GLP-1 receptor agonist: difference between revisions
Diff·revision 3 → 4·09:06, 4 Jul 2024
Difference between revision 3 and revision 4 of GLP-1 receptor agonist. 7 lines changed; the page grew by 1,146 bytes.
| Revision 3 — 20:29, 21 Jun 2024 TB500_Tarquin (talk) add the peptide length to the infobox 1,642 bytes ±0 | Revision 4 — 09:06, 4 Jul 2024 CiteBot (talk) bot: repair redlinked category 2,788 bytes +1,146 | ||
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| 10 | Native GLP-1 is unusable as a medicine because [[Dipeptidyl peptidase-4]] inactivates it within one to two minutes of secretion. Every clinically successful agonist therefore solves the same engineering problem in one of a small number of ways: substitution of the residue attacked by the protease, [[Albumin binding half-life extension|fatty-acid acylation]] that ties the molecule to serum albumin, fusion to an immunoglobulin fragment, or use of a naturally protease-resistant scaffold such as exendin-4.{{r|knudsen2019}} | 10 | Native GLP-1 is unusable as a medicine because [[Dipeptidyl peptidase-4]] inactivates it within one to two minutes of secretion. Every clinically successful agonist therefore solves the same engineering problem in one of a small number of ways: substitution of the residue attacked by the protease, [[Albumin binding half-life extension|fatty-acid acylation]] that ties the molecule to serum albumin, fusion to an immunoglobulin fragment, or use of a naturally protease-resistant scaffold such as exendin-4.{{r|knudsen2019}} |
| 11 | 11 | ||
| + | 12 | == Mechanism == | |
| + | 13 | The GLP-1 receptor is a class B G-protein-coupled receptor expressed on pancreatic beta cells, on gastric smooth muscle and enteric neurons, on cardiomyocytes, and at several sites in the central nervous system including the [[Arcuate nucleus|arcuate nucleus]] of the hypothalamus and the area postrema. Agonist binding couples principally to G<sub>s</sub>, raising intracellular cAMP.{{r|drucker2018}} | |
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| + | 15 | At the beta cell, the rise in cAMP amplifies glucose-stimulated [[Insulin secretion|insulin secretion]] without initiating it. Because the amplification requires a permissive glucose signal, agonism does not provoke insulin release at low glucose, and monotherapy carries a low intrinsic risk of [[Hypoglycaemia|hypoglycaemia]] — a property that distinguishes the class sharply from sulfonylureas.{{r|nauck2016}} | |
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| 12 | == References == | 17 | == References == |
| 13 | {{reflist}} | 18 | {{reflist}} |
| 14 | <ref name="drucker2018">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.</ref> | 19 | <ref name="drucker2018">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.</ref> |
| 15 | <ref name="knudsen2019">Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." ''Frontiers in Endocrinology'' 10:155 (2019). DOI:10.3389/fendo.2019.00155. PMID 31031702.</ref> | 20 | <ref name="knudsen2019">Knudsen LB, Lau J. "The discovery and development of liraglutide and semaglutide." ''Frontiers in Endocrinology'' 10:155 (2019). DOI:10.3389/fendo.2019.00155. PMID 31031702.</ref> |
| + | 21 | <ref name="nauck2016">Nauck MA, Meier JJ. "The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions." ''The Lancet Diabetes & Endocrinology'' 4(6):525–536 (2016). PMID 26876794.</ref> | |
| 16 | 22 | ||
| 17 | {{DEFAULTSORT:GLP-1 receptor agonist}} | 23 | {{DEFAULTSORT:GLP-1 receptor agonist}} |
| 18 | [[Category:GLP-1 receptor agonists]] | 24 | [[Category:GLP-1 receptor agonists]] |
| 19 | [[Category:Peptide drugs]] | 25 | [[Category:Peptide drugs]] |
| + | 26 | [[Category:Receptor pharmacology]] | |
| 20 | 27 |