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Diabetes 54:146-151, 2005
© 2005 by the American Diabetes Association, Inc.

Glucagon-like Peptide 1 Can Directly Protect the Heart Against Ischemia/Reperfusion Injury

Amal K. Bose1, Mihaela M. Mocanu1, Richard D. Carr2, Christian L. Brand2, and Derek M. Yellon1

1 Hatter Institute and Centre for Cardiology, University College London Hospital and Medical School, London, U.K
2 NovoNordisk, Bagsværd, Denmark

Glucagon-like peptide 1 (GLP-1), a gut incretin hormone that stimulates insulin secretion, also activates antiapoptotic signaling pathways such as phosphoinositide 3-kinase and mitogen-activated protein kinase in pancreatic and insulinoma cells. Since these kinases have been shown to protect against myocardial injury, we hypothesized that GLP-1 could directly protect the heart against such injury via these prosurvival signaling pathways. Both isolated perfused rat heart and whole animal models of ischemia/reperfusion were used, with infarct size measured as the end point of injury. In both studies, GLP-1 added before ischemia demonstrated a significant reduction in infarction compared with the valine pyrrolidide (an inhibitor of its breakdown) or saline groups. This protection was abolished in the in vitro hearts by the GLP-1 receptor antagonist exendin (9-39), the cAMP inhibitor Rp-cAMP, the PI3kinase inhibitor LY294002, and the p42/44 mitogen-activated protein kinase inhibitor UO126. Western blot analysis demonstrated the phosphorylation of the proapoptotic peptide BAD in the GLP-1–treated groups. We show for the first time that GLP-1 protects against myocardial infarction in the isolated and intact rat heart. This protection appears to involve activating multiple prosurvival kinases. This finding may represent a new therapeutic potential for this class of drug currently undergoing clinical trials in the treatment of type 2 diabetes.

Address correspondence and reprint requests to Professor Derek M. Yellon, The Hatter Institute for Cardiovascular Studies, University College London Hospital and Medical School, Grafton Way, London WC1E, U.K. E-mail: d.yellon{at}ucl.ac.uk


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HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Diabetes Diabetes Care Clinical Diabetes Diabetes Spectrum
Copyright © 2005 by the American Diabetes Association.