Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi


  • Joshua Reed
  • Venkateswarlu KanamarlapudiEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101967


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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  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. Donath MY, Burcelin R. GLP-1 effects on islets: hormonal, neuronal, or paracrine? Diabetes Care. 2013;36(Suppl 2):S145–8.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Donnelly D. The structure and function of the glucagon-like peptide-1 receptor and its ligands. Br J Pharmacol. 2012;166:27–41.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Goldstein B, Wieland D. Type 2 diabetes: principles and practice. 2nd ed. New York: Informa Healthcare; 2007.Google Scholar
  8. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87:1409–39.  https://doi.org/10.1152/physrev.00034.2006.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.Google Scholar
  13. 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.CrossRefPubMedGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  16. Shields D, Warren TG, Roth SE, Brenner MJ. Cell-free synthesis and processing of multiple precursors to glucagon. Nature. 1981;289(5797):511–4.PubMedCrossRefPubMedCentralGoogle Scholar
  17. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.CrossRefGoogle Scholar
  21. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 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.CrossRefPubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. Voet D, Voet JG. Biochemistry. 4th ed. New York: Wiley; 2011.Google Scholar
  26. 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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Institute of Life Science 1, School of MedicineSwansea UniversitySwanseaUK