Arjunolic acid from Cyclocarya paliurus selectively inhibits glucagon secretion from α cells and ameliorates diabetes via ephrin-A1 and EphA4 interaction

Besides insulin deficiency, glucagon excess is also regarded as a critical factor of type 2 diabetes mellitus (T2DM) according to the bi-hormonal hypothesis. Triterpenic acid-enriched fraction (TAE) of Cyclocarya paliurus leaves have been proved to effectively inhibit glucagon secretion, but the active ingredient for the efficacy and mechanism of TAE on glucagon secretion remains unclear. The present study was designed to identify the therapeutic component of TAE to treat T2DM and explore the exact mechanism. Herein, arjunolic acid (AA) screened from TAE selectively inhibited glucagon secretion in palmitate (PA)-induced αTC1-6 cells and isolated islets. Additionally, AA ameliorated hyperglycemia and hyperglucagonemia and improve pancreatic islet morphology and function in streptozotocin (STZ)-induced T2DM mice. Noticeably, the selective inhibition effect of AA on glucagon secretion from α-cell was regulated by facilitating ephrin-A1 and EphA4 interaction, subsequently activating PI3K and Akt pathway. Therefore, AA may be a promising agent for T2DM treatment.