin resistance is critical to devising appropriate prevention and treatment strategies. Recent evidence indicates high dietary fat intake increases mitochondrial hydrogen peroxide production and emission in muscle, shifting the intracellular redox environment to a more oxidized state. Blocking the hydrogen peroxide emission through the use of mitochondrial targeted antioxidants prevents the shift in cellular redox environment and preserves insulin sensitivity, providing evidence the mitochondrial respiratory system senses and initiates a counterbalance response to cellular nutritional overload. The long-term objectives of this project are to define the underlying bioenergetics mechanisms regulating mitochondrial hydrogen peroxide production/emission, to determine the impact on and integration with cellular redox systems, and to decipher the mechanism by which redox signaling networks link to the control of insulin sensitivity. The specific goals of this project ae to determine if flux through ¿-oxidation is a primary factor governing mitochondrial hydrogen peroxide emission, cellular redox state, and insulin sensitivity; to determine the mechanism(s) regulating hydrogen peroxide production/emission by the pyruvate dehydrogenase complex; and to determine the potential role of hydrogen peroxide induced redox regulation of phosphatase activity as a potential mediator of diet-induced insulin resistance. State-of-the-art mitochondrial function analyses as well as gain- and loss-of-function mouse models will be employed to address these goals. It is anticipated these studies will reveal new insights regarding the underlying mechanism by which metabolic imbalance leads to insulin resistance in skeletal muscle, providing the framework for devising appropriately targeted prevention and/or treatment strategies.