GLP-1 Increases Myocardial Glucose Uptake via p38α MAP Kinase Mediated, Nitric Oxide Dependent Mechanisms in Conscious Dogs with Dilated Cardiomyopathy

Background —We have shown that glucagon-like peptide-1 (GLP-1 [7-36] amide), stimulates myocardial glucose uptake in dilated cardiomyopathy (DCM) independent of an insulinotropic effect. The cellular mechanisms of GLP-1 induced myocardial glucose uptake are unknown. Methods and Results —Myocardial substrates and glucoregulatory hormones were measured in conscious, chronically instrumented dogs at Control (n=6), DCM (n=9), and DCM following treatment with a 48-hour infusion of GLP-1 (7-36) amide (n=9) or vehicle (Veh, n=6). GLP-1 receptors and cellular pathways implicated in myocardial glucose uptake (MGU) were measured in sarcolemmal membranes harvested from the four groups. GLP-1 stimulated MGU (DCM: 20±7; DCM+GLP-1: 61±12 nmol/min/g, p=0.001) independent of increased plasma insulin levels. The GLP-1 receptors were up-regulated in the sarcolemmal membranes (Con: 98±2; DCM: 256±58 DU, p=0.046) and were expressed in their activated (65 kDa) form in DCM. The GLP-1 induced increases in MGU did not involve adenylyl cyclase or Akt activation, but was associated with marked increases in p38α MAP kinase activity (DCM + Veh: 97±22 DCM+GLP-1: 170±36 pmol ATP /mg/min, p=0.051), induction of nitric oxide synthase 2 (NOS2) (DCM +Veh: 151±13; DCM+GLP-1: 306±12 DU, p=0.001), and GLUT-1 translocation (DCM+Veh: 21±3%; DCM+GLP-1: 39±3% membrane bound, p=0.005). The effects of GLP-1 on MGU were blocked by pretreatment with the p38α MAP kinase inhibitor or non-specific NOS inhibitor, nitro-L-arginine. Conclusions —GLP-1 stimulates myocardial glucose uptake through a non Akt-1 dependent mechanism by activating cellular pathways that have been identified in mediating chronic hibernation and the late phase of ischemic pre-conditioning.