Modulating ROS by Electromagnetic Fields to Treat Type 2 Diabetes

摘要 氧化还原稳态异常被认为是2型糖尿病的病理生理机制之一 （T2D）。然而，人们对这些机制知之甚少。氧化还原系统由促氧化剂调节， 如活性氧（ROS）和抗氧化剂如谷胱甘肽。t2 d患者 活性氧水平升高谷胱甘肽水平降低试图逆转T2 D中的这种氧化还原失衡 使用氧化还原调节药物或注入抗氧化剂已显示出逆转胰岛素抵抗的前景 在初步研究中，但由于其半衰期短和交付，最终在临床试验中失败 挑战需要新的方法和更好地理解T2 D中的氧化还原机制，以解决 T2 D的潜在病理生理学，目前无法通过现有方式有效解决。ROS 拥有一个不成对的电子，使它们具有顺磁性，并能够与外部施加的相互作用。 电磁场（EMF）。我们最近发现了一组独特的EMF参数， ROS和氧化还原稳态。当应用于T2 D小鼠模型和人类细胞时，发现EMF 对胰岛素敏感性、糖耐量和胰岛素抵抗有明显的改善作用， 在三天内抵抗，无不良影响。我们还发现，电磁场的应用改变了 葡萄糖代谢通量，增加葡萄糖并入糖原和降低脂肪酸水平。 通过注入氧化性氧化还原溶液清除顺磁性ROS或防止氧化还原适应 （GSSG）消除了这些惊人的治疗效果。这些发现使我们假设电磁场靶向 ROS诱导NRF 2介导的氧化还原反应，该反应部分通过改变 葡萄糖因此，本项目的目标是阐明氧化还原和代谢机制的基础 电磁场的胰岛素增敏作用。我们将在两个具体目标中测试我们的假设：1）确定 介导EMF治疗的胰岛素增敏作用的氧化还原机制;以及2）确定 EMF治疗或氧化还原调节重定向葡萄糖代谢命运的机制， 胰岛素敏感性使用电磁场作为氧化还原和血糖调节方式提供了一种新的方法， 这是一个前所未有的机会，可以研究氧化还原在T2 D病理生理学中的作用， 了解一种新的胰岛素增敏现象。我们将确定特定的代谢变化， 发生在响应电磁场暴露，并确定机制，其中氧化还原状态调节肝 代谢通量和胰岛素敏感性。这项工作将确定一个新的机械连接之间的两个以前 断开领域的调查，静态电磁场和血糖调节，并将桥梁氧化还原生物学与 葡萄糖代谢这项工作的顺利完成将为今后的临床应用奠定基础 开发一种可穿戴设备，该设备发射EMF以靶向氧化还原系统， T2 D管理

Abstract Aberrant redox homeostasis has been proposed to contribute to the pathophysiology of type 2 diabetes (T2D). However, the mechanisms are poorly understood. Redox systems are regulated by pro-oxidants, such as reactive oxygen species (ROS) and antioxidants such as glutathione. Patients with T2D have elevated levels of ROS and lower levels of glutathione. Attempts to reverse this redox imbalance in T2D using redox-modulating drugs or infusion of antioxidants has shown promise in reversing insulin resistance in preliminary studies, but ultimately have failed in clinical trials due to their short half-lives and delivery challenges. New methods and a better understanding of redox mechanisms in T2D are needed to address an underlying pathophysiology of T2D that is not currently effectively addressed by current modalities. ROS possess an unpaired electron, making them paramagnetic and capable of interacting with externally applied electromagnetic fields (EMFs). We recently identified a unique set of EMF parameters that rapidly modulate ROS and redox homeostasis. When applied to mouse models of T2D and human cells, EMFs were found to exert remarkable effects on glycemia and insulin sensitivity, reversing glucose intolerance and insulin resistance in three days, without adverse effects. We also found that application of EMFs altered the metabolic flux of glucose, increasing glucose incorporation into glycogen and reducing fatty acid levels. Scavenging paramagnetic ROS or preventing redox adaptations by infusing oxidizing redox solutions (GSSG) abolished these striking therapeutic effects. These findings lead us to hypothesize that EMFs target ROS to induce an NRF2-mediated redox response that is insulin sensitizing in part by altering the fate of glucose. Therefore, the goal of this project is to elucidate the redox and metabolic mechanisms underlying the insulin sensitizing effects of EMFs. We will test our hypotheses in two specific aims: 1) Determine the redox mechanisms that mediate the insulin-sensitizing effects of EMF-therapy; and 2) Determine the mechanisms by which EMF-therapy or redox modulation redirects the metabolic fate of glucose to improve insulin sensitivity. The use of EMFs as a redox- and glycemia-modulating modality provides an unprecedented opportunity to study the role of redox in T2D pathophysiology and to advance the understanding of a novel, insulin sensitizing phenomenon. We will identify specific metabolic changes that occur in response to EMF exposure and determine mechanisms by which the redox state regulates hepatic metabolic flux and insulin sensitivity. This work will identify a novel mechanistic link between two previously disconnected fields of inquiry, static EMFs and glycemic regulation and will bridge redox biology with glucose metabolism. Successful completion of this work will lay the foundation for the future clinical development of a wearable device that emits EMFs to target redox systems for the noninvasive management of T2D.