Abstract Insulin resistance involves impaired glucose clearance capacity by the skeletal muscle and adipose tissue and is also associated with muscle loss. However, the underlying mechanistic link between diabetes and muscle loss is not well understood. Here, we identify Isthmin-1 (Ism1) as a secreted signaling protein with multi-organ actions. By performing untargeted phosphoproteomics revealing the global signaling actions of Ism1, we identify that Ism1 stimulates adipose and skeletal muscle glucose uptake and an increase in skeletal muscle protein synthesis. Mechanistically, Ism1 activates pAKT-mTOR-S6 signaling independently of insulin or the insulin receptor. In mice, Ism1 ablation results in impaired glucose clearance capacity and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in systemic glucose regulation. Notably, the administration of recombinant Ism1 is sufficient to ameliorate diabetes in a diet-induced obese mouse model. Ism1 ablation also results in smaller skeletal muscle fiber size and lower muscle protein content, demonstrating that Ism1 is required for muscle proteostasis. These findings reveal a new secreted protein hormone that activates anabolic pathways in muscle and adipose tissue. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.