Modulating ROS by Electromagnetic Fields to Treat Type 2 Diabetes

摘要 异常的氧化还原动态平衡被认为与2型糖尿病的病理生理学有关。 (T2D)。然而，人们对这些机制知之甚少。氧化还原系统是由促氧化剂调节的， 如活性氧(ROS)和抗氧化剂，如谷胱甘肽。患有T2D的患者有 体内ROS水平升高，谷胱甘肽水平降低。试图扭转T2D中的这种氧化还原失衡 使用氧化还原调节药物或注射抗氧化剂在逆转胰岛素抵抗方面显示出了希望。 在初步研究中，但最终由于它们的半衰期和交付时间较短而在临床试验中失败 挑战。需要新的方法和对T2D中氧化还原机制的更好理解来解决 一种潜在的T2D的病理生理学，目前还没有被目前的模式有效地解决。ROS 拥有未配对的电子，使它们具有顺磁性，并能够与外部施加的电子相互作用 电磁场(EMF)。我们最近发现了一组独特的电动势参数，可以快速调制 ROS和氧化还原动态平衡。当应用于T2D和人类细胞的小鼠模型时，电磁场被发现 对血糖和胰岛素敏感性有显著作用，逆转糖耐量和胰岛素 三天内耐药，无不良反应。我们还发现，电磁场的应用改变了 葡萄糖的代谢流量，增加葡萄糖并入糖原，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)取消了这些显著的治疗作用。这些发现让我们假设电磁场的目标是 ROS诱导NRF2介导的氧化还原反应，这在一定程度上通过改变 葡萄糖。因此，这个项目的目标是阐明潜在的氧化还原和代谢机制。 电磁场的胰岛素增敏作用。我们将在两个具体目标中检验我们的假设：1)确定 介导电磁场治疗的胰岛素增敏作用的氧化还原机制；以及2)决定 电磁场治疗或氧化还原调节改变葡萄糖代谢命运以改善的机制 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 前所未有的机会研究氧化还原在T2D病理生理学中的作用并推动 对一种新的胰岛素增敏现象的理解。我们将确定特定的代谢变化， 发生在对电磁场暴露的响应中，并确定氧化还原状态调节肝脏的机制 代谢流量和胰岛素敏感性。这项工作将确定一种新的机制联系，在以前的 分离的研究领域，静态电动势和血糖调节，将架起氧化还原生物学与 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 开发一种可向非侵入性氧化还原系统发射电磁场的可穿戴设备 T2D的管理。

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.