Glucagon-Like Peptide-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 after treatment with a 48-hour infusion of GLP-1 (7-36) amide (n=9) or vehicle (n=6). 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: 20=7 nmol/min/g; DCM+GLP-1: 61 +/- 12 nmol/min/g; P=0.001) independent of increased plasma insulin levels. The GLP-1 receptors were upregulated in the sarcolemmal membranes (control: 98 +/- 2 density units; DCM: 256 +/- 58 density units; P=0.046) 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 alpha MAP kinase activity (DCM+vehicle: 97 +/- 22 pmol ATP/mg/min; DCM+GLP-1: 170 +/- 36 pmol ATP/mg/min; P=0.051), induction of nitric oxide synthase 2 (DCM+vehicle: 151 +/- 13 density units; DCM+GLP-1: 306 +/- 12 density units; P=0.001), and GLUT-1 translocation (DCM+vehicle: 21 +/- 3% membrane bound; DCM+GLP-1: 39 +/- 3% membrane bound; P=0.005). The effects of GLP-1 on myocardial glucose uptake were blocked by pretreatment with the p38 alpha MAP kinase inhibitor or the nonspecific nitric oxide synthase 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 preconditioning. (Circ Heart Fail. 2010;3:512-521.)