Physiology and pharmacology of glucagon-like peptide-1 receptor

Modern approaches to the treatment of type 2 diabetes mellitus (T2DM) are aimed not only at glycemic control, but also at reducing cardiovascular risks. The increasing prevalence of the disease and the need for effective treatment options highlight the importance of glucagon-like peptide-1 (GLP-1) receptor agonists in the pharmacotherapy structure.

The aim of the work was to review the literature regarding the physiology of GLP-1 and the therapeutic potential and development trends of its agonists.

Materials and methods. The search for the review materials was carried out using the abstract databases of PubMed, Google Scholar and e-Library. The search was carried out for publications from 2000 to 2023, using the following keywords: “GLP-1”; “GLP-1R agonists”; “GIP”; “exenatide”; “liraglutide”; “dulaglutide”; “semaglutide”; “lixisenatide”; “albiglutide”; “taspoglutide” taking into account various spellings.

Results. The interaction of almost all food components with enteroendocrine cells of the intestine leads to the secretion of incretins (primarily GLP-1) into the blood, triggering a complex of physiological reactions aimed primarily at the rapid utilization of incoming glucose (regulation of insulin and glucagon secretion), as well as the central regulation of dietary behavior (slowing gastric emptying and the formation of a feeling of satiety). A wide distribution of the GLP-1 receptor in various tissues and organs, its connection with intracellular signaling cascades aimed at launching energy-consuming remodeling (recovery) processes in endothelial cells, heart, neurons, beta cells, etc., is the basis for a wide range of pleiotropic effects of GLP-1 unrelated to its hypoglycemic effect. The discovery of synthetic GLP-1 receptor agonists with a long period of action has made it possible not only to therapeutically influence various parts of carbohydrate metabolism disorders, but also to increase the functional reserves of the target diabetes organs, reducing the risk of developing complications of the disease. Incretin-like drugs are well tolerated, with nausea being the most common side effect. The factors limiting a wider use of the drugs include their high cost and the preferred form of a subcutaneous solution. The current research is focused on the development of long-acting, oral, dual and triple agonists, fixed-dose combinations, and small molecule drugs.

Conclusion. GLP-1 receptor agonists are a class of effective and safe drugs for the treatment of diabetes and obesity, which is rapidly developing in the most advanced areas of pharmacy. A further development of this group and the solution of the identified problems will open up new opportunities for the treatment of diabetes and its complications.

1. Dedov II, Shestakova MV, Mayorov AYu, Mokrysheva NG, Vikulova OK, Galstyan GR, Kuraeva TL, Peterkova VA, Smirnova OM, Starostina EG, Surkova EV, Sukhareva OY, Tokmakova AY, Shamkhalova MS, Jarek-Martynova IR, Artemova EV, Beshlieva DD, Bondarenko ON, Volevodz NN, Gomova IS, Grigoryan OR, Dzhemilova ZN, Esayan RM, Ibragimova LI, Kalashnikov VY, Kononenko IV, Laptev DN, Lipatov DV, Melnikova OG, Mikhina MS, Michurova MS, Motovilin OG, Nikonova TV, Rozhivanov RV, Sklyanik IA, Shestakova EA Standards of specialized diabetes care Edited by Dedov II, Shestakova MV, Mayorov AYu 10th edition. Diabetes mellitus. 2021;24(1S):1–148. DOI: 10.14341/DM12802. Russian

2. Blonde L, Umpierrez GE, Reddy SS, McGill JB, Berga SL, Bush M, Chandrasekaran S, DeFronzo RA, Einhorn D, Galindo RJ, Gardner TW, Garg R, Garvey WT, Hirsch IB, Hurley DL, Izuora K, Kosiborod M, Olson D, Patel SB, Pop-Busui R, Sadhu AR, Samson SL, Stec C, Tamborlane WV Jr, Tuttle KR, Twining C, Vella A, Vellanki P, Weber SL. American Association of Clinical Endocrinology Clinical Practice Guideline: Developing a Diabetes Mellitus Comprehensive Care Plan-2022 Update. Endocr Pract. 2022;28(10):923–1049. DOI: 10.1016/j.eprac.2022.08.002

3. Saisho Y. Incretin-based therapy and pancreatitis: accumulating evidence and unresolved questions. Ann Transl Med. 2018;6(7):131. DOI: 10.21037/atm.2018.02.24

4. Müller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR, Fritsche A, Gribble F, Grill HJ, Habener JF, Holst JJ, Langhans W, Meier JJ, Nauck MA, Perez-Tilve D, Pocai A, Reimann F, Sandoval DA, Schwartz TW, Seeley RJ, Stemmer K, Tang-Christensen M, Woods SC, DiMarchi RD, Tschöp MH. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72–130. DOI: 10.1016/j.molmet.2019.09.010

5. Holst JJ. From the incretin concept and the discovery of GLP-1 to today’s diabetes therapy. Front Endocrinol (Lausanne). 2019;10:260. DOI: 10.3389/fendo.2019.00260

6. Sharma D, Verma S, Vaidya S, Kalia K, Tiwari V. Recent updates on GLP-1 agonists: Current advancements & challenges. Biomed. Pharmacother. 2018;108:952–62. DOI: 10.1016/j.biopha.2018.08.088

7. Brierley DI, de Lartigue G. Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. Br J Pharmacol. 2022;179(4):584–99. DOI: 10.1111/bph.15603

