In both Type 1 and type 2 diabetes, pancreatic beta‐cell failure plays an important role in the deterioration of glycemic control. In this study, we investigated whether hispidulin, a naturally occurring flavone, can be used to ameliorate diabetes in an animal model of insulin deficiency. Here, we report that oral administration of hispidulin (20 mg/kg) alleviates streptozotocin‐induced hyperglycemia in C57/BL6 male mice. Hispidulin effectively mitigates postprandial and fasting hyperglycemia and glucose tolerance, which was associated with higher circulating plasma insulin concentrations and improved glucose stimulated‐insulin secretion (GSIS). In addition, treatment with hispidulin reduced expression of pyruvate carboxylase and glucose 6‐phosphatase in the livers. In vitro, hispidulin suppressed glucose production in mouse primary hepatocytes, but potentiated GSIS in insulin‐secreting cells and mouse islets. These findings suggest that hispidulin could be a dual action, natural compound that exerts antidiabetic action via promoting beta‐cell function and suppressing hepatic glucose production.Support or Funding InformationThe work was supported by grants from NCCIH of NIH (1R01AT007077, 1R01AT007566)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.