Vindoline (VDL) is an indole alkaloid, possessing hypoglycemic and vasodilator effects, and it is also the prodrug of many vinca alkaloids. Vindoline as one of the alkaloids is highly present in young leaves and twigs of Catharanthus roseus, and oral administration of vindoline (100 mg/kg) had an acute hypoglycemic effect on rats. Vindoline acted as a Kv2.1 inhibitor able to reduce the voltage-dependent outward potassium currents finally enhancing insulin secretion. It protected β-cells from the cytokines-induced apoptosis following its inhibitory role in Kv2.1. Moreover, vindoline (20mg/kg) treatment significantly improved glucose homeostasis in db/db mice and STZ/HFD-induced type 2 diabetic rats, as reflected by its functions in increasing plasma insulin concentration, protecting the pancreatic β-cells from damage, decreasing fasting blood glucose and glycated hemoglobin (HbA1c), improving OGTT and reducing plasma triglyceride (TG).