Glucagon-like peptide-1 (revision 25)
Old revision·00:10, 12 Oct 2024·HalfLifeHavel
| Glucagon-like peptide-1 | |
|---|---|
Schematic of the GLP-1 (7–36) amide backbone. Residue identities are indicative only. | |
| Abbreviation | GLP-1 |
| Precursor | Proglucagon (gene GCG) |
| Principal source | Intestinal L cells |
| Molecular data | |
| Active forms | GLP-1 (7–37) and GLP-1 (7–36) amide |
| Residues | 31 (7–37) / 30 (7–36 amide) |
| Monoisotopic mass | ≈3,297 Da (7–36 amide) |
| Sequence position | Proglucagon 78–107 |
| Topic infobox · conventions | |
Glucagon-like peptide-1 (GLP-1) is a 30- or 31-residue peptide hormone released from enteroendocrine L cells of the distal small intestine and colon in response to nutrient ingestion. It is one of the two principal incretin hormones, the other being Glucose-dependent insulinotropic polypeptide (GIP).[1]
GLP-1 is generated by tissue-specific post-translational processing of proglucagon, the same precursor that yields glucagon in pancreatic alpha cells. In the intestine, prohormone convertase 1/3 liberates GLP-1 (7–37) and its C-terminally amidated form GLP-1 (7–36) amide, the latter accounting for the majority of circulating immunoreactive GLP-1 in humans.[2]
Its principal actions are glucose-dependent potentiation of insulin secretion, suppression of glucagon release, deceleration of gastric emptying and reduction of food intake through central satiety pathways.[1][3] Because the native hormone is inactivated within minutes by dipeptidyl peptidase-4, therapeutic exploitation of the pathway has depended on engineered analogues with extended half-lives — the GLP-1 receptor agonists — rather than on the hormone itself.[4]
Discovery and nomenclature
[edit]The existence of a gut-derived insulin secretagogue was inferred long before any such molecule was isolated: oral glucose was observed to provoke a substantially larger insulin response than an intravenous glucose load producing the same glycaemic excursion, a difference termed the incretin effect.[5]
Cloning of the proglucagon gene in the early 1980s revealed two glucagon-like sequences downstream of glucagon itself, designated glucagon-like peptide-1 and glucagon-like peptide-2. The full-length GLP-1 (1–37) proved to be biologically inert; N-terminal truncation to GLP-1 (7–37) yielded a potent insulinotropic peptide.[6] Physiological activity in humans was demonstrated shortly afterwards by infusion studies showing marked, glucose-dependent insulin release.[7]
The residue numbering convention retained in the literature is that of the full-length peptide, which is why the active species is conventionally written GLP-1 (7–36) amide rather than renumbered from its own N-terminus. This is a persistent source of confusion in secondary sources, and articles on this wiki follow the conventional numbering.
Biosynthesis and secretion
[edit]Proglucagon is encoded by a single gene (GCG) and is processed differently in different tissues. In pancreatic alpha cells, prohormone convertase 2 predominates and glucagon is the principal product. In intestinal L cells and in some neurons of the caudal brainstem, prohormone convertase 1/3 predominates and the products are GLP-1, GLP-2 and the glicentin-related fragments.[2]
L cells are open-type epithelial cells whose apical surface contacts the lumen, giving them direct access to nutrient stimuli. Secretion is biphasic: an early rise within 10–15 minutes of ingestion, attributed partly to neural and endocrine relay from the proximal gut, followed by a later phase as nutrients reach the ileum and colon.[1]
| Stimulus class | Examples | Relative potency |
|---|---|---|
| Carbohydrate | Glucose, sucrose | Moderate |
| Lipid | Long-chain fatty acids, monoacylglycerols | High |
| Protein | Peptones, specific amino acids | Moderate to high |
| Bile acids | Deoxycholate via TGR5 | Moderate |
| Short-chain fatty acids | Products of colonic fermentation | Low to moderate |
Reported fasting concentrations of total GLP-1 in healthy adults are of the order of 5–10 pmol/L, rising several-fold postprandially; absolute values differ substantially between assays, and cross-study comparison of concentrations is generally unsafe.[1]
Inactivation and clearance
[edit]GLP-1 is cleaved between residues 8 and 9 by dipeptidyl peptidase-4, a widely expressed serine exopeptidase present both as a membrane protein on endothelium and as a soluble plasma form. The resulting GLP-1 (9–36) amide is at best weakly active at the GLP-1 receptor and has historically been regarded as an inactive metabolite, although a degree of independent cardiovascular activity has been proposed.[8]
References
- ^ a b c d Holst JJ. "The physiology of glucagon-like peptide 1." Physiological Reviews 87(4):1409–1439 (2007). DOI:10.1152/physrev.00034.2006. PMID 17928588.
- ^ a b Baggio LL, Drucker DJ. "Biology of incretins: GLP-1 and GIP." Gastroenterology 132(6):2131–2157 (2007). DOI:10.1053/j.gastro.2007.03.054. PMID 17498508.
- ^ Drucker DJ. "Mechanisms of action and therapeutic application of glucagon-like peptide-1." Cell Metabolism 27(4):740–756 (2018). DOI:10.1016/j.cmet.2018.03.001. PMID 29617641.
- ^ Nauck MA, Meier JJ. "Incretin hormones: their role in health and disease." Diabetes, Obesity and Metabolism 20(Suppl 1):5–21 (2018). DOI:10.1111/dom.13129. PMID 29364588.
- ^ Nauck M, Stöckmann F, Ebert R, Creutzfeldt W. "Reduced incretin effect in type 2 (non-insulin-dependent) diabetes." Diabetologia 29(1):46–52 (1986). PMID 3514343.
- ^ Holst JJ, Ørskov C, Nielsen OV, Schwartz TW. "Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut." FEBS Letters 211(2):169–174 (1987). PMID 3542566.
- ^ Kreymann B, Williams G, Ghatei MA, Bloom SR. "Glucagon-like peptide-1 7–36: a physiological incretin in man." The Lancet 2(8571):1300–1304 (1987). PMID 2890903.
- ^ Deacon CF, Johnsen AH, Holst JJ. "Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo." Journal of Clinical Endocrinology and Metabolism 80(3):952–957 (1995). PMID 7883856.