8. Singh I, Wang L, Xia B, Liu J, Tahiri A, El Ouaamari A, Wheeler MB, Pang ZP. Activation of arcuate nucleus glucagon-like peptide-1 receptor-expressing neurons suppresses food intake. Cell Biosci. 2022;12(1):178. DOI: 10.1186/s13578-022-00914-3

9. Gabe MBN, Skov-Jeppesen K, Gasbjerg LS, Schiellerup SP, Martinussen C, Gadgaard S, Boer GA, Oeke J, Torz LJ, Veedfald S, Svane MS, Bojsen-Møller KN, Madsbad S, Holst JJ, Hartmann B, Rosenkilde MM. GIP and GLP-2 together improve bone turnover in humans supporting GIPR-GLP-2R co-agonists as future osteoporosis treatment. Pharmacol Res. 2022;176:106058. DOI: 10.1016/j.phrs.2022.106058

10. Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, Bone HG, Holst JJ, Christiansen C. Four-month treatment with GLP-2 significantly increases hip BMD: a randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone. 2009;45(5):833–42. DOI: 10.1016/j.bone.2009.07.008

11. Greco EV, Russo G, Giandalia A, Viazzi F, Pontremoli R, De Cosmo S. GLP-1 receptor agonists and kidney protection. Medicina (Kaunas). 2019;55(6):233. DOI: 10.3390/medicina55060233

12. Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, Xue H, Liu Y, Zhang Y. GLP-1 receptor agonists: beyond their pancreatic effects. front. Endocrinol. (Lausanne). 2021;12:721135. DOI: 10.3389/fendo.2021.721135

13. Whalley NM, Pritchard LE, Smith DM, White A. Processing of proglucagon to GLP-1 in pancreatic α-cells: is this a paracrine mechanism enabling GLP-1 to act on β-cells? J Endocrinol. 2011;211(1):99–106. DOI: 10.1530/JOE-11-0094

14. Wideman RD, Yu IL, Webber TD, Verchere CB, Johnson JD, Cheung AT, Kieffer TJ. Improving function and survival of pancreatic islets by endogenous production of glucagon-like peptide 1 (GLP-1). Proc Natl Acad Sci USA. 2006;103(36):13468–73. DOI: 10.1073/pnas.0600655103

15. Jun LS, Millican RL, Hawkins ED, Konkol DL, Showalter AD, Christe ME, Michael MD, Sloop KW. Absence of glucagon and insulin action reveals a role for the GLP-1 receptor in endogenous glucose production. Diabetes. 2015;64(3):819–27. DOI: 10.2337/db14-1052

16. Capozzi ME, Svendsen B, Encisco SE, Lewandowski SL, Martin MD, Lin H, Jaffe JL, Coch RW, Haldeman JM, MacDonald PE, Merrins MJ, D’Alessio DA, Campbell JE. β Cell tone is defined by proglucagon peptides through cAMP signaling. JCI Insight. 2019;4(5):e126742. DOI: 10.1172/jci.insight.126742

17. Zhao F, Zhou Q, Cong Z, Hang K, Zou X, Zhang C, Chen Y, Dai A, Liang A, Ming Q, Wang M, Chen LN, Xu P, Chang R, Feng W, Xia T, Zhang Y, Wu B, Yang D, Zhao L, Xu HE, Wang MW. Structural insights into multiplexed pharmacological actions of tirzepatide and peptide 20 at the GIP, GLP-1 or glucagon receptors. Nat Commun. 2022;13(1):1057. DOI: 10.1038/s41467-022-28683-0

18. Svendsen B, Larsen O, Gabe MBN, Christiansen CB, Rosenkilde MM, Drucker DJ, Holst JJ. Insulin Secretion Depends on Intra-islet Glucagon Signaling. Cell Rep. 2018;25(5):1127–1134.e2. DOI: 10.1016/j.celrep.2018.10.018

19. Holst J.J. Glucagon-like peptide-1: Are its roles as endogenous hormone and therapeutic wizard congruent? J Intern Med. – 2022;291(5):557–573. DOI: 10.1111/joim.13433

20. Malik F, Li Z. Non-peptide agonists and positive allosteric modulators of glucagon-like peptide-1 receptors: Alternative approaches for treatment of Type 2 diabetes. Br J Pharmacol. 2022;179(4):511–25. DOI: 10.1111/bph.15446

21. McLean BA, Wong CK, Campbell JE, Hodson DJ, Trapp S, Drucker DJ. Revisiting the complexity of GLP-1 action from sites of synthesis to receptor activation. Endocr Rev. 2021;42(2):101–132. DOI: 10.1210/endrev/bnaa032

22. Choe HJ., Cho YM. Peptidyl and Non-Peptidyl Oral Glucagon-Like Peptide-1 Receptor Agonists. Endocrinol. Metab. (Seoul). 2021;36(1):22–9. DOI: 10.3803/EnM.2021.102

23. Kawai T, Sun B, Yoshino H, Feng D, Suzuki Y, Fukazawa M, Nagao S, Wainscott DB, Showalter AD, Droz BA, Kobilka TS, Coghlan MP, Willard FS, Kawabe Y, Kobilka BK, Sloop KW. Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist. Proc Natl Acad Sci USA. 2020;117(47):29959–67. DOI: 10.1073/pnas.2014879117

24. Pyke C, Heller RS, Kirk RK, Ørskov C, Reedtz-Runge S, Kaastrup P, Hvelplund A, Bardram L, Calatayud D, Knudsen LB. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology. 2014;155(4):1280–90. DOI: 10.1210/en.2013-1934

