Vernonia amygdalina Delile extract inhibits the hepatic gluconeogenesis through the activation of adenosine-5'monophosph kinase.

AIMS: It has been reported that Vernonia amygdalina Delile(VA) presents an anti-diabetic effect, and the effect of VA on lowering glucose is formulated via suppressing the expression of the key hepatic gluconeogenesis enzyme. Therefore, we further explored the probable mechanism of VA on dismissing hepatic gluconeogenesis through the activation of adenosine-5' monophosphate kinase (AMPK) in vivo and in vitro. METHODS: We developed type 2 diabetic mice with STZ and oral administration with VA (50 mg/kg, 100 mg/kg and 150 mg/kg) once a day for 6 weeks. Fasting blood glucose (FBG), fasting insulin (FINS) and oral glucose tolerance tests (OGTT) were conducted. The expression levels of AMPK, phosphoenolpyruvate carboxykinase (PEPCK) and Glucose-6-phosphatase (G6Pase) proteins in live were evaluated by western blot. Then, we further explored the mechanism of VA on hepatic gluconeogenesis in vitro experiments. Glucose production and the expression of AMPK, PEPCK and G6Pase proteins were detected after VA treatment with the presence of the AMPK inhibitor Compound C. KEY FINDINGS: VA reduced FBG and caused a significant improvement in glucose tolerance and insulin resistance (HOMA-IR) in STZ-induced mice. VA inhibited the elevated expression of gluconeogenesis key enzymes (PEPCK and G6Pase) and up-regulated AMPK activity in liver. In palmitic acid (PA)-induced HepG2 cells, VA decreased glucose production and the expression of PEPCK and G6Pase proteins, also activated AMPK pathway. The effects of VA on gluconeogenesis could be reversed by Compound C. CONCLUSION: These results reveal that VA suppresses hepatic gluconeogenesis at least partially through activating the AMPK.

High-dose risedronate treatment partially preserves cancellous bone mass and microarchitecture during long-term disuse.

Disuse induces rapid and severe bone loss in larger mammals as a result of greatly elevated osteoclastic resorption. In this study, we tested whether risedronate (RIS), a potent inhibitor of osteoclastic activity, would effectively prevent cancellous bone loss in female beagles (5-7 years old, N = 28) subjected to single forelimb immobilization (IM) for 12 months. Age-matched, non-IM dogs served as controls (Con). Half the animals from each group received RIS 1 mg/kg p.o. daily (Con + RIS, IM + RIS). Remaining dogs received sterile water (Con, IM). Histomorphometry showed that IM caused a dramatic reduction in cancellous bone mass (-71%) of distal 2nd metacarpals, characterized by marked decreases in trabecular width (-51%) and number (-41%), and 4-fold increases in the indices of bone resorption (eroded surface, osteoclast number, and surface). Bone formation indices (calcein-labeled surface, osteoid surface, and bone formation rate) were also significantly higher in IM than in controls. Activation frequency in IM increased about 4-fold beyond control level. RIS treatment reduced, but did not abolish cancellous bone loss due to immobilization. IM animals treated with RIS lost nearly 50% of cancellous bone mass, while trabecular width and number were reduced by 31% and 25%, respectively. In both RIS-treated control and IM animals, overall bone formation parameters (mineralized bone surface fraction and bone formation rate) remained roughly at intact control levels; however, mineral apposition rate relative to intact control was reduced 40% in RIS-treated control and 86% in RIS-treated IM animals. These results indicate that high-dose RIS treatment might suppress osteoblastic function, especially under long-term disuse. Interestingly, bone resorption parameters in RIS-treated IM animals reached levels even higher than in vehicle-treated IM animals; values for eroded surface, osteoclast number, and surface were 84%, 53%, and 83% above vehicle-treated IM values, respectively. Our data indicate that risedronate treatment is partially effective in preventing cancellous bone loss during long-term disuse. Moreover, our results suggest that bisphosphonates can impair the ability of mature osteoclasts to resorb bone, but cannot overcome the strong stimulus for osteoclast recruitment caused by long-term disuse.