We used diabetic Epac1 floxed and endothelial cell specific knockout KO mice alone or treated with glycyrrhizin to investigate whether Epac1 could inhibit HMGB1 to protect the diabetic retina, as well as whether Epac1 and glycyrrhizin work synergistically to protect the retinal against diabetes-induced neuronal, vascular, and permeability changes. Here, RAPGEF3 is linked to diabetes mellitus.