25. Richards P, Parker HE, Adriaenssens AE, Hodgson JM, Cork SC, Trapp S, Gribble FM, Reimann F. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes. 2014;63(4):1224–33. DOI: 10.2337/db13-1440

26. Hjørne AP, Modvig IM, Holst JJ. The sensory mechanisms of nutrient-induced GLP-1 secretion. Metabolites. – 2022;12(5):420. DOI: 10.3390/metabo12050420

27. Mayendraraj A, Rosenkilde MM, Gasbjerg LS. GLP-1 and GIP receptor signaling in beta cells – A review of receptor interactions and co-stimulation. Peptides. 2022;151:170749. DOI: 10.1016/j.peptides.2022.170749

28. Wootten D, Reynolds CA, Smith KJ, Mobarec JC, Koole C, Savage EE, Pabreja K, Simms J, Sridhar R, Furness SGB, Liu M, Thompson PE, Miller LJ, Christopoulos A, Sexton PM. The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism. Cell. 2016;165(7):1632–43. DOI: 10.1016/j.cell.2016.05.023

29. Spreckley E, Murphy KG. The L-cell in nutritional sensing and the regulation of appetite. Front Nutr. 2015;2:23. DOI: 10.3389/fnut.2015.00023

30. Wang X, Liu H, Chen J, Li Y, Qu S. Multiple factors related to the secretion of glucagon-like peptide-1. Int J Endocrinol. 2015;2015:651757. DOI: 10.1155/2015/651757

31. Alavi SE, Cabot PJ, Moyle PM. Glucagon-Like Peptide-1 Receptor Agonists and Strategies To Improve Their Efficiency. Mol Pharm. 2019;16(6):2278–95. DOI: 10.1021/acs.molpharmaceut.9b00308

32. Eriksson L, Nyström T. Antidiabetic agents and endothelial dysfunction – beyond glucose control. Basic Clin Pharmacol Toxicol. 2015;117(1):15–25. DOI: 10.1111/bcpt.12402

33. Calanna S, Christensen M, Holst JJ, Laferrère B, Gluud LL, Vilsbøll T, Knop FK. Secretion of glucagon-like peptide-1 in patients with type 2 diabetes mellitus: systematic review and meta-analyses of clinical studies. Diabetologia. 2013;56(5):965–72. DOI: 10.1007/s00125-013-2841-0

34. Kuhre RE, Frost CR, Svendsen B, Holst JJ. Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine. Diabetes. 2015;64(2):370–82. DOI: 10.2337/db14-0807

35. Tyurenkov IN, Ozerov AA, Kurkin DV, Logvinova EO, Bakulin DA, Volotova EV, Borodin DD. Structure and biological activity of endogenous and synthetic agonists of GPR119. Russian Chemical Reviews. 2018;87(2):151–66. DOI: 10.1070/rcr4737

36. Tyurenkov IN, Kurkin DV, Volotova EV, Bakulin DA. The role of intestinal microflora, food composition, GPR41- and GPR43-receptors for short chain fatty acids in energy metabolism of vertebrates. Uspekhi fiziologicheskih nauk. 2017;48(2):100–12. Russian

37. Tyurenkov IN, Kurkin DV, Bakulin DA, Volotova EV, Morkovin EI, Chafeev MA, Karapetian RN. Chemistry and Hypoglycemic Activity of GPR119 Agonist ZB-16. Front Endocrinol (Lausanne). 2018;9:543. DOI: 10.3389/fendo.2018.00543

38. Im DS. GPR119 and GPR55 as receptors for fatty acid ethanolamides, oleoylethanolamide and palmitoylethanolamide. Int J Mol Sci. 2021;22(3):1034. DOI: 10.3390/ijms22031034

39. Higuchi N, Hira T, Yamada N, Hara H. Oral administration of corn zein hydrolysate stimulates GLP-1 and GIP secretion and improves glucose tolerance in male normal rats and Goto-Kakizaki rats. Endocrinology. 2013;154(9):3089–98. DOI: 10.1210/en.2012-2275

40. Gagnon J, Baggio LL, Drucker DJ, Brubaker PL. Ghrelin Is a Novel Regulator of GLP-1 Secretion. Diabetes. 2015;64(5):1513–21. DOI: 10.2337/db14-1176

41. Hansen L, Lampert S, Mineo H, Holst JJ. Neural regulation of glucagon-like peptide-1 secretion in pigs. Am J Physiol Endocrinol Metab. 2004;287(5):E939–947. DOI: 10.1152/ajpendo.00197.2004

42. Persson K, Gingerich RL, Nayak S, Wada K, Wada E, Ahrén B. Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice. Am J Physiol Endocrinol. Metab. 2000;279(5):E956–962. DOI: 10.1152/ajpendo.2000.279.5.E956

43. Han YE, Kang CW, Oh JH, Park SH, Ku CR, Cho YH, Lee MK, Lee EJ. Olfactory receptor OR51E1 mediates GLP-1 secretion in human and rodent enteroendocrine L cells. J Endocr Soc. 2018;2(11):1251–8. DOI: 10.1210/js.2018-00165

44. Tomas A, Jones B, Leech C. New Insights into Beta-Cell GLP-1 Receptor and cAMP Signaling. J Mol Biol. 2020;432(5):1347–66. DOI: 10.1016/j.jmb.2019.08.009

