Glucagon receptor and Glucagon-like peptide 1 receptor (GCGR/GLP-1R)

The Glucagon/GLP-1 pathways represent a synergistic therapeutic approach targeting two distinct Class B G protein-coupled receptors: the Glucagon receptor (GCGR) and the Glucagon-like peptide 1 receptor (GLP-1R) [7, 14]. These pathways play complementary roles in metabolic regulation; GLP-1R activation enhances glucose-dependent insulin secretion and promotes satiety, while GCGR activation increases energy expenditure and stimulates hepatic lipid metabolism [6, 12]. Therapeutic strategies targeting both pathways simultaneously, known as dual agonism, aim to leverage the weight-loss and liver-fat-reducing benefits of glucagon while using the GLP-1 component to maintain glycemic control and counteract potential glucagon-induced hyperglycemia [7, 12]. This dual-targeting approach is a major focus in the development of next-generation treatments for obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH) [11, 12]. These agents are designed to mimic the action of oxyntomodulin, an endogenous peptide that naturally activates both receptors to regulate energy balance [12].

Other names

Glucagon/GLP-1 pathwaysGCGR/GLP-1R dual targetOxyntomodulin-like pathwaysDual GCGR/GLP-1RGlucagon receptor and Glucagon-like peptide 1 receptor

Dual agonism of the glucagon receptor (GCGR) and the glucagon-like peptide 1 receptor (GLP-1R). Activation of GLP-1R stimulates glucose-dependent insulin secretion, suppresses glucagon release, and promotes satiety. Activation of GCGR increases energy expenditure, enhances thermogenesis, and promotes hepatic lipid oxidation. The combination provides synergistic weight loss and metabolic benefits while the GLP-1 component mitigates the hyperglycemic risk of glucagon.