Abstract The overall goal of this program is the development and commercialization of a novel, safe, and effective therapy for diabetic cardiovascular disease (dCVD). The worldwide prevalence of diabetes has risen from 108 million in 1980 to 422 million in 2014 and is expected to increase to 700 million by 2045. Ninety percent of those with diabetes have type 2 diabetes (T2D), and 35% of those with T2D have cardiac dysfunction. Those with T2D are 2-3 times more likely to develop dCVD. Cardiovascular complications due to hyperglycemia, especially myocardial infarction and heart failure, are the leading cause of T2D-related morbidity and mortality, accounting for 68% of all diabetic deaths. NovoMedix has developed safe, first-in-class, oral drugs that have the potential to prevent dCVD and significantly improve long term outcomes for those with T2D by activating AMPK, inhibiting mTOR, preventing activation of the inflammasome, and inhibiting secretion of IL-11. We, therefore, seek to demonstrate that Novomedix’s leading compound (NMLC) is cardioprotective in diabetic mice and provides protection against myocardial infarction following ischemia/reperfusion (I/R) injury. NMLC is an allosteric AMPK agonist, an independent specific inhibitor of mTORC1 and an inhibitor of IL-11 secretion that prevents heart failure in a mouse TAC model and decreases fibrosis and inflammation in liver and lung fibrosis models in mice. NMLC should reduce/reverse disease progression in dCVD by: 1) improving lipid and glucose homeostasis by activating AMPK; 2) reducing oxidative stress, inhibiting the production of ROS, and reducing inflammation by inhibition of the NLRP3 inflammasome and activation of AMPK; and 3) providing cardioprotection against I/R injury by activating AMPK and independently inhibiting mTOR, and 4) preventing post-I/R cardiac fibrosis by inhibition of IL-11 and mTOR and activation of AMPK. Dr. Das and Dr. Salloum (VCU) recently tested NMLC in diabetic mice and in isolated diabetic mouse adult ventricular cardiomyocytes. NMLC improved metabolic parameters in diabetic mice and protected cardiomyocytes (isolated from diabetic mice) following simulated ischemia/reoxygenation (SI/RO) injury. As a result of the unique potential of this drug to protect the heart against I/R injury in diabetic condition, we propose the following specific aims: 1) confirm NMLC mechanism of cardioprotection in vitro, assess inhibition of IL-11 in cardiac fibroblasts, assess AMPK/mTOR signaling in human cardiomyocytes in an SI/RO model with high glucose, and scale up NMLC for in vivo studies; 2) examine the cardiometabolic impact of NMLC in a mouse model of T2D, determine the effect of NMLC on metabolism and diabetes-induced changes in cardiac function, and confirm mechanism of cardioprotection of NMLC in vivo; and 3) determine the beneficial effect of NMLC in the post-myocardial infarction in db/db mice, determine the effect of NMLC on myocardial infarct and fibrosis after I/...