45. Gromada J, Brock B, Schmitz O, Rorsman P. Glucagon-like peptide-1: regulation of insulin secretion and therapeutic potential. Basic Clin Pharmacol Toxicol. – 2004;95(6):252–262. DOI: 10.1111/j.1742-7843.2004.t01-1-pto950502.x

46. Buteau J. GLP-1 receptor signaling: effects on pancreatic beta-cell proliferation and survival. Diabetes Metab. 2008;34(Suppl 2):S73–77. DOI: 10.1016/S1262-3636(08)73398-6

47. Park S, Dong X, Fisher TL, Dunn S, Omer AK, Weir G, White MF. Exendin-4 uses Irs2 signaling to mediate pancreatic beta cell growth and function. J Biol Chem. 2006;281(2):1159–68. DOI: 10.1074/jbc.M508307200

48. Peng W, Zhou R, Sun ZF, Long JW, Gong YQ. Novel insights into the roles and mechanisms of GLP-1 receptor agonists against aging-related diseases. Aging Dis. 2022;13(2):468–90. DOI: 10.14336/AD.2021.0928

49. Oh YS, Jun HS. Effects of glucagon-like peptide-1 on oxidative stress and Nrf2 signaling. Int J Mol Sci. 2017;19(1):26. DOI: 10.3390/ijms19010026

50. Urusova IA, Farilla L, Hui H, D’Amico E, Perfetti R. GLP-1 inhibition of pancreatic islet cell apoptosis. Trends Endocrinol Metab. – 2004;15(1):27–33. DOI: 10.1016/j.tem.2003.11.006

51. Drucker DJ. Mechanisms of action and therapeutic application of glucagon-like peptide-1. Cell Metab. 2018;27(4):740–56. DOI: 10.1016/j.cmet.2018.03.001

52. De Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F, Bengtsson M, Braha O, Braun M, Ramracheya R, Amisten S, Habib AM, Moritoh Y, Zhang E, Reimann F, Rosengren A, Shibasaki T, Gribble F, Renström E, Seino S, Eliasson L, Rorsman P. GLP-1 inhibits and adrenaline stimulates glucagon release by differential modulation of N- and L-type Ca2+ channel-dependent exocytosis. Cell Metab. 2010;11(6):543–53. DOI: 10.1016/j.cmet.2010.04.007

53. Ravassa S, Zudaire A, Díez J. GLP-1 and cardioprotection: from bench to bedside. Cardiovasc Res. 2012;94(2):316–23. DOI: 10.1093/cvr/cvs123

54. Bremholm L, Andersen U.B, Hornum M, Hilsted L, Veedfald S, Hartmann B, Holst J.J. Acute effects of glucagon-like peptide-1, GLP-19-36 amide, and exenatide on mesenteric blood flow, cardiovascular parameters, and biomarkers in healthy volunteers. Physiol Rep. 2017;5(4):e13102. DOI: 10.14814/phy2.13102

55. Sun F, Wu S, Guo S, Yu K, Yang Z, Li L, Zhang Y, Quan X, Ji L, Zhan S. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: A systematic review and network meta-analysis. Diabetes Res Clin Pract. 2015;110(1):26–37. DOI: 10.1016/j.diabres.2015.07.015

56. Erbil D, Eren CY, Demirel C, Küçüker MU, Solaroğlu I, Eser HY. GLP-1’s role in neuroprotection: a systematic review. Brain Inj. 2019;33(6):734–819. DOI: 10.1080/02699052.2019.1587000

57. Heppner KM, Kirigiti M, Secher A, Paulsen SJ, Buckingham R, Pyke C, Knudsen LB, Vrang N, Grove KL. Expression and distribution of glucagon-like peptide-1 receptor mRNA, protein and binding in the male nonhuman primate (Macaca mulatta) brain. Endocrinology. 2015;156(1):255–67. DOI: 10.1210/en.2014-1675

58. Kabahizi A, Wallace B, Lieu L, Chau D, Dong Y, Hwang ES, Williams KW. Glucagon-like peptide-1 (GLP-1) signalling in the brain: From neural circuits and metabolism to therapeutics. Br J Pharmacol. 2022;179(4):600–24. DOI: 10.1111/bph.15682

59. Trapp S, Brierley DI. Brain GLP-1 and the regulation of food intake: GLP-1 action in the brain and its implications for GLP-1 receptor agonists in obesity treatment. Br J Pharmacol. 2022;179(4):557–70. DOI: 10.1111/bph.15638

60. Alhadeff AL, Mergler BD, Zimmer DJ, Turner CA, Reiner DJ, Schmidt HD, Grill HJ, Hayes MR. Endogenous glucagon-like peptide-1 receptor signaling in the nucleus tractus solitarius is required for food intake control. Neuropsychopharmacology. 2017;42(7):1471–9. DOI: 10.1038/npp.2016.246

61. Ong ZY, Liu JJ, Pang ZP, Grill HJ. Paraventricular thalamic control of food intake and reward: role of glucagon-like peptide-1 receptor signaling. Neuropsychopharmacology. 2017;42(12):2387–97. DOI: 10.1038/npp.2017.150

62. Adams JM, Pei H, Sandoval DA, Seeley RJ, Chang RB, Liberles SD, Olson DP. Liraglutide modulates appetite and body weight through glucagon-like peptide 1 receptor-expressing glutamatergic neurons. Diabetes. 2018;67(8):1538–48. DOI: 10.2337/db17-1385

