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

Abstract

BackgroundThe 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 FindingsSprague-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/SignificanceAlbiglutide 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.

Cardioprotective effects of incretin during ischaemia-reperfusion

“…31 Recently, albiglutide, another GLP-1 analogue, has been shown to increase cAMP in an ischaemic myocardium and improve cardiac metabolic efficiency by increasing glucose metabolism and reducing fat oxidation, which results in 26% reduction of infarct size. 32 In a pig model, exenatide has been shown to reduce the infarct size, 33 whereas the other two studies with a shorter period of I/R using recombinant GLP-1 (rGLP-1) 34 or liraglutide 35 could not demonstrate any improvement in infarct size (Table 2). This discrepancy could be due to a different duration and site of occlusion, therapeutic drugs and drug concentrations.…”

Mechanisms of neuroprotective action of incretin mimetics

“…Кардиопротективный эффект инкретиномиметиков был получен в ряде работ на животных моделях in vivo и ex vivo [13,14,15]. Показано, что при моделировании ишемии миокарда у крыс путем окклюзии левой перед-ней нисходящей артерии на 30 минут введение агониста рецептора ГПП-1 в дозе 1, 3 и 10 мг/кг в течение трех дней до воспроизведения ишемии дозозависимо уменьшало размер зоны некроза миокарда, улучшало параметры постишемической гемодинамики, а также потребле-ние глюкозы миокардом [13].…”

“…Показано, что при моделировании ишемии миокарда у крыс путем окклюзии левой перед-ней нисходящей артерии на 30 минут введение агониста рецептора ГПП-1 в дозе 1, 3 и 10 мг/кг в течение трех дней до воспроизведения ишемии дозозависимо уменьшало размер зоны некроза миокарда, улучшало параметры постишемической гемодинамики, а также потребле-ние глюкозы миокардом [13]. При длительном лечении ГПП-1 крыс, перенесших инфаркт миокарда, увеличи-валась фракция выброса левого желудочка, уменьша-лись конечно-систолический и конечно-диастолический объемы левого желудочка, объем левого предсердия [16].…”

Incretin Therapy and Heart Failure

“…7 Furthermore, albiglutide therapy preserves myocardial viability and reduces the production of lactate after IR injury in the rat heart. 17 The genetic deletion or chemical inhibition of DPP-4 in mice improves their cardiac function after MI by activating cell survival signaling, including that of phosphorylated Akt and pGSK3β. 18 Combined treatment of mice with granulocyte colony-stimulating factor and a DPP-4 inhibitor preserves cardiac function via enhanced stem cell mobilization and cardiomyocyte regeneration after MI.…”