Reactome | GLP1R binds GLP1R agonists

GLP1R binds GLP1R agonists

Stable Identifier

R-HSA-9728664

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, extracellular region

ReviewStatus

5/5

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Glucagon-like peptide 1 receptor (GLP1R) is a G-protein coupled receptor for its endogenous incretin ligand glucagon-like peptide 1 (GLP1). It plays a role in the regulation of insulin secretion. GLP1R is highly expressed in pancreatic beta cells and its activation by GLP1 results in increasing insulin secretion and decreasing glucagon secretion, in a glucose dependent manner. Dipeptidyl peptidase-4 (DPP4) determines the half-life of GLP1 in the bloodstream. DPP4 cleaves two amino acids at the amino terminus of GLP1, rendering it biologically inactive.

Synthetic incretins which possess peptide structures that are more resistant to DPP4 degradation have been synthesised. They can act as GLP1R agonists (Miranda et al. 2008, Lau et al. 2015) and are used to treat type 2 diabetes mellitus (T2DM) (reviews - Holst 2004, Shaefer Jr et al. 2015, Lovshin 2017). GLP1R is also expressed in the brain where it can promote weight loss by mediating appetite suppression (Kinzig et al. 2002) and in the gastrointestinal tract where it can delay glucose absorption due to slower gastric emptying. Synthetic incretins can either be long-acting, once-weekly injectables (albiglutide, dulaglutide, semaglutide and exenatide (synthetic exendin-4)) or short-acting, once- or twice-daily injectables (lixisenatide and liraglutide).

The first GLP1R agonist exenatide is a synthetic version of exendin-4, an incretin hormone found in the saliva of the Gila monster Heloderma suspectum (Chen et al. 2006). It showed greater potency and a longer duration of action than native GLP1 when administered subcutaneously.

Literature References

PubMed ID	Title	Journal	Year
26308095	Discovery of the Once-Weekly Glucagon-Like Peptide-1 (GLP-1) Analogue Semaglutide Lau, J, Bloch, P, Schäffer, L, Pettersson, I, Spetzler, J, Kofoed, J, Madsen, K, Knudsen, LB, McGuire, J, Steensgaard, DB, Strauss, HM, Gram, DX, Knudsen, SM, Nielsen, FS, Thygesen, P, Reedtz-Runge, S, Kruse, T	J. Med. Chem.	2015
18412318	Design and synthesis of conformationally constrained glucagon-like peptide-1 derivatives with increased plasma stability and prolonged in vivo activity Miranda, LP, Winters, KA, Gegg, CV, Patel, A, Aral, J, Long, J, Zhang, J, Diamond, S, Guido, M, Stanislaus, S, Ma, M, Li, H, Rose, MJ, Poppe, L, Véniant, MM	J. Med. Chem.	2008