63. Hayes MR, Leichner TM, Zhao S, Lee GS, Chowansky A, Zimmer D, De Jonghe BC, Kanoski SE, Grill HJ, Bence KK. Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab. 2011;13(3):320–30. DOI: 10.1016/j.cmet.2011.02.001

64. Sirohi S, Schurdak JD, Seeley RJ, Benoit SC, Davis JF. Central & peripheral glucagon-like peptide-1 receptor signaling differentially regulate addictive behaviors. Physiol Behav. 2016;161:140–4. DOI: 10.1016/j.physbeh.2016.04.013

65. Dossat AM, Diaz R, Gallo L, Panagos A, Kay K, Williams DL. Nucleus accumbens GLP-1 receptors influence meal size and palatability. Am J Physiol Endocrinol Metab. 2013;304(12):E1314–1320. DOI: 10.1152/ajpendo.00137.2013

66. Hisadome K, Reimann F, Gribble FM, Trapp S. CCK stimulation of GLP-1 neurons involves α1-adrenoceptor-mediated increase in glutamatergic synaptic inputs. Diabetes. 2011;60(11):2701–9. DOI: 10.2337/db11-0489

67. Gaykema RP, Newmyer BA, Ottolini M, Raje V, Warthen DM, Lambeth PS, Niccum M, Yao T, Huang Y, Schulman IG, Harris TE, Patel MK, Williams KW, Scott MM. Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. J Clin Invest. 2017;127(3):1031–45. DOI: 10.1172/JCI81335

68. Holt MK, Richards JE, Cook DR, Brierley DI, Williams DL, Reimann F, Gribble FM, Trapp S. Preproglucagon neurons in the nucleus of the solitary tract are the main source of brain GLP-1, mediate stress-induced hypophagia, and limit unusually large intakes of food. Diabetes. 2019;68(1):21–33. DOI: 10.2337/db18-0729

69. Lee SJ, Sanchez-Watts G, Krieger JP, Pignalosa A, Norell PN, Cortella A, Pettersen KG, Vrdoljak D, Hayes MR, Kanoski SE, Langhans W, Watts AG. Loss of dorsomedial hypothalamic GLP-1 signaling reduces BAT thermogenesis and increases adiposity. Mol Metab. 2018;11:33–46. DOI: 10.1016/j.molmet.2018.03.008

70. Maselli DB, Camilleri M. Effects of GLP-1 and Its Analogs on Gastric Physiology in Diabetes Mellitus and Obesity. Adv Exp Med Biol. 2021;1307:171–92. DOI: 10.1007/5584_2020_496

71. Ghosal S, Packard AEB, Mahbod P, McKlveen JM, Seeley RJ, Myers B, Ulrich-Lai Y, Smith EP, D’Alessio DA, Herman JP. Disruption of glucagon-like peptide 1 signaling in sim1 neurons reduces physiological and behavioral reactivity to acute and chronic stress. J Neurosci. 2017;37(1):184–93. DOI: 10.1523/JNEUROSCI.1104-16.2016

72. Salcedo I, Tweedie D, Li Y, Greig NH. Neuroprotective and neurotrophic actions of glucagon-like peptide-1: an emerging opportunity to treat neurodegenerative and cerebrovascular disorders. Br J Pharmacol. 2012;166(5):1586–99. DOI: 10.1111/j.1476-5381.2012.01971.x

73. Monti G, Gomes Moreira D, Richner M, Mutsaers HAM, Ferreira N, Jan A. GLP-1 receptor agonists in neurodegeneration: neurovascular unit in the spotlight. Cells. 2022;11(13):2023. DOI: 10.3390/cells11132023

74. Chang CC, Lin TC, Ho HL, Kuo CY, Li HH, Korolenko TA, Chen WJ, Lai TJ, Ho YJ, Lin CL. GLP-1 analogue liraglutide attenuates mutant huntingtin-induced neurotoxicity by restoration of neuronal insulin signaling. Int J Mol Sci. 2018;19(9):2505. DOI: 10.3390/ijms19092505

75. Qi L, Ke L, Liu X, Liao L, Ke S, Liu X, Wang Y, Lin X, Zhou Y, Wu L, Chen Z, Liu L. Subcutaneous administration of liraglutide ameliorates learning and memory impairment by modulating tau hyperphosphorylation via the glycogen synthase kinase-3β pathway in an amyloid β protein induced Alzheimer disease mouse model. Eur J Pharmacol. 2016;783:23–32. DOI: 10.1016/j.ejphar.2016.04.052

76. Chen S, Sun J, Zhao G, Guo A, Chen Y, Fu R, Deng Y. Liraglutide improves water maze learning and memory performance while reduces hyperphosphorylation of tau and neurofilaments in APP/PS1/Tau triple transgenic mice. Neurochem Res. 2017;42(8):2326–35. DOI: 10.1007/s11064-017-2250-8

77. Hansen HH, Fabricius K, Barkholt P, Niehoff ML, Morley JE, Jelsing J, Pyke C, Knudsen LB, Farr SA, Vrang N. The GLP-1 receptor agonist liraglutide improves memory function and increases hippocampal ca1 neuronal numbers in a senescence-accelerated mouse model of Alzheimer’s disease. J Alzheimers Dis. 2015;46(4):877–88. DOI: 10.3233/JAD-143090

