Development of therapeutic agents for type II DM by using AMPK as molecular target

• Main Authors: Wei-Lu Chen, 陳韋陸
• Other Authors: 李宏謨
• Format: Others
• Language: zh-TW
• Published: 2007
• Online Access: http://ndltd.ncl.edu.tw/handle/10109027987302236361

碩士 === 臺北醫學大學 === 細胞及分子生物研究所 === 95 === AMPK activated protein kinase (AMPK) is a key sensor and regulator of intracellular and whole body energy metabolism. Activation of AMPK has been shown to reduce visceral fat content, cholesterol synthesis and increase hepatic glucose disposal. Thus, AMPK has been considered as a molecular target for type II DM. In order to develop a potential drug for type II DM, we have screened 84 compounds isolated form Chinese herbal medicine for AMPK activator. We found that compound TMU023 stimulated a dose dependent AMPK phosphorylation in NRK52E cells. The activation of AMPK is associated with increased phosphorylation of its downstream substrate, acetyl CoA carboxylase (ACC), and increased fatty acid b-oxidation in NRK52E cells. Treatment of H89, a pharmacological inhibitor specific for PKA, inhibited TMU023-activated AMPK phosphorylation, ACC phosphorylation, and fatty acid b-oxidation, suggesting TMU023 mediated AMPK activation through PKA dependent signaling pathway. Advanced glycosylation end products (AGE) have been linked to the pathogenesis of diabetic complications. To explore whether TMU023 exerts other beneficial effects to attenuate AGE formation, a high throughput screening assay using Amadori products as substrate has been developed. We demonstrated that in addition to AMPK activation, TMU023 was able to suppress AGE formation in vitro. Taken together, our results suggest that TMU023 may serve as a potential therapeutic agent for type II DM.