Abstract 3878: Glucagon-Like Peptide-1 Metabolite Protects the Myocardium Against Ischemia-Reperfusion Injury in Diabetes Mellitus

Abstract

Background: Glucagon-Like Peptide-1 (GLP-1) is an incretin hormone with potent plasma glucose lowering actions that is rapidly degraded by the enzyme Dipeptidyl Peptidase-IV to GLP-1(9 –36) amide . GLP-1(9 –36) amide (GLP1dp) has previously been viewed to be biologically inactive. However, our laboratory has demonstrated that GLP1dp inhibits hyperglycemia-induced production of oxidant species and prevents the inactivation of both eNOS and prostacyclin synthase in cells and diabetic animals. We investigated the effects of GLP1dp in two in vivo diabetic murine models of myocardial ischemia-reperfusion (MI-R) injury. Methods: Diabetic (db/db and STZ-diabetic) mice were treated with 2.4 μg/day of GLP1dp via Alzet pump for 7 days and subjected to 45 min of left coronary artery occlusion and 2 hr of R. At 2 hr of R, hearts were excised and evaluated for infarct (INF) size. Results: Diabetic (db/db) and STZ-diabetic mice treated with GLP1dp exhibited a 37% and 33% reduction in myocardial infarct size following MI-R respectively. Additionally, GLP1dp significantly reduced oxidative stress in the myocardium of these mice. Both models of diabetic mice (db/db and STZ-diabetic) exhibited elevated baseline blood glucose (BG) values of 386 ± 25 and 435 ± 15 mg/dl respectively. After 7 days of GLP1dp therapy, db/db mice exhibited a 48% reduction in BG values. In contrast, no reduction in BG was observed in the STZ-diabetic mice. Conclusion : Administration of GLP1dp peptide confers cardioprotection in diabetic mice by attenuating the extent of oxidant-mediated injury following MI-R. The cardioprotective actions of GLP1dp appear to be independent of any effects on blood glucose.