Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone released by enteroendocrine cells lining the intestine in response to the presence of nutrients. GLP-1 is known to cause increased secretion of insulin from the pancreas and has been identified as one of the crucial components of insulin and in turn glucose homeostasis. GLP-1 has a very short half life of 1-2 minutes, being rapidly degraded by a ubiquitous enzyme called dipeptidyl dipeptidase IV and also undergoing renal excretion. Interestingly GLP-1 mRNA transcripts have been identified in several organs outside of the expected enteropancreatic axis including the heart. Insulin has been shown to reduce cell death in the ischemic-reperfused rat myocardium and in isolated rat myocytes via its ability to activate prosurvival kinase signalling pathways. We propose that GLP-1 could protect the myocardium against ischaemia-reperfusion injury by activating similar prosurvival signalling pathways. Both in-vivo (open chest) and in-vitro (Langendorff perfused) rat heart models of regional ischaemia and reperfusion were used. In-vivo treatment with GLP-1 produced a significant reduction in infarction (% infarct/risk zone) compared to valine pyrrolidide (VP), (an inhibitor of the enzyme dipeptidyl peptidase), and control groups (20.0 2.8, vs. 47.3 4.3, and 44.3 2.4, respectively PO.001). In isolated perfused hearts (where there is no circulating insulin) GLP-1 significantly reduced infarct size compared to VP and control (26.7 2.7 vs. 52.6 4.7 and 58.7 4.1, PO.001) groups respectively. Protection was abolished in the presence of the PI3kinase inhibitor, LY294002 (58.6 4.1), the ERK 1/2 MAPK inhibitor, U0126 (48.3 8.6), the p70s6K inhibitor, Rapamycin (57.1 4.9%) and by the GLP-1 receptor antagonist exendin-9-39 (57.3 3.8). GLP-1 protects the myocardium against ischaemic - reperfusion injury when given throughout ischaemia - reperfusion or when given just five minutes prior to the onset of reperfusion or as a preconditioning mimetic. To further elucidate the mechanism of GLP-1 mediated myocardial preservation we carried out Western blot studies examining the phosphorylation of components of the RISK pathway which showed an increase in the phosphorylation of BAD. The increased phosphorylation of the pro-death peptide BAD, confirmed the potential anti- apoptotic effect of GLP-1. In conclusion we have demonstrated for the first time that GLP-1 protects the rat myocardium against ischaemia-reperfusion injury, both in vivo and in vitro. GLP-1 appears to protect via the up regulation of specific prosurvival kinase pathways. This may represent a new therapeutic potential for this class of drugs currently undergoing trials in the treatment of non-insulin dependent diabetes.

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