78. Gejl M, Brock B, Egefjord L, Vang K, Rungby J, Gjedde A. Blood-brain glucose transfer in Alzheimer’s disease: effect of GLP-1 analog treatment. Sci Rep. 2017;7(1):17490. DOI: 10.1038/s41598-017-17718-y

79. Watson KT, Wroolie TE, Tong G, Foland-Ross LC, Frangou S, Singh M, McIntyre RS, Roat-Shumway S, Myoraku A, Reiss AL, Rasgon NL. Neural correlates of liraglutideeffects in persons at risk for Alzheimer’s disease. Behav Brain Res. 2019;356:271–8. DOI: 10.1016/j.bbr.2018.08.006

80. Femminella GD, Frangou E, Love SB, Busza G, Holmes C, Ritchie C, Lawrence R, McFarlane B, Tadros G, Ridha BH, Bannister C, Walker Z, Archer H, Coulthard E, Underwood BR, Prasanna A, Koranteng P, Karim S, Junaid K, McGuinness B, Nilforooshan R, Macharouthu A, Donaldson A, Thacker S, Russell G, Malik N, Mate V, Knight L, Kshemendran S, Harrison J, Hölscher C, Brooks DJ, Passmore AP, Ballard C, Edison P. Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer’s disease: study protocol for a randomised controlled trial (ELAD study). Trials. 2019;20(1):191. DOI: 10.1186/s13063-019-3259-x

81. Li Y, Perry T, Kindy MS, Harvey BK, Tweedie D, Holloway HW, Powers K, Shen H, Egan JM, Sambamurti K, Brossi A, Lahiri DK, Mattson MP, Hoffer BJ, Wang Y, Greig NH. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci USA. 2009;106(4):1285–90. DOI: 10.1073/pnas.0806720106

82. Rampersaud N, Harkavyi A, Giordano G, Lever R, Whitton J, Whitton PS. Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson’s disease with combined noradrenergic and serotonergic lesions. Neuropeptides. 2012;46(5):183–93. DOI: 10.1016/j.npep.2012.07.004

83. Athauda D, Maclagan K, Skene SS, Bajwa-Joseph M, Letchford D, Chowdhury K, Hibbert S, Budnik N, Zampedri L, Dickson J, Li Y, Aviles-Olmos I, Warner TT, Limousin P, Lees AJ, Greig NH, Tebbs S, Foltynie T. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10103):1664–75. DOI: 10.1016/S0140-6736(17)31585-4

84. Basalay MV, Davidson SM, Yellon DM. Neuroprotection in rats following ischaemia-reperfusion injury by GLP-1 analogues-liraglutide and semaglutide. cardiovasc. Drugs Ther. 2019;33(6):661–7. DOI: 10.1007/s10557-019-06915-8

85. Gerstein HC, Colhoun HM, Dagenais GR, Diaz R, Lakshmanan M, Pais P, Probstfield J, Botros FT, Riddle MC, Rydén L, Xavier D, Atisso CM, Dyal L, Hall S, Rao-Melacini P, Wong G, Avezum A, Basile J, Chung N, Conget I, Cushman WC, Franek E, Hancu N, Hanefeld M, Holt S, Jansky P, Keltai M, Lanas F, Leiter LA, Lopez-Jaramillo P, Cardona Munoz EG, Pirags V, Pogosova N, Raubenheimer PJ, Shaw JE, Sheu WH, Temelkova-Kurktschiev T; REWIND Investigators. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394(10193):131–8. DOI: 10.1016/S0140-6736(19)31150-X

86. Hansen MS, Frost M. Alliances of the gut and bone axis. Semin Cell Dev Biol. 2022;123):74–81. DOI: 10.1016/j.semcdb.2021.06.024

87. Mieczkowska A, Mansur S, Bouvard B, Flatt PR, Thorens B, Irwin N, Chappard D, Mabilleau G. Double incretin receptor knock-out (DIRKO) mice present with alterations of trabecular and cortical micromorphology and bone strength. Osteoporos Int. 2015;26(1):209–18. DOI: 10.1007/s00198-014-2845-8

88. Maagensen H, Helsted MM, Gasbjerg LS, Vilsbøll T, Knop FK. The Gut-Bone Axis in Diabetes. Curr Osteoporos Rep. 2022. DOI: 10.1007/s11914-022-00767-2

89. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes – state-of-the-art. Mol Metab. 2021;46:101102. DOI: 10.1016/j.molmet.2020.101102

90. Tomlinson B, Hu M, Zhang Y, Chan P, Liu ZM. An overview of new GLP-1 receptor agonists for type 2 diabetes. Expert Opin Investig Drugs. 2016;25(2):145–58. DOI: 10.1517/13543784.2016.1123249

91. Yang X, Qiang Q, Li N, Feng P, Wei W, Hölscher C. Neuroprotective Mechanisms of Glucagon-Like Peptide-1-Based Therapies in Ischemic Stroke: An Update Based on Preclinical Research. Front Neurol. 2022;13:844697. DOI: 10.3389/fneur.2022.844697

92. Cheang JY, Moyle PM. Glucagon-like peptide-1 (GLP-1)-based therapeutics: current status and future opportunities beyond Type 2 Diabetes. Chem Med Chem. 2018;13(7):662–71. DOI: 10.1002/cmdc.201700781

93. Kalra S, Bhattacharya S, Kapoor N. Contemporary classification of glucagon-like peptide 1 receptor Agonists (GLP1RAs). Diabetes Ther. 2021;12(8):2133–47. DOI: 10.1007/s13300-021-01113-y

