title: GLP-1 (7-36) amide restores myocardial insulin sensitivity and prevents the progression of heart failure in senescent beagles.
abstract: BACKGROUND
  We previously demonstrated that older beagles have impaired whole body and myocardial insulin responsiveness (MIR), and that glucagon-like peptide-1 (GLP-1 [7-36] amide) improves MIR in young beagles with dilated cardiomyopathy (DCM). Here, we sought to determine if aging alone predisposes to an accelerated course of DCM, and if GLP-1 [7-36] amide would restore MIR and impact the course of DCM in older beagles.
  
  
  METHODS
  Eight young beagles (Young-Control) and sixteen old beagles underwent chronic left ventricle (LV) instrumentation. Seven old beagles were treated with GLP-1 (7-36) amide (2.5 pmol/kg/min) for 2 weeks prior to instrumentation and for 35 days thereafter (Old + GLP-1), while other 9 served as control (Old-Control). All dogs underwent baseline metabolic determinations and LV biopsy for mitochondria isolation prior to the development of DCM induced by rapid pacing (240 min-1). Hemodynamic measurements were performed routinely as heart failure progressed.
  
  
  RESULTS
  At baseline, all old beagles had elevated non-esterifed fatty acids (NEFA), and impaired MIR. GLP-1 reduced plasma NEFA (Old-Control: 853 ± 34; Old + GLP-1: 531 ± 33 μmol/L, p < 0.02), improved MIR (Old-Control: 289 ± 54; Old + GLP-1: 512 ± 44 mg/min/100 mg, p < 0.05), and increased uncoupling protein-3 (UCP-3) expression in isolated mitochondria. Compared to the Young-Control, the Old-Controls experienced an accelerated course of DCM (7 days versus 29 days, p < 0.005) and excess mortality, while the Old + GLP-1 experienced increased latency to the onset of DCM (7 days versus 23 days, p < 0.005) and reduced mortality.
  
  
  CONCLUSIONS
  Aging is associated with myocardial insulin resistance, which predispose to an accelerated course of DCM. GLP-1 treatment is associated with increased MIR and protection against an accelerated course of DCM in older beagles.
authors: Melissa
authors: M
authors: Chen
authors: Franca S
authors: FS
authors: Angeli
authors: You-Tang
authors: YT
authors: Shen
authors: Departments of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. rs3mt@virginia.edu.
authors: Richard P
authors: RP
authors: Shannon
mesh_terms: D000375:Aging / Q000097:blood* / Q000187:drug effects / Q000473:pathology; D000818:Animals; D002316:Cardiotonic Agents / Q000008:administration & dosage; D018450:Disease Progression; D004285:Dogs; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage*; D006333:Heart Failure / Q000097:blood* / Q000473:pathology / Q000517:prevention & control*; D007262:Infusions, Intravenous; D007333:Insulin Resistance / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000008:administration & dosage*; D011897:Random Allocation
chemical_list: D002316:Cardiotonic Agents; D010446:Peptide Fragments; C055453:glucagon-like peptide 1 (7-36)amide; D052216:Glucagon-Like Peptide 1