Active metabolite of GLP-1 mediates myocardial glucose uptake and improves left ventricular performance in conscious dogs with dilated cardiomyopathy.
We have shown previously that the glucagon-like peptide-1 (GLP-1)-(7-36) amide increases myocardial glucose uptake and improves left ventricular (LV) and systemic hemodynamics in both conscious dogs with pacing-induced dilated cardiomyopathy (DCM) and humans with LV systolic dysfunction after acute myocardial infarction. However, GLP-1-(7-36) is rapidly degraded in the plasma to GLP-1-(9-36) by dipeptidyl peptidase IV (DPP IV), raising the issue of which peptide is the active moiety. By way of methodology, we compared the efficacy of a 48-h continuous intravenous infusion of GLP-1-(7-36) (1.5 pmol.kg(-1).min(-1)) to GLP-1-(9-36) (1.5 pmol.kg(-1).min(-1)) in 28 conscious, chronically instrumented dogs with pacing-induced DCM by measuring LV function and transmyocardial substrate uptake under basal and insulin-stimulated conditions using hyperinsulinemic-euglycemic clamps. As a result, dogs with DCM demonstrated myocardial insulin resistance under basal and insulin-stimulated conditions. Both GLP-1-(7-36) and GLP-1-(9-36) significantly reduced (P < 0.01) LV end-diastolic pressure [GLP-1-(7-36), 28 +/- 1 to 15 +/- 2 mmHg; GLP-1-(9-36), 29 +/- 2 to 16 +/- 1 mmHg] and significantly increased (P < 0.01) the first derivative of LV pressure [GLP-1-(7-36), 1,315 +/- 81 to 2,195 +/- 102 mmHg/s; GLP-1-(9-36), 1,336 +/- 77 to 2,208 +/- 68 mmHg] and cardiac output [GLP-1-(7-36), 1.5 +/- 0.1 to 1.9 +/- 0.1 l/min; GLP-1-(9-36), 2.0 +/- 0.1 to 2.4 +/- 0.05 l/min], whereas an equivolume infusion of saline had no effect. Both peptides increased myocardial glucose uptake but without a significant increase in plasma insulin. During the GLP-1-(9-36) infusion, negligible active (NH2-terminal) peptide was measured in the plasma. In conclusion, in DCM, GLP-1-(9-36) mimics the effects of GLP-1-(7-36) in stimulating myocardial glucose uptake and improving LV and systemic hemodynamics through insulinomimetic as opposed to insulinotropic effects. These data suggest that GLP-1-(9-36) amide is an active peptide.
Nikolaidis
Lazaros A
LA
Dept. of Medicine, Allegheny General Hospital, 320 E. North Ave., Pittsburgh, PA 15212, USA.
Elahi
Dariush
D
Shen
You-Tang
YT
Shannon
Richard P
RP
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D003243:Consciousness; D003326:Coronary Circulation / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005934:Glucagon / Q000008:administration & dosage*; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004763:Glucagon-Like Peptides / Q000008:administration & dosage*; D005947:Glucose / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage*; D010455:Peptides / Q000008:administration & dosage*; D013318:Stroke Volume / Q000187:drug effects; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000209:etiology / Q000503:physiopathology* / Q000517:prevention & control
D010446:Peptide Fragments; D010455:Peptides; C114437:glucagon-like peptide-1 (9-36)-amide; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose