Glucagon (revision 17)
Old revision·11:44, 8 May 2025·FreightFenna
| GlucagonPancreatic hormone | |
|---|---|
| Source | Pancreatic islet alpha cell |
| Precursor | Proglucagon (gene GCG) |
| Receptor | Glucagon receptor (GCGR), class B GPCR |
| Molecular data | |
| Residues | 29 |
| Molecular formula | C153H225N43O49S |
| Monoisotopic mass | ≈3,483 Da |
| Plasma half-life | 4–6 minutes |
| Principal actions | |
| Liver | Glycogenolysis, gluconeogenesis |
| Adipose | Lipolysis |
| Whole body | Increased energy expenditure |
| Compound infobox · conventions | |
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]
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.[1]
Secretion and its control
[edit]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]
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
[edit]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 Gs; hepatic cAMP activates protein kinase A, which phosphorylates glycogen phosphorylase kinase and the transcriptional machinery driving gluconeogenic gene expression.[1]
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.[2]
Therapeutic use as an agonist target
[edit]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.[2]
The obstacle is that the same agonism raises blood glucose. The design solution is a fixed intramolecular ratio: retatrutide engages GIP, GLP-1 and glucagon receptors; 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.[2]
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). PMID 25834231.
- ^ a b c d 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.
- ^ Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." Cell Metabolism 17(6):819–837 (2013). PMID 23684623.