Proglucagon (revision 18)
Old revision·11:21, 2 Mar 2025·IpamorelinIsold
| ProglucagonProhormone | |
|---|---|
A single 160-residue precursor yielding different products in pancreatic and intestinal tissue. | |
| Gene | GCG |
| Length | 160 residues (preproglucagon 180) |
| Processing enzymes | Prohormone convertase 1/3 and 2 |
| Principal products | |
| Pancreatic alpha cell | Glucagon, glicentin-related pancreatic polypeptide |
| Intestinal L cell | GLP-1, GLP-2, oxyntomodulin, glicentin |
| Brainstem | GLP-1, GLP-2 |
| Topic infobox · conventions | |
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]
Gene and transcript
[edit]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]
Tissue-specific processing
[edit]Processing is directed by which prohormone convertase is expressed.
| Tissue | Dominant convertase | Principal products |
|---|---|---|
| Pancreatic alpha cell | PC2 | Glucagon, GRPP, major proglucagon fragment |
| Intestinal L cell | PC1/3 | GLP-1, GLP-2, oxyntomodulin, glicentin |
| Caudal brainstem | PC1/3 | GLP-1, GLP-2 |
The boundaries are not absolute. Alpha cells upregulate PC1/3 under metabolic stress and can secrete GLP-1 directly, a phenomenon described in islets from donors with type 2 diabetes and in rodent models of beta-cell injury. The physiological importance of islet-derived GLP-1 in humans is debated; the quantities are small relative to intestinal secretion but are delivered locally, where concentration at the receptor may matter more than circulating concentration.[3]
Oxyntomodulin, a 37-residue product of L-cell processing, is a weak agonist at both the glucagon receptor and the GLP-1 receptor. It is the natural template for the dual glucagon/GLP-1 agonists now in development, and its existence is why such a molecule was thought plausible in the first place.[1]
Consequences for measurement
[edit]Immunoassays for the products of proglucagon are notoriously cross-reactive. Antisera raised against the C-terminus of glucagon detect glicentin and oxyntomodulin, both of which contain the glucagon sequence; assays raised against the N-terminus detect the major proglucagon fragment. Reported fasting glucagon concentrations vary several-fold between published methods.[2]
Sandwich assays using two antibodies against opposite ends of the mature glucagon sequence, and LC-MS methods, have improved the position substantially.[4] Any comparison of glucagon data across studies should establish which assay was used before the numbers are treated as commensurable — this is a frequent source of apparent contradiction in the incretin literature.[3]
See also
References
- ^ a b c d Sandoval DA, D'Alessio DA. "Physiology of proglucagon peptides: role of glucagon and GLP-1 in health and disease." Physiological Reviews 95(2):513–548 (2015). DOI:10.1152/physrev.00013.2014. PMID 25834231.
- ^ a b c Holst JJ. "The physiology of glucagon-like peptide 1." Physiological Reviews 87(4):1409–1439 (2007). PMID 17928588.
- ^ a b Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." Cell Metabolism 17(6):819–837 (2013). PMID 23684623.
- ^ Wewer Albrechtsen NJ, Hartmann B, Veedfald S, et al. "Hyperglucagonaemia analysed by glucagon sandwich ELISA: nonspecific interference or truly elevated levels?" Diabetologia 57(9):1919–1926 (2014). DOI:10.1007/s00125-014-3283-z. PMID 24891019.