Sodium-glucose cotransporter-2 (SGLT2) inhibitors are used to treat hyperglycemia in type 2 diabetes (T2D) due to their ability to increase urinary glucose excretion; however, new evidence suggests SGLT2 inhibition also improves skeletal muscle insulin action as a mechanism to improve glycemia. Recent studies in humans and rodent models report SGLT2 inhibitor treatment increases insulin-stimulated glucose disposal, even after accounting for urinary glucose losses. Despite the clinical significance of these findings, mechanisms to explain this effect remain unresolved. The current project will test the hypothesis that SGLT2 inhibitor treatment stimulates changes in skeletal muscle fat metabolism that serve to improve skeletal muscle insulin action. Our preliminary studies in model systems demonstrate SGLT2 inhibitor treatment alters mitochondrial function, can induce energetic stress signaling (AMP-activated protein kinase), and even lower accumulation of bioactive lipids known to negatively regulate insulin signaling. These findings support our hypothesis and highlight the need to better understand the impact of SGLT2 inhibition on human skeletal muscle given its critical role in regulating whole-body glucose metabolism. The current project will also test the hypothesis that SGLT2 inhibition may provide therapeutic benefit (via improved skeletal muscle metabolism) before the onset of T2D. Treating individuals with prediabetes with SGLT2 inhibitors is an especially attractive option given their dysglycemia, high risk for advanced cardiometabolic disease and limited current treatment options (i.e., lifestyle modification and metformin). Taken together, the overall objectives of the current proposal are to identify mechanisms of how SGLT2 inhibition improves skeletal muscle insulin action and test the ability of SGLT2 inhibition to improve skeletal muscle metabolism among individuals with prediabetes. The current project is a randomized, double-blind, 13-week intervention comparing SGLT2 inhibition with placebo among overweight and obese adults with prediabetes. Participants will undergo robust metabolic phenotyping before and in response to the intervention to achieve the following specific aims: Aim 1: Test the hypothesis that SGLT2 inhibition improves skeletal muscle insulin action and insulin signaling in prediabetes; Aim 2: Determine mechanisms responsible for increased skeletal muscle fat oxidation during SGLT2 inhibition; Aim 3: Determine the extent to which SGLT2 inhibition lowers skeletal muscle diacylglycerol and ceramide content in prediabetes. The proposed studies can be expected to generate new information regarding the mechanisms of how SGLT2 inhibition can improve skeletal muscle metabolism and provide new understanding of the therapeutic potential of using SGLT2 inhibitors as a treatment for prediabetes.