Glucagon (revision 3)

Glucagon is a 29-residue peptide hormone secreted by the alpha cells of the pancreatic islets and processed from proglucagon by prohormone convertase 2. Its principal physiological role is counter-regulatory: falling blood glucose stimulates its release, and it acts on hepatocytes to mobilise glycogen and increase gluconeogenesis.^[1]

Glucagon has been used clinically for decades as rescue treatment for severe hypoglycaemia and as a smooth-muscle relaxant for gastrointestinal imaging. Its more recent interest to this wiki is as a deliberate pharmacological target: agonism at the glucagon receptor increases energy expenditure and hepatic fat oxidation, and several investigational peptides combine it with GLP-1 agonism so that the glycaemic penalty is offset.^[2]

Alpha cells constitute roughly 30–40% of the human islet and are distributed throughout it rather than confined to a mantle as in rodents. Secretion is stimulated by hypoglycaemia, by adrenergic input during stress and exercise, and by amino acids — a protein meal raises both insulin and glucagon, which is teleologically sensible since the insulin response would otherwise produce hypoglycaemia.^[1]

Suppression of glucagon is mediated by several converging signals: direct glucose sensing by the alpha cell, paracrine inhibition by insulin, somatostatin and zinc from neighbouring cells, and incretin action. GLP-1 suppresses glucagon secretion; GIP, in contrast, stimulates it at euglycaemia while remaining neutral or suppressive at hyperglycaemia. This difference is one of the more interesting unresolved points in the pharmacology of dual agonists.^[3]