Contemporary Updates on the Physiology of Glucagon like Peptide-1 and Its Agonist to Treat Type 2 Diabetes Mellitus

  • Anju DasEmail author
  • K. M. Geetha
  • Iswar Hazarika


Pathogenesis of diabetes mellitus involves scores of different factors, out of which Glucagon like factor-1 (GLP-1) plays a foremost role. GLP-1 is a peptide-hormone of the incretin system. It exhibits glucagonostatic as well as glucose dependent insulinotropic action. GLP-1 augments regeneration of β-cell, boost secretion of insulin and trim down weight gain in type-2 diabetes. GLP-1 discharge from the L cells of intestine is mediated by neural and hormonal factors which are stimulated by the occurrence of nutrients in the gastrointestinal tract. Conversely, GLP-1 is instantaneously shattered by enzyme dipeptidyl peptidase-IV. GLP-1 is also cleared by renal clearance. Diminished GLP-1 leads to attenuated insulin release leading to type-2 diabetes. Substitution of GLP-1 regularizes the insulin release and prevents type-2 diabetes. However, GLP-1 holding infinitesimal plasma half life limits its therapeutic effects. To surmount the limitations of indigenous GLP-1, several GLP-1 receptor agonist like Exenatide are been developed. Modifications in pharmaceutical formulation are also been made to meet the patients adherence to the medication of GLP-1 agonist.

Graphic Abstract


Incretin GLP-1 GLP-1 agonist Incretin mimetics Diabetes mellitus Insulin Hypoglycaemia 



Authors like to acknowledge the dean and the management of College of Pharmaceutical Sciences, Dayananda Sagar University, Bangalore for their constant support to fulfil this work.


This project was self funded and received no grant from any outside agency.

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with any animals or human participants performed by any of the authors.


