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 noninvasiv...