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 coupled 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 mg kg−1 week−1 starting at 1 week post-MI) for 3 weeks.ResultsEchocardiographic 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 < 0.05) and limited adverse remodelling (LV mass: 129 ± 7 vs 176 ± 14 mg in vehicle-treated MI hearts, p < 0.05) post MI. In isolated working hearts an increase in insulin-stimulated glucose oxidation was evident in the mAb A-treated MI hearts (1661 ± 192 vs 924 ± 165 nmol g dry wt−1 min−1 in vehicle-treated MI hearts, p < 0.05), 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 ± 27 vs 183 ± 41 µmol g protein−1 in vehicle-treated MI hearts, p < 0.05) 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.
Highlights
Following a myocardial infarction (MI) adverse remodelling can occur in the non-infarcted myocardium [1]
As antagonising glucagon signalling is shown to improve insulin sensitivity of the whole body, we investigated the potential cardioprotection of mAb A, a human IgG2 monoclonal antibody against the glucagon receptor (GCGR) receptor, and whether it can enhance cardiac insulin sensitivity and, as a result, improve cardiac function post-MI
No detectable changes in tissue doppler of the mitral valve E′/A′ ratio were in seen in mAb A treated mice compared to vehicle-treated mice (Fig. 1f ), E/E′ ratio was significantly improved in the mAb A-treated MI mice (28.4 ± 2.8 mm s−1 vs 32.5 ± 2.7 mm s−1 vehicle-treated post MI mice, p < 0.05, Fig. 1g)
Summary
Following a myocardial infarction (MI) adverse remodelling can occur in the non-infarcted myocardium [1]. Cardiac insulin resistance is further aggravated in HF associated with diabetes [5, 6] While it is not clear how this cardiac insulin resistance occurs in HF, a major hallmark of cardiac insulin insensitivity is a marked reduction in mitochondrial insulin-stimulated glucose oxidation [3, 4]. This is of significance, since enhancing insulin sensitivity can effectively reduce the cardiac energy deficit and improve cardiac function in the failing heart [2, 7]. 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)
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