Proglucagon (revision 7)

Proglucagon is the single precursor protein from which glucagon, Glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2, oxyntomodulin and glicentin are all derived. It is encoded by one gene, GCG, and transcribed identically in the pancreatic alpha cell, the intestinal L cell and a population of neurons in the caudal brainstem.^[1]

The products differ between those tissues because the processing enzymes do. Prohormone convertase 2 predominates in the alpha cell and liberates glucagon; prohormone convertase 1/3 predominates in the L cell and the brainstem and liberates GLP-1 and GLP-2 instead. A single transcript therefore yields a hyperglycaemic hormone in one tissue and a hypoglycaemic one in another.^[2]

This arrangement has direct therapeutic consequences. The structural relatedness of the products is why a single engineered peptide can be designed to act at two or three receptors of the family at once — the basis of the dual and triple agonists — and why measuring "glucagon" by an antibody raised against a shared epitope has generated a long history of unreliable data.^[1]

GCG lies on human chromosome 2 and comprises six exons. A single mRNA species is produced in all expressing tissues; there is no tissue-specific splicing in humans. Translation yields preproglucagon of 180 residues, from which the 20-residue signal peptide is removed co-translationally to give the 160-residue prohormone.^[1]

Transcription in the alpha cell is suppressed by insulin and by glucose, and stimulated during fasting — the arrangement expected of a counter-regulatory hormone. In the L cell, transcription responds instead to luminal nutrients and to short-chain fatty acids produced by colonic fermentation, and is comparatively insensitive to circulating glucose.^[2]