Frontiers in Endocrinology · Oct 30, 2026
Advances in the Molecular Pharmacology of Glucagon Receptor Agonism in Treating Obesity and Diabetes
By Aaron Novikoff, Timo D. Müller
Glucagon receptor pharmacology has developed into an increasingly important field in the treatment of obesity and type 2 diabetes. Despite the canonical hyperglycemic liability of acute glucagon action, studies of chronic agonism in both rodents and humans have revealed therapeutically relevant increases in energy expenditure and suppression of food intake, positioning glucagon as an independent but complementary strategy to incretin receptor agonism. The development of optimized, long-acting glucagon analogues has enabled robust mechanistic interrogation of these effects, with both historical and contemporary studies implicating cyclic AMP (cAMP) signaling dynamics as a primary mediator of glucagon efficacy. Early efforts to define glucagon structure-activity relationships and develop peptide-based (ant)agonists also provided the first insights into the potential fine-tuning of receptor activity via partial or biased agonism, a concept surprisingly inherent to current clinically relevant polyagonists. In parallel, differing strategies to incorporate glucagon activity into unimolecular polyagonists have highlighted structure-function approaches aimed at optimizing glucagon receptor engagement and limiting unintended effects, while the continued maturation of glucagon pharmacotherapy and peptide chemistry further expands the rationale for exploring novel receptor and signaling cascade co-targets. In this review, we summarize the mechanistic and pharmacological developments within the landscape of glucagon-based therapeutics, with particular emphasis on receptor signaling, metabolic biology, and the therapeutic application in obesity and diabetes.