Historical Background
In the 1960s, it was shown that orally administered glucose induces a much stronger insulin response than that induced by intravenously administered glucose, despite the similar resulting plasma glucose levels; this was termed the “incretin effect” (Creutzfeldt 2005; Graaf et al. 2016). Gastric inhibitory peptide (GIP) was the first incretin hormone to be discovered in 1975, which is produced by K cells of the small intestine (Creutzfeldt 2005). It was then observed in 1981 that antibodies against GIP did not abolish the incretin effect which led to the discovery of glucagon-like peptide-1 (GLP-1) in the translational products of mRNAs isolated from pancreatic islets of anglerfish (Shields et al. 1981; Graaf et al. 2016). Subsequently, it was shown that hamster and human preproglucagon cDNAs encode GLP-1 and 2, but only GLP-1 possessed incretin...
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Al-Sabah S, Donnelly D. The positive charge at Lys-288 of the glucagon-like peptide-1 (GLP-1) receptor is important for binding the N-terminus of peptide agonists. FEBS Lett. 2003;553:342–6. https://doi.org/10.1016/S0014-5793(03)01043-3.
Aronoff SL, Berkowitz K, Shreiner B, Want L. Glucose metabolism and regulation: beyond insulin and glucagon. Diabetes Spectr. 2004;17:183–90. https://doi.org/10.2337/diaspect.17.3.183.
Brissova M, Shiota M, Nicholson WE, Gannon M, Knobel SM, Piston DW, Wright CV, Powers AC. Reduction in pancreatic transcription factor PDX-1 impairs glucose-stimulated insulin secretion. J Biol Chem. 2002;277(13):11225–32.
Creutzfeldt W. The [pre-] history of the incretin concept. Regul Pept. 2005;128:87–91. https://doi.org/10.1016/j.regpep.2004.08.004.
Donath MY, Burcelin R. GLP-1 effects on islets: hormonal, neuronal, or paracrine? Diabetes Care. 2013;36(Suppl 2):S145–8.
Donnelly D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol. 2012;166:27–41.
Goldstein B, Wieland D. Type 2 diabetes: principles and practice. 2nd ed. New York: Informa Healthcare; 2007.
Graaf C, Donnelly D, Wootten D, Lau J, Sexton PM, Miller LJ, et al. Glucagon-like peptide-1 and its class B G protein–coupled receptors: a long march to therapeutic successes. Pharmacol Rev. 2016;68:954–1013. https://doi.org/10.1124/pr.115.011395.
Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409–39. https://doi.org/10.1152/physrev.00034.2006.
Kanamarlapudi V, Thompson A, Kelly E, López Bernal A. ARF6 activated by the LHCG receptor through the cytohesin family of guanine nucleotide exchange factors mediates the receptor internalization and signaling. J Biol Chem. 2012;287:20443–55. https://doi.org/10.1074/jbc.M112.362087.
Lamont BJ, Li Y, Kwan E, Brown TJ, Gaisano H, Drucker DJ. Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. J Clin Invest. 2012;122:388–402. https://doi.org/10.1172/JCI42497.
Lin CH, Lee YS, Huang YY, Hsieh SH, Chen ZS, Tsai CN. Polymorphisms of GLP-1 receptor gene and response to GLP-1 analogue in patients with poorly controlled type 2 diabetes. J Diab Res. 2015;176949.
Meloni AR, DeYoung MB, Lowe C, Parkes DG. GLP-1 receptor activated insulin secretion from pancreatic β-cells: mechanism and glucose dependence. Diabetes Obes Metab. 2013;15:15–27. https://doi.org/10.1111/j.1463-1326.2012.01663.x.
Nolte WM, Fortin J-P, Stevens BD, Aspnes GE, Griffith DA, Hoth LR, et al. A potentiator of orthosteric ligand activity at GLP-1R acts via covalent modification. Nat Chem Biol. 2014;10:629–31. https://doi.org/10.1038/nchembio.1581.. http://www.nature.com/nchembio/journal/v10/n8/abs/nchembio.1581.html#supplementary-information.
Salehi M, Aulinger B, D’Alessio DA. Effect of glycemia on plasma incretins and the incretin effect during oral glucose tolerance test. Diabetes. 2012;61:2728–33. https://doi.org/10.2337/db11-1825.
Shields D, Warren TG, Roth SE, Brenner MJ. Cell-free synthesis and processing of multiple precursors to glucagon. Nature. 1981;289(5797):511–4.
Smith EP, An Z, Wagner C, Lewis AG, Cohen EB, Li B, et al. The role of β-cell GLP-1 signaling in glucose regulation and response to diabetes drugs. Cell Metab. 2014;19:1050–7. https://doi.org/10.1016/j.cmet.2014.04.005.
Takhar S, Gyomorey S, Su RC, Mathi SK, Li X, Wheeler MB. The third cytoplasmic domain of the GLP-1[7–36 amide] receptor is required for coupling to the adenylyl cyclase system. Endocrinology. 1996;137:2175–8.
ten Kulve JS, van Bloemendaal L, Balesar R, Ijzerman RG, Swaab DF, Diamant M, et al. Decreased hypothalamic glucagon-like peptide-1 receptor expression in type 2 diabetes patients. J Clin Endocrinol Metab. 2015;101:2122–9. https://doi.org/10.1210/jc.2015-3291.
Thompson A, Kanamarlapudi V. Type 2 diabetes mellitus and glucagon like peptide-1 receptor signalling. Clin Exp Pharmacol. 2013;3:138. https://doi.org/10.4172/2161-1459.1000138.
Thompson A, Kanamarlapudi V. The regions within the N-terminus critical for human glucagon like peptide-1 receptor (hGLP-1R) cell surface expression. Sci Rep. 2014;4:7410. https://doi.org/10.1038/srep07410.
Thompson A, Kanamarlapudi V. Distinct regions in the C-terminus required for GLP-1R cell surface expression, activity and internalisation. Mol Cell Endocrinol. 2015a;413:66–77. https://doi.org/10.1016/j.mce.2015.06.012.
Thompson A, Kanamarlapudi V. Agonist-induced internalisation of the glucagon-like peptide-1 receptor is mediated by the Gαq pathway. Biochem Pharmacol. 2015b;93:72–84. https://doi.org/10.1016/j.bcp.2014.10.015.
Thompson A, Stephens J, Bain S, Kanamarlapudi V. Molecular characterisation of small molecule agonists effect on the human glucagon like peptide-1 receptor internalisation. PLoS One. 2016;11(4):e0154229. doi:10.1371/journal. pone.0154229.
Voet D, Voet JG. Biochemistry. 4th ed. New York: Wiley; 2011.
Wang Z, Thurmond DC. Mechanisms of biphasic insulin-granule exocytosis – roles of the cytoskeleton, small GTPases and SNARE proteins. J Cell Sci. 2009;122:893–903. https://doi.org/10.1242/jcs.034355.
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Reed, J., Kanamarlapudi, V. (2018). GLP-1R. In: Choi, S. (eds) Encyclopedia of Signaling Molecules. Springer, Cham. https://doi.org/10.1007/978-3-319-67199-4_101967
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