Glucagon is a 29-amino-acid peptide hormone. α cells of the pancreatic islets make it from proglucagon with the help of the enzyme PC2 [1][3]. Its classic role is described as the opposite of insulin: it protects the body from low glucose.
Receptor and effects
Glucagon acts through the GCGR receptor (G protein Gs), mostly on hepatocytes. In the liver it triggers glycogen breakdown and gluconeogenesis, and blood glucose rises [1][2]. Glucagon secretion climbs at low glucose and during fasting, while insulin and GLP-1 restrain it [4].
Work in recent years shows a wider picture. Glucagon raises amino acid catabolism, fat oxidation and energy expenditure, and in experiments it lowers food intake [1][3]. These effects drew attention to the receptor as an additional target.
Glucagon and diabetes
Excess glucagon and a disordered α-cell response are treated as a separate contributor to raised glucose in type 2 diabetes [2][3]. For a long time the aim was therefore to block the receptor, not to activate it.
Why glucagon sits in triple agonists
The paradox is that co-agonist molecules combine GCGR agonism with GLP-1R and GIPR: the GLP-1 effect on appetite and glucose offsets the glucose rise from glucagon, while energy expenditure goes up. Retatrutide acts on all three receptors, and in a phase 2 trial it lowered body weight in a dose-dependent way [5][6].
Reference material. Not medical advice. The molecules mentioned are for laboratory research only (RUO).
See also: GLP-1, GIP, comparison of the three axes.