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

Oxyntomodulin (OXM) is a 37-amino acid peptide hormone derived from the proglucagon gene, primarily secreted by intestinal L-cells in response to nutrient ingestion [1, 2]. It functions as a natural dual agonist, activating both the glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) [2, 7]. Through GLP-1R activation, it suppresses appetite and stimulates glucose-dependent insulin secretion, while GCGR activation increases energy expenditure and promotes hepatic lipid metabolism [1, 8]. This dual mechanism makes it a highly attractive therapeutic target for metabolic disorders, as the energy-burning effects of glucagon complement the calorie-reducing effects of GLP-1 [7, 9]. Synthetic analogs of oxyntomodulin are currently being developed to treat obesity and type 2 diabetes, aiming to achieve superior weight loss compared to selective GLP-1 agonists while maintaining glycemic control [4, 6]. Additionally, its role in increasing energy expenditure and liver fat reduction has led to investigations for its use in treating metabolic dysfunction-associated steatotic liver disease (MASLD) [4, 10]. Clinical trials have demonstrated that oxyntomodulin-based therapies can significantly reduce body weight and improve metabolic profiles in patients with obesity [2, 5]. However, the development of these drugs requires careful balancing of the two receptor activities to maximize efficacy while minimizing potential side effects like hyperglycemia or increased heart rate [7, 8].

Other names

OxyntomodulinOXMGlucagon-37EnteroglucagonProglucagon (33-69)

Dual agonism of the Glucagon receptor (GCGR) and Glucagon-like peptide 1 receptor (GLP-1R)