A new role for glucagon: from secondary hormone to key player

Background and aims: In the years immediately after its discovery, glucagon was considered only as an “antidote” for the treatment of insulin-induced hypoglycemia. The advent of specific radioimmunoassay (RIA) techniques has enabled a better understanding of glucagon's role, revealing its close connection with the pathogenesis of diabetes mellitus. This review briefly summarizes the studies regarding the pathophysiology of glucagon and its different therapeutic implications in metabolic disorders. Data synthesis: A comprehensive literature search was conducted utilizing PubMed and Scopus, employing the keywords “glucagon”, “insulin”, “glucose counterregulation”, and “diabetes mellitus”. This search was restricted to studies published within the past fifteen years, without imposing limitations on study types. However, we mention certain historical aspects of the discovery of glucagon. In type 1 diabetes mellitus, research has concentrated on glucagon's role as a direct counterregulatory hormone to insulin, and on delineating the condition of “glucagon excess” in absolute insulin deficiency, considered a critical factor in the onset of diabetic ketoacidosis (DKA). Conversely, in type 2 diabetes mellitus, research has transitioned from glucagon antagonism to the “paradoxical” activity of glucagon agonism, given its potential positive effects on energy consumption. This has facilitated the development of incretin-based molecules with multi-receptor action, demonstrating significant clinical efficacy in glycemic control, weight loss, and hepatic fat diminution. Conclusions: This review highlights the fundamental role of glucagon in the pathogenesis of diabetes mellitus and its significant therapeutic implications, based on recent research findings.