Targeting the glucagon receptor improves cardiac function and enhances insulin sensitivity following a myocardial infarction

Abstract

BackgroundIn heart failure the myocardium becomes insulin resistant which negatively influences cardiac energy metabolism and function, while increasing cardiac insulin signalling improves cardiac function and prevents adverse remodelling in the failing heart. Glucagon’s action on cardiac glucose and lipid homeostasis counteract that of insulin’s action. We hypothesised that pharmacological antagonism of myocardial glucagon action, using a human monoclonal antibody (mAb A) against glucagon receptor (GCGR), a G-protein\xa0coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI).MethodsMale C57BL/6 mice were subjected to a permanent left anterior descending coronary artery ligation to induce MI, following which they received either saline or mAb A (4\xa0mg\xa0kg−1\xa0week−1 starting at 1\xa0week post-MI) for 3\xa0weeks.ResultsEchocardiographic assessment at 4\xa0weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0\u2009±\u20092.3% vs 30.7\u2009±\u20091.7% in vehicle-treated MI heart, p\u2009<\u20090.05) and limited adverse remodelling (LV mass: 129\u2009±\u20097 vs 176\u2009±\u200914\xa0mg in vehicle-treated MI hearts, p\u2009<\u20090.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661\u2009±\u2009192 vs 924\u2009±\u2009165\xa0nmol\xa0g dry wt−1\xa0min−1 in vehicle-treated MI hearts, p\u2009<\u20090.05), concomitant with a decrease in ketone oxidation and fatty acid oxidation rates. The increase in insulin stimulated glucose oxidation was accompanied by activation of the IRS-1/Akt/AS160/GSK-3β pathway, an increase in GLUT4 expression and a reduction in pyruvate dehydrogenase phosphorylation. This enhancement in insulin sensitivity occurred in parallel with a reduction in cardiac branched chain amino acids content (374\u2009±\u200927 vs 183\u2009±\u200941\xa0µmol\xa0g protein−1 in vehicle-treated MI hearts, p\u2009<\u20090.05) and inhibition of the mTOR/P70S6K hypertrophic signalling pathway. The MI-induced increase in the phosphorylation of transforming growth factor β-activated kinase 1 (p-TAK1) and p38 MAPK was also reduced by mAb A treatment.ConclusionsmAb A-mediated cardioprotection post-myocardial infarction is associated with improved insulin sensitivity and a selective enhancement of glucose oxidation via, at least in part, enhancing branched chain amino acids catabolism. Antagonizing glucagon action represents a novel and effective pharmacological intervention to alleviate cardiac dysfunction and adverse remodelling post-myocardial infarction.