  1. Ahrén B (2004) Sensory nerves contribute to insulin secretion by glucagonlike peptide-1 in mice. Am J Physiol 286:R269–R272Google Scholar
  2. Anini Y, Brubaker PL (2003a) Muscarinic receptors control glucagon-like peptide-1 secretion by human endocrine L cells. Endocrinology 144:3244–3250CrossRefPubMedGoogle Scholar
  3. Anini Y, Brubaker PL (2003b) Role of leptin in the regulation of glucagon-like peptide-1 secretion. Diabetes 52:252–259CrossRefPubMedGoogle Scholar
  4. Bado A, Levasseur S, Attoub S et al (1998) The stomach is a source of leptin. Nature 394:780–793CrossRefGoogle Scholar
  5. Baggio LL, Huang Q, Brown TJ, Drucker DJ (2004) A recombinant human glucagonlike peptide (GLP)-1–albumin protein (albugon) mimics peptidergic activation of GLP-1 receptor–dependent pathways coupled with satiety, gastrointestinal motility, and glucose homeostasis. Diabetes 53(9):2492–2500CrossRefPubMedGoogle Scholar
  6. Balkan B, Li X (2000) Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms. Am J Physiol 279:R1449–R1454Google Scholar
  7. Bertsch T, McKeirnan K (2018) ITCA 650. Clin Diabetes 36(3):265–267CrossRefPubMedPubMedCentralGoogle Scholar
  8. Brubaker PL, Drucker DJ (2002) Structure-function of the glucagon receptor family of G protein-coupled receptors: the glucagon, GIP, GLP-1, and GLP-2 receptors. Recept Channels 8(3–4):179–188CrossRefPubMedGoogle Scholar
  9. Claustre J, Brechet S, Plaisancie P et al (1999) Stimulatory effect of beta-adrenergic agonists on ileal L cell secretion and modulation by alpha-adrenergic activation. J Endocrinol 162:271–278CrossRefPubMedGoogle Scholar
  10. Cordier-Bussat M, Bernard C, Levenez F et al (1998) Peptones stimulate both the secretion of the incretin hormone glucagon-like peptide 1 and the transcription of the proglucagon gene. Diabetes 47:1038–1045CrossRefPubMedGoogle Scholar
  11. Cork SC, Richards JE, Holt MK, Gribble FM, Reimann F, Trapp S (2015) Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab 4(10):718–731CrossRefPubMedPubMedCentralGoogle Scholar
  12. D’Alessio DA, Prigeon RL, Ensinck JW (1995) Enteral enhancement of glucose disposition by both insulin-dependent and insulin-independent processes. A physiological role of glucagon-like peptide I. Diabetes 44:1433–1437CrossRefPubMedGoogle Scholar
  13. Deacon CF, Jahnsen AH, Holst JJ (1995) 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. J Clin Endocrinol Metab 80:952–957PubMedGoogle Scholar
  14. Dennis MS, Zhang M, Meng YG, Kadkhodayan M, Kirchhofer D, Combs D, Damico LA (2002) Albumin binding as a general strategy for improving the pharmacokinetics of proteins. J Biol Chem 277(38):35035–35043CrossRefPubMedGoogle Scholar
  15. DeYoung MB, MacConell L, Sarin V, Trautmann M, Herbert P (2011) Encapsulation of exenatide in poly-(D, L-lactide-co-glycolide) microspheres produced an investigational long-acting once-weekly formulation for type 2 diabetes. Diabetes Technol Ther 13(11):1145–1154CrossRefPubMedPubMedCentralGoogle Scholar
  16. Dillon JS, Tanizawa Y, Wheeler MB, Leng XH, Ligon BB, Rabin DU, Yoo-Warren H, Permutt MA, Boyd AE 3rd (1993) Cloning and functional expression of the human glucagon-like peptide-1 (GLP-1) receptor. Endocrinology 133(4):1907–1910CrossRefPubMedGoogle Scholar
  17. Doyle ME, Egan JM (2007) Mechanisms of action of glucagon-like peptide 1 in the pancreas. Pharmacol Ther 113(3):546–593CrossRefPubMedGoogle Scholar
  18. Drucker DJ (2005) Biologic actions and therapeutic potential of the proglucagon-derived peptides. Nat Clin Pract End Met 1:22–31CrossRefGoogle Scholar
  19. Drucker DJ, Philippe J, Mojsov S, Chick WL, Habener JF (1987) Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc Natl Acad Sci USA 84(10):3434–3438CrossRefPubMedGoogle Scholar
  20. During MJ, Cao L, Zuzga DS, Francis JS, Fitzsimons HL, Jiao X, Bland RJ, Klugmann M, Banks WA, Drucker DJ, Haile CN (2003) Glucagon-like peptide-1 receptor is involved in learning and neuroprotection. Nat Med 9(9):1173CrossRefPubMedGoogle Scholar
  21. Eissele R, Göke R, Willemer S et al (1992) Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig and man. Eur J Clin Invest 22:283–291CrossRefPubMedGoogle Scholar
  22. Elliot RM, Morgan LM, Tredger JA et al (1993) Glucagon-like peptide-1 (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute postprandial and 24-h secretion patterns. J Endocrinol 138:159–166CrossRefGoogle Scholar
  23. Fehmann HC, Göke R, Göke B (1995) Cell and molecular biology of the incretin hormones glucagon-like peptide 1 and glucose-dependent insulin releasing polypeptide. Endocr Rev 16:390–410CrossRefPubMedGoogle Scholar
