The apelin/elabela‑apelin receptor (APJ) signaling system is a key regulator of metabolic homeostasis and cardiovascular function in diabetes mellitus. However, its therapeutic application is complicated by its functional divergence: the system exerts protective effects in some tissues while driving pathology in others. The present review examined these distinct roles, focusing on how the biological outcome depends on the specific ligand, disease stage and tissue microenvironment. It discussed the molecular mechanisms underlying this divergence, as well as the varying roles of the same receptor at different stages of the same disease. Finally, it evaluated emerging therapeutic strategies, such as stabilized analogs and biased agonists, proposing that precise targeting of the APJ conformational landscape offers a pathway to move beyond glycemic control toward multi‑organ protection in diabetes.
Han et al. (Fri,) studied this question.