Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha 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.


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 p38alpha 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 p38alpha 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.
Bhashyam
Siva
S
Department of Medicine, Allegheny General Hospital, Pittsburgh, Pa 19104, USA.
Fields
Anjali V
AV
Patterson
Brandy
B
Testani
Jeffrey M
JM
Chen
Li
L
Shen
You-Tang
YT
Shannon
Richard P
RP
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000503:physiopathology; D003243:Consciousness; D004195:Disease Models, Animal; D004285:Dogs; D005260:Female; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D011336:Probability; D011897:Random Allocation; D018027:Receptors, Glucagon / Q000378:metabolism; D015398:Signal Transduction; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D051275:Glucose Transporter Type 4; D018027:Receptors, Glucagon; D052216:Glucagon-Like Peptide 1; D019001:Nitric Oxide Synthase; D048051:p38 Mitogen-Activated Protein Kinases
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