  24. Feinle C, Chapman IM, Wishart J, Horowitz M (2002) Plasma glucagon-like peptide-1 (GLP-1) responses to duodenal fat and glucose infusions in lean and obese men. Peptides 23:1491–1495CrossRefPubMedGoogle Scholar
  25. Frías JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, Jabbour SA (2016) Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol 4(12):1004–1016CrossRefPubMedPubMedCentralGoogle Scholar
  26. Fukasawa KM, Fukasawa K, Sahara N et al (1981) Immunohistochemical localization of dipeptidyl aminopeptidase IV in rat kidney, liver, and salivary glands. J Histochem Cytochem 29:337–343CrossRefPubMedGoogle Scholar
  27. Garber A, Abrahamson M, Barzilay J, Blonde L, Bloomgarden Z, Bush M, Dagogo-Jack S, Davidson M, Einhorn D, Garvey W, Grunberger G (2013) American Association of Clinical Endocrinologists’ comprehensive diabetes management algorithm 2013 consensus statement. Endocr Pract 19(Supplement 2):1–48CrossRefGoogle Scholar
  28. Glaesner W, Mark Vick A, Millican R, Ellis B, Tschang SH, Tian Y, Bokvist K, Brenner M, Koester A, Porksen N (2010) Engineering and characterization of the longacting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes Metab Res Rev 26(4):287–296CrossRefPubMedGoogle Scholar
  29. Gromada J, Holst JJ, Rorsman P (1998) Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflügers Arch 435(5):583–594CrossRefPubMedGoogle Scholar
  30. Hansen L, Holst JJ (2002) The effects of duodenal peptides on glucagon-like peptide-1 secretion from the ileum. A duodeno-ileal loop? Regul Pept 110:39–45CrossRefPubMedGoogle Scholar
  31. Hansen L, Deacon CF, Ørskov C, Holst JJ (1999) Glucagon-like peptide-1- (7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140:5356–5363CrossRefPubMedGoogle Scholar
  32. Hansen L, Hartmann B, Minco H, Holst JJ (2004) Glucagon-like peptide-1 secretion is influenced by perfusate glucose concentration and by a feedback mechanism involving somatostatin in isolated perfused porcine ileum. Regul Pept 118:11–18CrossRefPubMedGoogle Scholar
  33. Herrmann-Rinke C, Horsch D, McGregor GP, Göke B (1996) Galanin is a potent inhibitor of glucagon-like peptide-1 secretion from rat ileum. Peptides 17:571–576CrossRefPubMedGoogle Scholar
  34. Hinnen D (2017) Glucagon-like peptide 1 receptor agonists for type 2 diabetes. Diabetes Spectr 30(3):202–210CrossRefPubMedPubMedCentralGoogle Scholar
  35. Holst JJ (2007) The physiology of glucagon-like peptide 1. Physiol Rev 87(4):1409–1439CrossRefPubMedPubMedCentralGoogle Scholar
  36. Holst JJ, Vilsbøll T, Deacon CF (2009) The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol 297(1–2):127–136CrossRefPubMedGoogle Scholar
  37. Horsch D, Göke R, Eissele R et al (1997) Reciprocal cellular distribution of glucagon-like peptide-1 (GLP-1) immunoreactivity and GLP-1 receptor mRNA in pancreatic islets of rat. Pancreas 14:290–294CrossRefPubMedGoogle Scholar
  38. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR (2012) Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 55(6):1577–1596CrossRefPubMedGoogle Scholar
  39. Kieffer TJ, McIntosh CHS, Pederson RA (1995) Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide- 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136:3585–3596CrossRefPubMedGoogle Scholar
  40. Kinzig KP, D’Alessio DA, Seeley RJ (2002) The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci 22(23):10470–10476CrossRefPubMedPubMedCentralGoogle Scholar
  41. Kjems LL, Holst JJ, Vølund A, Madsbad S (2003) The influence of GLP-1 on glucose-stimulated insulin secretion: effects on β-cell sensitivity in type 2 and nondiabetic subjects. Diabetes 52(2):380–386CrossRefPubMedGoogle Scholar
  42. Lau J, Bloch P, Schäffer L, Pettersson I, Spetzler J, Kofoed J, Madsen K, Knudsen LB, McGuire J, Steensgaard DB, Strauss HM (2015) Discovery of the once-weekly glucagon-like peptide-1 (GLP-1) analogue semaglutide. J Med Chem 58(18):7370–7380CrossRefPubMedGoogle Scholar
  43. Leech CA, Chepurny OG, Holz GG (2010) Epac2-dependent rap1 activation and the control of islet insulin secretion by glucagon-like peptide-1. In: Litwack G (ed) Vitamins & hormones. Academic Press, Cambridge, pp 279–302Google Scholar
  44. Ma X, Hui H, Liu Z, He G, Hu J, Meng J, Guan L, Luo X (2009) Poly-GLP-1, a novel long-lasting glucagon-like peptide-1 polymer, ameliorates hyperglycaemia by improving insulin sensitivity and increasing pancreatic beta-cell proliferation. Diabetes Obes Metab 11(10):953–965CrossRefPubMedGoogle Scholar
  45. Madsen K, Knudsen LB, Agersoe H, Nielsen PF, Thøgersen H, Wilken M, Johansen NL (2007) Structure-activity and protraction relationship of long-acting glucagon- like peptide-1 derivatives: importance of fatty acid length, polarity, and bulkiness. J Med Chem 50(24):6126–6132CrossRefPubMedGoogle Scholar
