Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy.
BACKGROUND
The failing heart demonstrates a preference for glucose as its metabolic substrate. Whether enhancing myocardial glucose uptake favorably influences left ventricular (LV) contractile performance in heart failure remains uncertain. Glucagon-like peptide-1 (GLP-1) is a naturally occurring incretin with potent insulinotropic effects the action of which is attenuated when glucose levels fall below 4 mmol. We examined the impact of recombinant GLP-1 (rGLP-1) on LV and systemic hemodynamics and myocardial substrate uptake in conscious dogs with advanced dilated cardiomyopathy (DCM) as a mechanism for overcoming myocardial insulin resistance and enhancing myocardial glucose uptake.


RESULTS
Thirty-five dogs were instrumented and studied in the fully conscious state. Advanced DCM was induced by 28 days of rapid pacing. Sixteen dogs with advanced DCM received a 48-hour infusion of rGLP-1 (1.5 pmol x kg(-1) x min(-1)). Eight dogs with DCM served as controls and received 48 hours of a saline infusion (3 mL/d). Infusion of rGLP-1 was associated with significant (P<0.02) increases in LV dP/dt (98%), stroke volume (102%), and cardiac output (57%) and significant decreases in LV end-diastolic pressure, heart rate, and systemic vascular resistance. rGLP-1 increased myocardial insulin sensitivity and myocardial glucose uptake. There were no significant changes in the saline control group.


CONCLUSIONS
rGLP-1 dramatically improved LV and systemic hemodynamics in conscious dogs with advanced DCM induced by rapid pacing. rGLP-1 has insulinomimetic and glucagonostatic properties, with resultant increases in myocardial glucose uptake. rGLP-1 may be a useful metabolic adjuvant in decompensated heart failure.
Department of Medicine, Allegheny General Hospital, Pittsburgh, PA 15212, USA.
Lazaros A
LA
Nikolaidis
Dariush
D
Elahi
Teresa
T
Hentosz
Aaron
A
Doverspike
Rhonda
R
Huerbin
Lee
L
Zourelias
Carol
C
Stolarski
You-tang
YT
Shen
Richard P
RP
Shannon
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D002304:Cardiac Pacing, Artificial / Q000009:adverse effects; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D003243:Consciousness; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005934:Glucagon / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D052216:Glucagon-Like Peptide 1; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D006333:Heart Failure / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D006439:Hemodynamics / Q000187:drug effects; D006946:Hyperinsulinism / Q000150:complications; D007262:Infusions, Intravenous; D007333:Insulin Resistance; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010101:Oxygen Consumption; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D011498:Protein Precursors / Q000008:administration & dosage / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism
D001786:Blood Glucose; D005227:Fatty Acids; D010446:Peptide Fragments; D011498:Protein Precursors; D011994:Recombinant Proteins; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D005947:Glucose