94. Ametov AS, Shokhin IE, Rogozhina EA, Bodrova TG, Nevretdinova ME, Bely PA, Zaslavskaya KYa, Kurkin DV, Koryanova KN, Mishchenko ES, Noskov SM. Russian development for drug independence in endocrinology: comparative analysis of bioequivalence, safety and tolerability of the first domestic liraglutide. Pharmacy & Pharmacology. 2023;11(3):255–76. DOI: 10.19163/2307-9266-2023-11-3-255-276

95. Arefeva AN, Banko VV, Sadovskikh MO, Noskov SM. Pharmacokinetics of first semaglutid drug in Russian Federation: results of open-label randomized clinical trial. Medical Council. 2023;(16):77–82. DOI: 10.21518/ms2023-312. Russian

96. Zhang X, Belousoff MJ, Zhao P, Kooistra AJ, Truong TT, Ang SY, Underwood CR, Egebjerg T, Šenel P, Stewart GD, Liang YL, Glukhova A, Venugopal H, Christopoulos A, Furness SGB, Miller LJ, Reedtz-Runge S, Langmead CJ, Gloriam DE, Danev R, Sexton PM, Wootten D. Differential GLP-1R binding and activation by peptide and non-peptide agonists. Mol Cell. 2020;80(3):485–500.e7. DOI: 10.1016/j.molcel.2020.09.020

97. Zhao P, Liang YL, Belousoff MJ, Deganutti G, Fletcher MM, Willard FS, Bell MG, Christe ME, Sloop KW, Inoue A, Truong TT, Clydesdale L, Furness SGB, Christopoulos A, Wang MW, Miller LJ, Reynolds CA, Danev R, Sexton PM, Wootten D. Activation of the GLP-1 receptor by a non-peptidic agonist. Nature. 2020;577(7790):432–6. DOI: 10.1038/s41586-019-1902-z

98. Freeman JLR, Dunn IM, Valcarce C. Beyond topline results for the oral (non-peptide) GLP-1R agonist TTP273 in type 2 diabetes: how much and when. Diabetol. Conf. 53rd Annu. Meet. Eur. Assoc. study diabetes, EASD 2017. Port. 2017;60:S51-S52.

99. Girdhar K, Thakur S, Gaur P, Choubey A, Dogra S, Dehury B, Kumar S, Biswas B, Dwivedi DK, Ghosh S, Mondal P. Design, synthesis, and biological evaluation of a small molecule oral agonist of the glucagon-like-peptide-1 receptor. J Biol Chem. 2022;298(5):101889. DOI: 10.1016/j.jbc.2022.101889

100. Karakasis P, Patoulias D, Pamporis K, Stachteas P, Bougioukas K.I, Klisic A, Fragakis N, Rizzo M. Safety and efficacy of the new, oral, small-molecule, GLP-1 receptor agonists orforglipron and danuglipron for the treatment of type 2 diabetes and obesity: systematic review and meta-analysis of randomized controlled trials. Metabolism. 2023;149:155710. DOI: 10.1016/j.metabol.2023.155710

101. Bueno AB, Sun B, Willard FS, Feng D, Ho JD, Wainscott DB, Showalter AD, Vieth M, Chen Q, Stutsman C, Chau B, Ficorilli J, Agejas FJ, Cumming GR, Jiménez A, Rojo I, Kobilka TS, Kobilka BK, Sloop KW. Structural insights into probe-dependent positive allosterism of the GLP-1 receptor. Nat Chem Biol. 2020;16(10):1105–10. DOI: 10.1038/s41589-020-0589-7

102. King K, Lin NP, Cheng YH, Chen GH, Chein RJ. Isolation of Positive Modulator of Glucagon-like Peptide-1 Signaling from Trigonella foenum-graecum (Fenugreek) Seed. J Biol Chem. 2015;290(43):26235–48. DOI: 10.1074/jbc.M115.672097

103. Huthmacher JA, Meier JJ, Nauck MA. Efficacy and safety of short- and long-acting glucagon-like peptide 1 receptor agonists on a background of basal insulin in type 2 diabetes: a meta-analysis. Diabetes Care. 2020;43(9):2303–12. DOI: 10.2337/dc20-0498

104. Baggio LL, Drucker DJ. Glucagon-like peptide-1 receptor co-agonists for treating metabolic disease. Mol Metab. 2021;46:101090. DOI: 10.1016/j.molmet.2020.101090

105. Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, Zhang L, Habegger KM, Fischer K, Campbell JE, Sandoval D, Seeley RJ, Bleicher K, Uhles S, Riboulet W, Funk J, Hertel C, Belli S, Sebokova E, Conde-Knape K, Konkar A, Drucker DJ, Gelfanov V, Pfluger PT, Müller TD, Perez-Tilve D, DiMarchi RD, Tschöp MH. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21(1):27–36. DOI: 10.1038/nm.3761

106. Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, Kirchner H, Holland J, Hembree J, Raver C, Lockie SH, Smiley DL, Gelfanov V, Yang B, Hofmann S, Bruemmer D, Drucker DJ, Pfluger PT, Perez-Tilve D, Gidda J, Vignati L, Zhang L, Hauptman JB, Lau M, Brecheisen M, Uhles S, Riboulet W, Hainaut E, Sebokova E, Conde-Knape K, Konkar A, DiMarchi RD, Tschöp MH. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med. 2013;5(209):209ra151. DOI: 10.1126/scitranslmed.3007218