  46. Meier JJ, Nauck MA, Kranz D et al (2004) Secretion, degradation, and elimination of glucagon-like peptide-1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes 53:654–662CrossRefPubMedGoogle Scholar
  47. Mentzel S, Dijkman HB, van Son JP et al (1996) Organ distribution of aminopeptidase A and dipeptidyl peptidase IV in normal mice. J Histochem Cytochem 44:445–461CrossRefPubMedGoogle Scholar
  48. Merchenthaler I, Lane M, Shughrue P (1999) Distribution of pre-proglucagon and glucagon-like peptide-1 receptor messenger RNAs in the rat central nervous system. J Comp Neurol 403:261–280CrossRefPubMedGoogle Scholar
  49. Mojsov S, Kopczynski MG, Habener JF (1990) Both amidated and nonamidated forms of glucagon-like peptide I are synthesized in the rat intestine and the pancreas. J Biol Chem 265:8001–8008PubMedGoogle Scholar
  50. Nauck MA, Bartels E, Orskov C, Ebert R, Creutzfeldt W (1993a) Additive insulinotropic effects of exogenous synthetic human gastric inhibitory polypeptide and glucagon-like peptide-1-(7-36) amide infused at near-physiological insulinotropic hormone and glucose concentrations. J Clin Endocrinol Metab 76(4):912–917PubMedGoogle Scholar
  51. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W (1993b) Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Investig 91(1):301–307CrossRefPubMedGoogle Scholar
  52. Nishizawa M, Nakabayashi H, Kawai K et al (2000) The hepatic vagal reception of intraportal GLP-1 is via receptor different from the pancreatic GLP-1 receptor. J Auton Nerv Syst 80:14–21CrossRefPubMedGoogle Scholar
  53. Ørskov C, Rabenhøj L, Wettergren A, Kofod H, Holst JJ (1994a) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43(4):535–539CrossRefPubMedGoogle Scholar
  54. Ørskov C, Rabenhøj L, Wettergren A et al (1994b) Tissue and plasma concentrations of amidated and glycine-extended glucagon-like peptide I in humans. Diabetes 43:535–539CrossRefPubMedGoogle Scholar
  55. Parkes D, Jodka C, Smoth P et al (2001) Pharmacokinetic actions of exendin-4 in the rat: comparison with glucagon-like peptide-1. Drug Dev Res 53:260–267CrossRefGoogle Scholar
  56. Roberge JN, Gronau KA, Brubaker PL (1996) Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut. Endocrinology 137:2383–2388CrossRefPubMedGoogle Scholar
  57. Rouille Y, Martin S, Steiner DF (1995) Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. J Biol Chem 270:26488–26496CrossRefPubMedGoogle Scholar
  58. Sharma D, Verma S, Vaidya S, Kalia K, Tiwari V (2018) Recent updates on GLP-1 agonists: current advancements & challenges. Biomed Pharmacother 1(108):952–962CrossRefGoogle Scholar
  59. Steensgaard DB, Thomsen JK, Olsen HB, Knudsen LB (2008) The molecular basis for the delayed absorption of the once-daily human GLP-1 analoge, Liraglutide. Diabetes 57:A164–A164Google Scholar
  60. Thorens B (1992) Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA 89(18):8641–8645CrossRefPubMedGoogle Scholar
  61. Triplitt C, DeFronzo RA (2006) Exenatide: first-in-class incretin mimetic for the treatment of type 2 diabetes mellitus. Expert Rev Endocrinol Metab 1(3):329–341CrossRefPubMedGoogle Scholar
  62. Trujillo JM, Nuffer W, Ellis SL (2015) GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther Adv Endocrinol Metab 6(1):19–28CrossRefPubMedPubMedCentralGoogle Scholar
  63. Underwood CR, Garibay P, Knudsen LB, Hastrup S, Peters GH, Rudolph R, Reedtz-Runge S (2010) Crystal structure of glucagon-like peptide-1 in complex with the extracellular domain of the glucagon-like peptide-1 receptor. J Biol Chem 285(1):723–730CrossRefPubMedGoogle Scholar
  64. Vilsbøll T, Holst JJ (2004) Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia 47(3):357–366CrossRefPubMedGoogle Scholar
  65. Werner U, Haschke G, Herling AW, Kramer W (2010) Pharmacological profile of lixisenatide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes. Regul Pept 164(2):58–64CrossRefPubMedGoogle Scholar
  66. Williams EK, Chang RB, Strochlic DE, Umans BD, Lowell BB, Liberles SD (2016) Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166(1):209–221CrossRefPubMedPubMedCentralGoogle Scholar
  67. Yoshimoto S, Hirota M, Ohboshi C, Shima K (1989) Identification of glucagon-like peptide-1 (7-36) amide in rat brain. Ann Clin Biochem 26:169–171CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Pharmacology, College of Pharmaceutical SciencesDayananda Sagar UniversityBangaloreIndia
  2. 2.Department of PharmacologyGirijananda Chowdhury Institute of Pharmaceutical SciencesGuwahatiIndia

Personalised recommendations