Source of Proglucagon

{{Infobox concept | name = Proglucagon | subtitle = Prohormone | image = peptide-chain.svg | caption = 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 = [[Glucagon-like peptide-1|GLP-1]], GLP-2, oxyntomodulin, glicentin | Brainstem = GLP-1, GLP-2 }} '''Proglucagon''' is the single precursor protein from which [[Glucagon|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 [[Enteroendocrine L cell|L cell]] and a population of neurons in the caudal brainstem.{{r|sandoval2015}} 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.{{r|holst2007}} 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 incretin agonist|dual]] and triple agonists — and why measuring "glucagon" by an antibody raised against a shared epitope has generated a long history of unreliable data.{{r|sandoval2015}} == Gene and transcript == ''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.{{r|sandoval2015}} 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.{{r|holst2007}} == Tissue-specific processing == 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.{{r|campbell2013}} 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.{{r|sandoval2015}} == Consequences for measurement == 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.{{r|holst2007}} Sandwich assays using two antibodies against opposite ends of the mature glucagon sequence, and [[Liquid chromatography-mass spectrometry|LC-MS]] methods, have improved the position substantially.{{r|wewer2014}} 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.{{r|campbell2013}} == Therapeutic exploitation of the family == Because glucagon, GLP-1 and GIP receptors share a common ancestry and their ligands share a common precursor or fold, peptides can be engineered to engage more than one. Tirzepatide engages GIP and GLP-1 receptors; [[Retatrutide|retatrutide]] adds the glucagon receptor; [[Survodutide|survodutide]] engages glucagon and GLP-1 receptors.{{r|campbell2013}} Adding glucagon-receptor agonism is counter-intuitive, since glucagon raises blood glucose. The rationale is that glucagon-receptor agonism increases energy expenditure and hepatic fat oxidation, and that concurrent GLP-1 agonism more than offsets the glycaemic penalty. The balance between the two is a dose-ratio problem rather than a binary one, and it is the principal design difficulty of the triple agonists.{{r|sandoval2015}} == References == {{reflist}} <ref name="sandoval2015">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.</ref> <ref name="holst2007">Holst JJ. "The physiology of glucagon-like peptide 1." ''Physiological Reviews'' 87(4):1409–1439 (2007). PMID 17928588.</ref> <ref name="campbell2013">Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." ''Cell Metabolism'' 17(6):819–837 (2013). PMID 23684623.</ref> <ref name="wewer2014">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.</ref> == External links == * [https://www.ncbi.nlm.nih.gov/gene/2641 GCG — Gene entry] — NCBI Gene record for the proglucagon gene. == See also == * [[Glucagon]] * [[Glucagon-like peptide-1]] * [[Enteroendocrine L cell]] * [[Dual incretin agonist]] * [[Retatrutide]] {{DEFAULTSORT:Proglucagon}} [[Category:Incretin biology]] [[Category:Compounds and pharmacology]] [[Category:Gastrointestinal physiology]]