Source of Glucagon

{{Infobox compound | name = Glucagon | subtitle = Pancreatic hormone | image = peptide-chain.svg | Source = Pancreatic islet alpha cell | Precursor = [[Proglucagon]] (gene GCG) | Receptor = Glucagon receptor (GCGR), class B GPCR <!-- Molecular data --> | Residues = 29 | Molecular formula = {{math|C_{153}H_{225}N_{43}O_{49}S}} | Monoisotopic mass = ≈3,483 Da | Plasma half-life = 4–6 minutes <!-- Principal actions --> | Liver = Glycogenolysis, gluconeogenesis | Adipose = Lipolysis | Whole body = Increased energy expenditure }} {{hatnote|For the precursor from which glucagon is derived, see [[Proglucagon]].}} '''Glucagon''' is a 29-residue peptide hormone secreted by the alpha cells of the pancreatic islets and processed from [[Proglucagon|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.{{r|sandoval2015}} Glucagon has been used clinically for decades as rescue treatment for severe [[Hypoglycaemia|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 receptor agonist|GLP-1 agonism]] so that the glycaemic penalty is offset.{{r|coskun2022}} Hyperglucagonaemia is a feature of type 2 diabetes and contributes to fasting hyperglycaemia through unrestrained hepatic glucose output. Suppression of glucagon secretion is one of the mechanisms by which incretin-based therapies lower fasting glucose, and it is glucose-dependent — suppression relaxes as glucose falls, which is part of why those therapies do not by themselves cause hypoglycaemia.{{r|sandoval2015}} == Secretion and its control == 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.{{r|sandoval2015}} 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.{{r|campbell2013}} In type 1 diabetes the alpha-cell response to hypoglycaemia is lost early, which removes the first line of defence against insulin-induced hypoglycaemia and is a principal reason that condition is harder to manage than the pathophysiology alone would suggest. == Receptor and signalling == The glucagon receptor is a class B GPCR with the same two-domain architecture as the [[GLP-1 receptor]] and roughly 45% sequence identity to it in the transmembrane region. It couples principally to G_s; hepatic cAMP activates protein kinase A, which phosphorylates glycogen phosphorylase kinase and the transcriptional machinery driving gluconeogenic gene expression.{{r|sandoval2015}} The receptor relatedness is what makes multi-receptor agonism chemically tractable, and it also makes selectivity a design constraint rather than a given: an unmodified glucagon analogue has appreciable activity at the GLP-1 receptor and vice versa. Reported potency ratios for the multi-receptor peptides are assay-dependent and should be compared only within a single publication's system.{{r|coskun2022}} == Therapeutic use as an agonist target == Chronic glucagon-receptor agonism increases resting energy expenditure by an amount that is modest in absolute terms — figures in the region of 3–8% appear in early-phase work — and increases hepatic fatty-acid oxidation, reducing liver fat. Both are desirable in obesity and in metabolic liver disease.{{r|coskun2022}} The obstacle is that the same agonism raises blood glucose. The design solution is a fixed intramolecular ratio: [[Retatrutide|retatrutide]] engages GIP, GLP-1 and glucagon receptors; [[Survodutide|survodutide]] engages glucagon and GLP-1 receptors; efinopegdutide engages glucagon and GLP-1 receptors with a different balance and has been studied principally for hepatic fat. In each case the GLP-1 component is dosed sufficiently to dominate the net glycaemic effect. Reported weight loss with the triple agonist at the highest doses studied exceeds that reported for GLP-1 monotherapy, though cross-trial comparison of this kind is unreliable and the programmes differ in population, duration and escalation schedule.{{r|coskun2022}} == Formulation and stability == Glucagon is a notoriously difficult peptide to formulate. At neutral pH it aggregates rapidly into amyloid-like fibrils, so the traditional rescue product was supplied as a lyophilised powder with an acidic diluent for reconstitution immediately before use — an arrangement poorly suited to an emergency.{{r|usp1503}} Non-aqueous and analogue-based ready-to-use formulations have since been introduced. The fibrillation behaviour is a useful reference point for anyone handling research peptides. [[Peptide aggregation|Aggregation]] is not a rare failure mode; it is the expected behaviour of a hydrophobic peptide held near its isoelectric point at concentration, and a solution that has gone faintly hazy after [[Reconstitution of lyophilised peptides|reconstitution]] should be treated as changed material rather than as a cosmetic problem.{{r|usp1503}} == 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). PMID 25834231.</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="coskun2022">Coskun T, Urva S, Roell WC, et al. "LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss." ''Cell Metabolism'' 34(9):1234–1247 (2022). DOI:10.1016/j.cmet.2022.07.013. PMID 35985340.</ref> <ref name="usp1503">United States Pharmacopeia, General Chapter <1503>, ''Quality Attributes of Synthetic Peptide Drug Substances''.</ref> == See also == * [[Proglucagon]] * [[Glucagon-like peptide-1]] * [[Retatrutide]] * [[Survodutide]] * [[Peptide aggregation]] * [[Hypoglycaemia]] {{DEFAULTSORT:Glucagon}} [[Category:Peptide drugs]] [[Category:Incretin biology]] [[Category:Compounds and pharmacology]]