Role of glucagon in metabolic diseases

Currently, diabetes is defined as "a chronic hyperglycemic state resulting from the absolute or relative insufficiency of insulin action," emphasizing its characterization as an insulin-related disease. However, glucagon dysregulation should also play a critical role in the pathophysiology of type 2 diabetes. The pathophysiological relevance of glucagon in type 2 diabetes has long remained uncertain, largely owing to the lack of a reliable assay for measuring plasma glucagon concentrations. We recently developed a highly accurate glucagon sandwich enzyme-linked immunosorbent assay, demonstrating its utility in characterizing patients with type 2 diabetes and its potential for near-term clinical application. In parallel, glucagon has emerged as a promising therapeutic target. Although glucagon receptor antagonists produce potent glucose-lowering effects without increasing the risk of hypoglycemia, their clinical development has not progressed to phase 3 trials because of adverse effects, including weight gain and worsening hepatic steatosis. In contrast, we demonstrated that α-methyl D-glucopyranoside, an endogenous glucagon secretagogue, reduces body weight and improves hepatic steatosis and glucose intolerance in an obese diabetic mouse model. Furthermore, dual glucagon/glucagon-like peptide 1 (GLP-1) receptor agonists and triple glucagon/GLP-1/glucose-dependent insulinotropic polypeptide receptor agonists are currently undergoing phase 3 clinical trials for the treatment of obesity and metabolic dysfunction-associated steatotic liver disease. Taken together, glucagon plays a key role in the pathophysiology, diagnosis, and treatment of metabolic diseases.