Résumé
Glucagon-like peptide-1 is an incretin hormone proposed to have insulinomimetic effects on peripheral insulin-sensitive tissue. We examined these effects on the heart by using isolated; perfused rat hearts and adult ventricular myocytes. During normoxic perfusion; no effects of escalating concentrations of GLP-1 on either heart rate or left ventricular developed pressure were found. With functional performance as readout; we found that GLP-1 directly protected the heart against damage incurred by global low-flow ischaemia. This protection was sensitive to the presence of iodo-acetate; implicating activation of glycolysis; and was abolished by wortmannin; indicative of Pi-3-kinase as mediator of protection. in addition; GLP-1 had an infarct-sparing effect when supported by the presence of the dipeptidyl peptidase-iv inhibitor valine pyrrolidide. GLP-1 could not directly activate protein kinase B (also called Akt) or the extracellular regulated kinases Erk1/2 in hearts or cardiocytes under normoxic conditions; but phosphorylation of the AMP-activated kinase (AMPK) on Thr172 was enhanced. in addition; the glycolytic enzyme phosphofructokinase-2 was activated dose dependently. During reperfusion after ischaemia; modulation of the phosphorylation of PKB/Akt as well as AMPK was evident. GLP-1 therefore directly protected the heart against low-flow ischaemia by enhancing glycolysis; probably via activation of AMP kinase and by modulating the profile of activation of the survival kinase PKB/Akt