Albiglutide, a Long Lasting Glucagon-Like Peptide-1 Analog, Protects the Rat Heart against Ischemia/Reperfusion Injury: Evidence for Improving Cardiac Metabolic Efficiency

BACKGROUND: The cardioprotective effects of glucagon-like peptide-1 (GLP-1) and analogs have been previously reported. We tested the hypothesis that albiglutide, a novel long half-life analog of GLP-1, may protect the heart against I/R injury by increasing carbohydrate utilization and improving cardiac energetic efficiency. METHODS/PRINCIPAL FINDINGS: Sprague-Dawley rats were treated with albiglutide and subjected to 30 min myocardial ischemia followed by 24 h reperfusion. Left ventricle infarct size, hemodynamics, function and energetics were determined. In addition, cardiac glucose disposal, carbohydrate metabolism and metabolic gene expression were assessed. Albiglutide significantly reduced infarct size and concomitantly improved post-ischemic hemodynamics, cardiac function and energetic parameters. Albiglutide markedly increased both in vivo and ex vivo cardiac glucose uptake while reducing lactate efflux. Analysis of metabolic substrate utilization directly in the heart showed that albiglutide increased the relative carbohydrate versus fat oxidation which in part was due to an increase in both glucose and lactate oxidation. Metabolic gene expression analysis indicated upregulation of key glucose metabolism genes in the non-ischemic myocardium by albiglutide. CONCLUSION/SIGNIFICANCE: Albiglutide reduced myocardial infarct size and improved cardiac function and energetics following myocardial I/R injury. The observed benefits were associated with enhanced myocardial glucose uptake and a shift toward a more energetically favorable substrate metabolism by increasing both glucose and lactate oxidation. These findings suggest that albiglutide may have direct therapeutic potential for improving cardiac energetics and function

Cardiac glucose metabolism <i>in vivo</i> and <i>ex vivo</i>.

<p>Cardiac [³H]-2-deoxyglucose uptake was examined <i>in vivo</i> over a 30 min period (A). Additionally, cardiac glucose uptake (B), lactate production (C) and tissue lactate concentration (D) were measured directly in the Langendorff perfused hearts. Values are presented as mean ± SEM. *p<0.05 vs. vehicle.</p

Infarct size, ischemic area and hemodynamics in rats following 3 days of albiglutide administration.

<p>Data are presented as mean ± SEM, n = 8–10 per group.</p><p>*p<0.01 vs. vehicle;</p><p>†p<0.05 vs. vehicle.</p

Effect of albiglutide on metabolic gene transcriptional changes in the heart.

<p>Gene transcription regulation in albiglutide vs. vehicle treated hearts. Data are presented as fold change vs. vehicle, n = 8 per group.</p

Principal Component Analysis of metabolic genes.

<p>Principal Component Analysis of the gene expression data collected from normal and ischemia injured heart samples was performed and presented for normal hearts (A) and area at risk hearts following 30 min myocardial ischemia and 24 h reperfusion (B) and area not at risk hearts from the same animals (C).</p

Lactate disposition <i>ex vivo</i>.

<p>Net lactate efflux across the heart during a 30 min perfusion period using a 1 mM 3-¹³C lactate precursor (A), cardiac tissue lactate concentration (B), and relative lactate oxidation as reflected by increased glutamate labeling (C). Values are presented as mean ± SEM. *p<0.05 vs. vehicle.</p

Cardiac function and high energy metabolites following myocardial ischemia/reperfusion injury.

<p>LV ejection fraction (A) and LV end systolic volume (B) were assessed by MRI immediately following the ³¹P MRS measurement at 24 h post-reperfusion. A voxel (15.8×11×17 mm) was orthogonally positioned in all 3 scout image planes of the heart and representative ³¹P MRS spectra from sham, vehicle- and albiglutide-treated hearts are presented with the prominent high-energy phosphate peaks visible (i.e., γ-ATP at −2.4 ppm, α-ATP at −7.5 ppm, β-ATP at −16 ppm, PCr at 0 ppm, intracellular inorganic phosphate (P_i(in)) at 4.9 ppm, and extracellular inorganic phosphate (P_i(ex)) at 5.1 ppm) (C). The resulting PCr/ATP ratio (D) PCr/Pi ratio (E) and cellular pH (F) are shown. Absolute whole heart ATP and PCr concentrations are shown in (G) and (H). Values are presented as mean ± SEM. *p<0.001, ^‡p<0.01 and ^§p<0.05 vs. sham; ^†p<0.01 and ^IIp<0.05 vs. vehicle.</p

Clinical chemistry profile in rats following 3 days of albiglutide administration.

<p>Data are presented as mean ± SEM, n = 8–10 per group.</p><p>*p<0.01 vs. vehicle;</p><p>†p<0.05 vs.vehicle.</p