Cucurbitacin-D inhibits hepatic gluconeogenesis through activation of Stat3 signaling

Background: Cucurbitacins belong to a class of highly oxidized tetracyclic triterpenoids, which are widely distributed in the plant. Objective: In this study, we addressed the roles of Cucurbitacin-D (CuD) in diabetic db/db mice and streptozotocin (STZ)-treated C57BL/6 mice. Methods: C57BL/6 mice were injected with streptozotocin for induction of diabetes followed by determination of gluconeogenesis. Western blot and real time PCR were performed to measure the gene expression involved in signaling transduction. Results: We found CuD improved serum glucose concentrations, even without improving insulin sensitivity. Consistently, hepatic phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase), two key enzymes in the gluconeogenesis, were down-regulated by CuD. Besides, hepatic triglyceride contents were also reduced, accompanied by decreased expression of lipogenic genes. At the molecular level, CuD was shown to activate signal transducer and activator of transcription 3 (Stat3) signaling in vivo and in vitro. Conclusions: Our data suggest that CuD improves fasting blood glucose by direct inhibition of gluconeogenesis in liver, suggesting a new therapeutic approach for the treatment of type 2 diabetes.