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 异常的氧化还原稳态已被认为有助于 2 型糖尿病的病理生理学 （T2D）。然而，人们对其机制知之甚少。氧化还原系统受促氧化剂调节， 例如活性氧 (ROS) 和抗氧化剂，例如谷胱甘肽。 T2D 患者有 ROS 水平升高，谷胱甘肽水平降低。尝试扭转 T2D 中的氧化还原不平衡 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 进行了初步研究，但由于半衰期和递送时间短，最终在临床试验中失败 挑战。需要新的方法和更好地理解 T2D 中的氧化还原机制来解决 目前的治疗方法尚未有效解决 T2D 的潜在病理生理学问题。活性氧 拥有不成对的电子，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)。我们最近确定了一组独特的 EMF 参数，可以快速调节 ROS 和氧化还原稳态。当应用于 T2D 小鼠模型和人类细胞时，发现 EMF 可以 对血糖和胰岛素敏感性发挥显着作用，逆转葡萄糖不耐受和胰岛素 三天耐药，无不良影响。我们还发现 EMF 的应用改变了 葡萄糖的代谢通量，增加葡萄糖与糖原的结合并降低脂肪酸水平。 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）废除了这些惊人的治疗效果。这些发现使我们推测电磁场的目标是 ROS 诱导 NRF2 介导的氧化还原反应，该反应部分通过改变胰岛素的命运来使胰岛素敏感 葡萄糖。因此，该项目的目标是阐明潜在的氧化还原和代谢机制 EMF 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 疗法的胰岛素增敏作用的氧化还原机制； 2) 确定 EMF 疗法或氧化还原调节重定向葡萄糖的代谢命运以改善的机制 胰岛素敏感性。使用 EMF 作为氧化还原和血糖调节方式提供了一种 研究氧化还原在 T2D 病理生理学中的作用并推进 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 响应 EMF 暴露而发生，并确定氧化还原状态调节肝脏的机制 代谢通量和胰岛素敏感性。这项工作将确定两个先前的研究之间的新颖的机制联系 相互独立的探究领域、静态电磁场和血糖调节，并将氧化还原生物学与 葡萄糖代谢。本次工作的顺利完成，将为今后的临床工作奠定基础。 开发一种可向非侵入性氧化还原系统发射 EMF 的可穿戴设备 T2D 的管理。