Glucagon in health and diabetes

Abstract For decades all attention focused on the hormone insulin as a key player in diabetes and the role of glucagon was less studied or understood. We now know that both these pancreatic hormones play a critical role in maintaining glucose homeostasis in the body and the secretion of one controls the secretion of the other in an inverse relationship as described by the bihormonal theory of Unger. Glucagon, secreted by the α-cells of the islets of pancreas is a key hormone that has a “hyperglycemic” effect and is secreted in response to low plasma glucose concentration. Besides hypoglycemia, glucagon release is also stimulated by prolonged fasting or starvation, exercise as well as consumption of protein-rich meals. It is regulated by several key endocrine and paracrine mechanisms and the autonomic system in response to various stimuli including nutrient intake through various complex neurohormonal factors. It primarily increases endogenous hepatic glucose production, stimulates lipid and protein catabolism, and plays a key role in appetite regulation and increasing energy expenditure. Therefore, glucagon functions as a counter-regulatory hormone to insulin stimulating hepatic glycogenolysis, gluconeogenesis, fatty acid oxidation, and ketogenesis. With mounting evidence, there has been a paradigm shift in the management of diabetes following the advent of new agents that address different pathophysiological mechanisms contributing to worsening hyperglycemia. Targeting the alpha-cell defect and consequent glucagon hypersecretion has therefore emerged as an important therapeutic strategy in type 2 diabetes mellitus (T2DM) management as well as body weight management. The currently available medications, including glucagon-like peptide 1 (GLP-1) receptor agonists, DPP-4 inhibitors, and amylin mimics (pramlintide), essentially focus on lowering glucagon levels and correcting this critical pathophysiological component in the multifactorial T2DM management strategies.