Abstract 788: Glucagon-Like Peptide-1 (GLP-1) Increases Myocardial Glucose Uptake Through a p38α MAP Kinase Mediated, Nitric Oxide Dependent Mechanism in Conscious Dogs with Dilated Cardiomyopathy
Background: The development of dilated cardiomyopathy (DCM) in conscious dogs is associated with myocardial insulin resistance that limits metabolic flexibility under circumstances in which glucose uptake and oxidation are preferred. We have shown that the incretin, GLP-1, stimulates myocardial glucose uptake in DCM, independent of an insulinotropic effect. The cellular mechanisms of GLP-1 induced myocardial glucose uptake are unknown.
Methods: Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at Control (n=24), after 30 days of rapid pacing, DCM (n=9), and DCM following treatment with a 48-hour infusion of GLP-1 (7–36) amide (n=9). GLP-1 receptors and cellular pathways involved in myocardial glucose uptake were measured in sarcolemmal membranes harvested from the three groups.
Results: GLP-1 stimulated myocardial glucose uptake (DCM: 1.52±0.55; DCM+GLP-1: 7.51±0.74 μmol/min) independent of increased plasma insulin levels. The GLP-1 receptors were up-regulated in the myocardium (Con: 98±2; DCM: 256± 58 DU, p<0.05) and were expressed in their activated (65 kDa) form in DCM. The GLP-1 induced increases in myocardial glucose uptake did not involve adenylyl cyclase or Akt activation, but was associated with marked increases in p38α MAP kinase activity (DCM: 97±22; DCM+GLP-1: 170±36 pmol ATP/mg/min, p<0.05), induction of NOS2 (DCM: 151±13; DCM+GLP-1: 306±12 DU, p<0.05) increased myocardial NO uptake (DCM: −72±19; DCM + GLP-1: 122±22 nmol/min, p<0.05), and GLUT-1 translocation (DCM: 21±3%; DCM+GLP-1: 39±3% membrane bound, p<0.05). The effects of GLP-1 on myocardial glucose uptake were blocked by pretreatment with the NOS inhibitor, nitro-L-arginine.
Conclusion: GLP-1 stimulates myocardial glucose uptake through a non-Akt dependent mechanism, by activating cellular pathways that have been identified in mediating chronic hibernation and the late phase of ischemic pre-conditioning. These mechanisms may underlie the beneficial myocardial effects of GLP-1 in experimental and clinical trials.