Luteolin Protects Pancreatic beta Cells against Apoptosis through Regulation of Autophagy and ROS Clearance

Diabetes, which is mainly characterized by increased apoptosis and dysfunction of beta (beta) cells, is a metabolic disease caused by impairment of pancreatic islet function. Previous studies have demonstrated that death-associated protein kinase-related apoptosis-inducing kinase-2 (Drak2) is involved in regulating beta cell survival. Since natural products have multiple targets and often are multifunctional, making them promising compounds for the treatment of diabetes, we identified Drak2 inhibitors from a natural product library. Among the identified products, luteolin, a flavonoid, was found to be the most effective compound. In vitro, luteolin effectively alleviated palmitate (PA)-induced apoptosis of beta cells and PA-induced impairment of primary islet function. In vivo, luteolin showed a tendency to lower blood glucose levels. It also alleviated STZ-induced apoptosis of beta cells and metabolic disruption in mice. This function of luteolin partially relied on Drak2 inhibition. Furthermore, luteolin was also found to effectively relieve oxidative stress and promote autophagy in beta cells, possibly improving beta cell function and slowing the progression of diabetes. In conclusion, our findings show the promising effect of Drak2 inhibitors in relieving diabetes and offer a potential therapeutic target for the protection of beta cells. We also reveal some of the underlying mechanisms of luteolin's cytoprotective function.