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Open Access Original investigation

GLP-1 (7–36) amide restores myocardial insulin sensitivity and prevents the progression of heart failure in senescent beagles

Melissa Chen1, Franca S Angeli1, You-tang Shen1 and Richard P Shannon123*

Author Affiliations

1 Departments of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

2 Department of Medicine, University of Virginia School of Medicine, Philadelphia, PA, USA

3 University of Virginia Health System, Charlottesville, 22908, VA, USA

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Cardiovascular Diabetology 2014, 13:115  doi:10.1186/s12933-014-0115-x

Published: 31 July 2014

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.

Conclusion

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.

Keywords:
Glucagon-like pepetide-1; Dilated cardiomyopathy; Myocardial insulin resistance; Aging