Glucagon-like peptide-1 (revision 71)
Old revision·22:48, 6 Dec 2025·ArcuateArt
| Glucagon-like peptide-1Endogenous incretin hormone | |
|---|---|
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 |
| Pharmacokinetics | |
| Plasma half-life | 1.5–2 minutes |
| Primary inactivation | DPP-4 cleavage at Ala8 |
| Secondary clearance | Renal; neutral endopeptidase |
| Receptor | |
| Target | GLP-1 receptor (GLP1R) |
| Receptor family | Class B secretin-like GPCR |
| Principal coupling | Gs → adenylyl cyclase → cAMP |
| 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]
The consequence is a plasma half-life of approximately 1.5–2 minutes, and an estimated 50–75% of newly secreted GLP-1 is degraded before it leaves the intestinal capillary bed. Two therapeutic strategies follow directly from this: inhibit the enzyme, which is the mechanism of the gliptin class, or engineer the peptide so that it resists the enzyme, which is the mechanism of the agonist class.[4]
Substitution at position 8 — alanine to aminoisobutyric acid in tirzepatide, or to 2-aminoisobutyric acid in several other constructs — is the most common resistance strategy, usually combined with albumin-binding acylation to slow renal clearance.
Physiological actions
[edit]- Insulinotropic action
- GLP-1 amplifies glucose-stimulated insulin secretion. The effect is strictly glucose-dependent: at euglycaemia, GLP-1 infusion produces little insulin release, which is the basis of the low intrinsic hypoglycaemia risk of the drug class in the absence of insulin or sulfonylurea co-therapy.[1]
- Glucagon suppression
- Postprandial glucagon secretion is reduced, again in a glucose-dependent manner, contributing to lower hepatic glucose output.
- Gastric emptying
- Emptying of solids and liquids is slowed, flattening postprandial glucose excursions and contributing to both satiety and the class's gastrointestinal adverse effects.[3]
- Central effects
- GLP-1 receptors in the arcuate nucleus, area postrema and nucleus tractus solitarius mediate reductions in food intake. Peripherally administered agonists reach these sites in part through regions of incomplete blood–brain barrier.
Actions on the heart, kidney, liver and immune system have all been described, and cardiovascular and renal benefit has been demonstrated for several agonists in outcome trials; the extent to which those benefits are receptor-mediated rather than secondary to weight and glycaemic change remains an open question.[3]
Impaired incretin response in disease
[edit]In type 2 diabetes the incretin effect is markedly attenuated. The dominant lesion appears to be loss of beta-cell responsiveness to GIP rather than deficient GLP-1 secretion, since pharmacological GLP-1 concentrations restore much of the insulin response whereas GIP does not.[5][4] This asymmetry is the reason the GLP-1 arm of the axis, and not the GIP arm, was pursued first as a monotherapy target — and it is also why the later demonstration that GIP co-agonism adds clinical benefit in dual agonists was regarded as surprising.
Whether GLP-1 secretion itself is reduced in obesity and type 2 diabetes has been contested for two decades; meta-analytic work suggests differences are small and heterogeneous between studies.[citation needed]
Therapeutic exploitation
[edit]The pathway is targeted clinically in three ways: degradation-resistant peptide agonists (exenatide, liraglutide, dulaglutide, semaglutide), enzyme inhibition (the DPP-4 inhibitor class), and non-peptide agonists suitable for oral administration (orforglipron). Multi-receptor constructs extend the approach to GIP (tirzepatide), glucagon (survodutide, retatrutide) and amylin (CagriSema) co-agonism.
See also
- GLP-1 receptor
- Glucose-dependent insulinotropic polypeptide
- Incretin effect
- Dipeptidyl peptidase-4
- GLP-1 receptor agonist
- Amylin
References
- ^ a b c d e 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.
- ^ a b c 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.
- ^ a b c 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.
- ^ a b 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.
Further reading
- Holst JJ. "Discovery of the GLP-1 based drugs for the treatment of diabetes and obesity." Peptides (2024) — a participant's account of the pathway from isolation to clinic.
- Campbell JE, Drucker DJ. "Pharmacology, physiology, and mechanisms of incretin hormone action." Cell Metabolism 17(6):819–837 (2013).
External links
- GCG — glucagon (gene entry) — NCBI Gene record for the proglucagon gene.