| 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(db/db) mice. | |
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MedLine Citation:
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PMID: 20956520 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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 has potent anti-diabetic action in diabetic mouse models that is mediated at least in part through AMPK activation. The in vivo anti-diabetogenic effects occur at a dose substantially lower than that used for anti-leukemia therapy. We suggest that CDDO-Me holds promise as a potential anti-diabetic agent. |
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Authors:
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Pradip K Saha; Vasumathi T Reddy; Marina Konopleva; Michael Andreeff; Lawrence Chan |
Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2010-10-18 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 285 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-12-20 Completed Date: 2011-01-24 Revised Date: 2011-12-26 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 40581-92 Citation Subset: IM |
Affiliation:
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Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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genetics,
metabolism Acetyl-CoA Carboxylase / genetics, metabolism Adipose Tissue / metabolism Animals Diabetes Mellitus, Experimental / blood, drug therapy*, genetics Diet / adverse effects* Enzyme Activation / drug effects, genetics Fatty Acids, Nonesterified / blood Glucose / metabolism Hypoglycemic Agents / pharmacology*, therapeutic use Insulin / blood Mice Mice, Mutant Strains Muscle, Skeletal / metabolism Oleanolic Acid / analogs & derivatives*, pharmacology, therapeutic use Phosphorylation / drug effects, genetics Protein-Serine-Threonine Kinases / metabolism Triglycerides / blood |
| Grant Support | |
ID/Acronym/Agency:
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HL51586/HL/NHLBI NIH HHS; P30-DK079638/DK/NIDDK NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Fatty Acids, Nonesterified; 0/Hypoglycemic Agents; 0/Insulin; 0/Triglycerides; 0/methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate; 50-99-7/Glucose; 508-02-1/Oleanolic Acid; EC 2.7.1.-/Stk11 protein, mouse; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 2.7.11.1/Protein-Serine-Threonine Kinases; EC 6.4.1.2/Acetyl-CoA Carboxylase |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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