Modulating ROS by Electromagnetic Fields to Treat Type 2 Diabetes

通过电磁场调节 ROS 治疗 2 型糖尿病

• 批准号: 10570226
• 负责人: E Dale Abel
• 金额: $ 46.85万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570226
• 关键词: Address; Adherence; Adverse effects; Animals; Antioxidants; Biological Availability; Biological Markers; Biology; Carbon; Catabolism; Cells; Clinical Trials; Diabetes Mellitus; Disease; Drug Modulation; Electromagnetic Energy; Electromagnetic Fields; Electrons; Electrostatics; Equilibrium; Fatty Acids; Foundations; Functional disorder; Future; Genetic; Glucose; Glucose Intolerance; Glutathione; Glutathione Disulfide; Glycogen; Goals; Hepatic; Hepatocyte; Homeostasis; Hour; Human; Hydrogen Peroxide; Hypoglycemic Agents; Infusion procedures; Insulin; Insulin Resistance; Intervention; Knockout Mice; Link; Liver; Malignant Neoplasms; Mediating; Medicine; Mental Depression; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Methodology; Methods; Modality; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxidation-Reduction; Pathway interactions; Patients; Penetration; Pentosephosphate Pathway; Planet Earth; Production; Property; Protein Isoforms; Publications; Reactive Oxygen Species; Regulation; Risk; Rodent; Role; Signal Transduction; Superoxide Dismutase; Superoxides; Surface; System; Testing; Therapeutic; Therapeutic Effect; Tissues; Tracer; Transcranial magnetic stimulation; Translating; Work; catalase; clinical application; clinical development; glucose metabolism; glucose uptake; improved; in vivo; innovation; insight; insulin sensitivity; lipid biosynthesis; metabolomics; mouse model; new therapeutic target; non-invasive system; novel; novel marker; nucleotide metabolism; overexpression; pharmacologic; prevent; response; side effect; therapeutic target; tool; tumor; wearable device

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.

抽象的 已经提出异常氧化还原稳态为2型糖尿病的病理生理做出贡献 （T2D）。但是，这些机制知之甚少。氧化还原系统受促氧化剂的调节， 例如活性氧（ROS）和抗氧化剂，例如谷胱甘肽。 T2D患者有 ROS的水平升高和谷胱甘肽的较低水平。试图扭转T2D中这种氧化还原不平衡的尝试 使用氧化还原调节药物或输注抗氧化剂已显示出逆转胰岛素抵抗的希望 在初步研究中，但由于其半衰期和分娩，最终在临床试验中失败了 挑战。需要新方法和对T2D中的氧化还原机制的更好理解以解决 当前方式目前尚未有效解决T2D的潜在病理生理学。罗斯 拥有不成对的电子，使其成为顺磁性并能够与外部应用相互作用 电磁场（EMFS）。我们最近确定了一组独特的EMF参数，该参数迅速调制 ROS和氧化还原稳态。当应用于T2D和人类细胞的小鼠模型时，发现EMFS 对血糖和胰岛素敏感性产生显着影响，逆转葡萄糖不耐症和胰岛素 三天内的阻力，没有不利影响。我们还发现，EMF的应用改变了 葡萄糖的代谢通量，将葡萄糖掺入糖原中并降低脂肪酸水平。 清除顺磁性ROS或通过注入氧化氧化还原溶液来防止氧化还原适应 （GSSG）废除了这些惊人的治疗作用。这些发现导致我们假设EMF针对 ROS诱导NRF2介导的氧化还原反应，该反应通过改变的命运，部分胰岛素敏感 葡萄糖。因此，该项目的目的是阐明氧化还原和代谢机制 EMF的胰岛素敏化作用。我们将以两个具体目的测试我们的假设：1）确定 介导EMF-疗法的胰岛素敏化作用的氧化还原机制； 2）确定 EMF-疗法或氧化还原调制重定向葡萄糖的代谢命运以改善的机制 胰岛素灵敏度。将EMF用作氧化还原和糖化模式的使用提供了 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促进 了解一种新颖的胰岛素敏化现象。我们将确定特定的代谢变化 响应EMF暴露并确定氧化还原状态调节肝的机制 代谢通量和胰岛素敏感性。这项工作将确定以前两个之间的新机械联系 探究，静态EMF和血糖调节的连接领域，将桥接氧化还原生物学 葡萄糖代谢。成功完成这项工作将为未来的临床奠定基础 开发可穿戴设备，该设备发射EMF以靶向氧化还原系统，以供无创 T2D的管理。