The Glucagonocentric Basis of Diabetic Cardiomyopathy: Pancreas–Heart Crosstalk Linking α‐Cell Dysregulation to Cardiac Metabolic Stress and Fibrosis

Type 2 diabetes mellitus (T2DM) is increasingly recognized as a disorder of inappropriate glucagon secretion in addition to β-cell dysfunction and insulin resistance. Chronic hyperglucagonemia, driven by α-cell dysregulation, contributes directly to the development of diabetic cardiomyopathy (DCM) through hepatic, systemic, and myocardial mechanisms. Emerging evidence shows that glucagon receptor (GCGR) signaling is active in cardiomyocytes, endothelial cells, and vascular smooth muscle, where persistent activation promotes cAMP/PKA-mediated stress, calcium dysregulation, oxidative injury, and adverse remodeling. Hyperglucagonemia further exacerbates metabolic toxicity by enhancing fatty acid flux, lipotoxic intermediate accumulation, and amino-acid driven proteolysis. These changes converge on myocardial fibrosis, diastolic dysfunction, and cardiac steatosis characteristic of DCM. Therapeutic interventions that modulate glucagon biology including glucagon receptor antagonists (GRAs), GLP-1 receptor agonists, and multi-agonist incretin therapies demonstrate cardioprotective potential by restoring glucagon-insulin balance and attenuating glucagon-driven metabolic stress. This mini-review highlights mechanistic links and therapeutic implications.