The Triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic-acid Methyl Ester Has Potent Anti-diabetic Effects in Diet-induced Diabetic Mice and Lepr Mice

作者：Pradip Kumar Saha, Vasumathi T. Reddy, Marina Y Konopleva, Michael Andreeff, Lawrence Chan · 发表于：Journal of Biological Chemistry · 年份：2010 · DOI：10.1074/jbc.m110.176545 · 被引用次数：108 · 研究领域：Metabolism, Diabetes, and Cancer、Cancer, Hypoxia, and Metabolism、Genomics, phytochemicals, and oxidative stress

The triterpenoid 2-Cyano-3,12-dioxooleana-1,9-dien-28-oic-acid (CDDO) and its methyl ester (CDDO-Me) are undergoing clinical trials in cancer and leukemia therapy. Here we report that CDDO-Me ameliorates diabetes in high fat diet-fed type 2 diabetic mice and in Lepr(db/db) mice. CDDO-Me reduces proinflammatory cytokine expression in these animals. Oral CDDO-Me administration reduces total body fat, plasma triglyceride, and free fatty acid levels. It also improves glucose tolerance and insulin tolerance tests. Its potent glucose-lowering activity results from enhanced insulin action. Hyperinsulinemic-euglycemic clamp reveals an increased glucose infusion rate required to maintain euglycemia and showed a significant increase in muscle-specific insulin-stimulated glucose uptake (71% soleus, 58% gastrocnemius) and peripheral glucose clearance as documented by a 48% increase in glucose disposal rate. CDDO-Me activates AMP-activated protein kinase (AMPK) and via LKB1 activation in muscle and liver in vivo. Treatment of isolated hepatocytes with CDDO-Me directly stimulates AMPK activity and LKB1 phosphorylation and decreases acetyl-coA carboxylase activity; it also down-regulates lipogenic gene expression, suppresses gluconeogenesis, and increases glucose uptake. Inhibition of AMPK phosphorylation using compound C and lentiviral-mediated knockdown of AMPK completely blocks the CDDO-Me-induced effect on hepatocytes as well as C(2)C(12) cells. We conclude that the triterpenoid CDDO-Me...