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

• Published in: Cardiovascular diabetology 2019-01, Vol.18 (1), p.1-1, Article 1
• Main Authors: Karwi, Qutuba G, Zhang, Liyan, Wagg, Cory S, Wang, Wang, Ghandi, Manoj, Thai, Dung, Yan, Hai, Ussher, John R, Oudit, Gavin Y, Lopaschuk, Gary D
• Format: Article
• Language: English
• Subjects: AKT protein; Amino acids; Animals; Antibodies, Monoclonal - pharmacology; Blood Glucose - drug effects; Blood Glucose - metabolism; Branched chain amino acids; Cardiac function; Catabolism; Chain branching; Coronary artery; Dehydrogenases; Diabetes; Disease Models, Animal; Ejection; Energy; Energy metabolism; Energy Metabolism - drug effects; Eutrophication; Fatty acids; G protein-coupled receptors; Glucagon; Glucose; Glucose oxidation; Heart attacks; Heart diseases; Heart failure; Homeostasis; Infarction; Insulin; Insulin receptor substrate 1; Insulin Resistance; Insulin sensitivity; Insulin signalling; Isolated Heart Preparation; Kinases; Male; MAP kinase; Metabolism; Mice, Inbred C57BL; Monoclonal antibodies; Myocardial infarction; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Myocardium; Myocardium - metabolism; Original Investigation; Oxidation; Peptides; Phosphorylation; Proteins; Pyruvic acid; Receptors, Glucagon - antagonists & inhibitors; Receptors, Glucagon - metabolism; Recovery of Function; Sensitivity; Signal transduction; Signal Transduction - drug effects; Stroke Volume - drug effects; TAK1 protein; TOR protein; Transforming growth factor; Transforming growth factor-b; Ventricular Function, Left - drug effects; Ventricular Remodeling - drug effects
• ISSN: 1475-2840; 1475-2840
• DOI: 10.1186/s12933-019-0806-4

In 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 coupled receptor, will enhance insulin sensitivity and improve cardiac energy metabolism and function post myocardial infarction (MI). Male 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 mg kg  week starting at 1 week post-MI) for 3 weeks. Echocardiographic assessment at 4 weeks post-MI showed that mAb A treatment improved % ejection fraction (40.0 ± 2.3% vs 30.7 ± 1.7% in vehicle-treated MI heart, p