The molecular pharmacology of glucagon agonists in diabetes and obesity

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2023-07, Vol.165, p.171003, Article 171003
• Main Authors: Novikoff, Aaron, Müller, Timo D.
• Format: Article
• Language: English
• Subjects: Animals; Biased agonism; Diabetes; Diabetes Mellitus, Type 2 - drug therapy; Dual-agonists; energy expenditure; food intake; Glucagon; Glucagon - agonists; Glucagon - therapeutic use; glucagon receptors; Glucagon-Like Peptide 1 - metabolism; half life; Humans; Mice; noninsulin-dependent diabetes mellitus; Obesity; Obesity - drug therapy; Obesity - metabolism; Pharmacology; Receptors, Glucagon - metabolism; solubility; therapeutics; Tri-agonists
• ISSN: 0196-9781; 1873-5169; 1873-5169
• DOI: 10.1016/j.peptides.2023.171003

Within recent decades glucagon receptor (GcgR) agonism has drawn attention as a therapeutic tool for the treatment of type 2 diabetes and obesity. In both mice and humans, glucagon administration enhances energy expenditure and suppresses food intake suggesting a promising metabolic utility. Therefore synthetic optimization of glucagon-based pharmacology to further resolve the physiological and cellular underpinnings mediating these effects has advanced. Chemical modifications to the glucagon sequence have allowed for greater peptide solubility, stability, circulating half-life, and understanding of the structure-function potential behind partial and “super”-agonists. The knowledge gained from such modifications has provided a basis for the development of long-acting glucagon analogues, chimeric unimolecular dual- and tri-agonists, and novel strategies for nuclear hormone targeting into glucagon receptor-expressing tissues. In this review, we summarize the developments leading toward the current advanced state of glucagon-based pharmacology, while highlighting the associated biological and therapeutic effects in the context of diabetes and obesity. •GcgR agonism facilitates anti-obesogenic effects despite hyperglycemic properties.•Intracellular GcgR activity is primarily Gαs coupled and moderated by many intracellular factors.•Gcg analogue development is optimized from chemical and biological endpoints.•Partial, super, and biased Gcg analogues have not been extensively explored in vivo.•Unimolecular dual-/tri-agonist and Gcg-hormone conjugates are promising therapeutic horizons.