Glucagon-Like Peptide-1 Increases Myocardial Glucose Uptake via p38 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 (n6), DCM (n9) and DCM after treatment with a 48-hour infusion of GLP-1 (7–36) amide (n9) or vehicle (n6). GLP-1 receptors and cellular pathways implicated in myocardial glucose uptake were measured in sarcolemmal membranes harvested from the 4 groups. GLP-1 stimulated myocardial glucose uptake (DCM: 207 nmol/min/g; DCMGLP-1: 6112 nmol/min/g; P0.001) independent of increased plasma insulin levels. The GLP-1 receptors were upregulated in the sarcolemmal membranes (control: 982 density units; DCM: 25658 density units; P0.046) 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 p38 MAP kinase activity (DCMvehicle: 9722 pmol ATP/mg/min; DCMGLP-1: 17036 pmol ATP/mg/min; P0.051), induction of nitric oxide synthase 2 (DCMvehicle: 15113 density units; DCMGLP-1: 30612 density units; P0.001), and GLUT-1 translocation (DCMvehicle: 213 % membrane bound; DCMGLP-1: 393% membrane bound; P0.005). The effects of GLP-1 on myocardial glucose uptake were blocked by pretreatment wit