107. Bech EM, Voldum-Clausen K, Pedersen SL, Fabricius K, Rudkjær LCB, Hansen HH, Jelsing J. Adrenomedullin and glucagon-like peptide-1 have additive effects on food intake in mice. Biomed Pharmacother. 2019;109:167–73. DOI: 10.1016/j.biopha.2018.10.040

108. Decara J, Rivera P, Arrabal S, Vargas A, Serrano A, Pavón FJ, Dieguez C, Nogueiras R, Rodríguez de Fonseca F, Suárez J. Cooperative role of the glucagon-like peptide-1 receptor and β3-adrenergic-mediated signalling on fat mass reduction through the downregulation of PKA/AKT/AMPK signalling in the adipose tissue and muscle of rats. Acta Physiol. (Oxf.). 2018;222(4):e13008. DOI: 10.1111/apha.13008

109. Bojanowska E, Radziszewska E. Combined stimulation of glucagon-like peptide-1 receptor and inhibition of cannabinoid CB1 receptor act synergistically to reduce food intake and body weight in the rat. J Physiol Pharmacol. 2011;62(4):395–402.

110. Jouihan H, Will S, Guionaud S, Boland ML, Oldham S, Ravn P, Celeste A, Trevaskis JL. Superior reductions in hepatic steatosis and fibrosis with co-administration of a glucagon-like peptide-1 receptor agonist and obeticholic acid in mice. Mol Metab. 2017;6(11):1360–70. DOI: 10.1016/j.molmet.2017.09.001

111. Elvert R, Bossart M, Herling AW, Weiss T, Zhang B, Kannt A, Wagner M, Haack T, Evers A, Dudda A, Keil S, Lorenz M, Lorenz K, Riz M, Hennerici W, Larsen PJ. Team players or opponents: coadministration of selective glucagon and GLP-1 receptor agonists in obese diabetic monkeys. Endocrinology. 2018;159(8):3105–19. DOI: 10.1210/en.2018-00399

112. Druzhilov MA, Kuznetsova TYu, Chumakova GA. Multiagonists of the “incretin axis” as a promising tool for managing cardiometabolic risk in visceral obesity. Russian Journal of Cardiology. 2022;27(4):4755. DOI: 10.15829/1560-4071-2022-4755. Russian

113. Simonsen L, Lau J, Kruse T, Guo T, McGuire J, Jeppesen JF, Niss K, Sauerberg P, Raun K, Dornonville de la Cour C. Preclinical evaluation of a protracted GLP-1/glucagon receptor co-agonist: Translational difficulties and pitfalls. PLoS One. 2022;17(3):e0264974. DOI: 10.1371/journal.pone.0264974

114. van Witteloostuijn SB, Dalbøge LS, Hansen G, Midtgaard SR, Jensen GV, Jensen KJ, Vrang N, Jelsing J, Pedersen SL. GUB06-046, a novel secretin/glucagon-like peptide 1 co-agonist, decreases food intake, improves glycemic control, and preserves beta cell mass in diabetic mice. J Pept Sci. 2017;23(12):845–54. DOI: 10.1002/psc.3048

115. Stensen S, Gasbjerg LS, Helsted MM, Hartmann B, Christensen MB, Knop FK. GIP and the gut-bone axis – Physiological, pathophysiological and potential therapeutic implications. Peptides. 2020;125:170197. DOI: 10.1016/j.peptides.2019.170197

116. Del Prato S, Kahn SE, Pavo I, Weerakkody GJ, Yang Z, Doupis J, Aizenberg D, Wynne AG, Riesmeyer JS, Heine RJ, Wiese RJ; SURPASS-4 Investigators. Tirzepatide versus insulin glargine in type 2 diabetes and increased cardiovascular risk (SURPASS-4): a randomised, open-label, parallel-group, multicentre, phase 3 trial. Lancet. 2021;398(10313):1811–24. DOI: 10.1016/S0140-6736(21)02188-7

117. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML; Retatrutide Phase 2 Obesity Trial Investigators. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med. 2023;389(6):514-26. DOI: 10.1056/NEJMoa2301972

118. Fosgerau K, Jessen L, Lind Tolborg J, Østerlund T, Schæffer Larsen K, Rolsted K, Brorson M, Jelsing J, Skovlund Ryge Neerup T. The novel GLP-1-gastrin dual agonist, ZP3022, increases β-cell mass and prevents diabetes in db/db mice. Diabetes Obes Metab. 2013;15(1):62–71. DOI: 10.1111/j.1463-1326.2012.01676.x

119. Chodorge M, Celeste AJ, Grimsby J, Konkar A, Davidsson P, Fairman D, Jenkinson L, Naylor J, White N, Seaman JC, Dickson K, Kemp B, Spooner J, Rossy E, Hornigold DC, Trevaskis JL, Bond NJ, London TB, Buchanan A, Vaughan T, Rondinone CM, Osbourn JK. Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment. Sci Rep. 2018;8(1):17545. DOI: 10.1038/s41598-018-35869-4

120. Jain M, Carlson G, Cook W, Morrow L, Petrone M, White NE, Wang T, Naylor J, Ambery P, Lee C, Hirshberg B. Randomised, phase 1, dose-finding study of MEDI4166, a PCSK9 antibody and GLP-1 analogue fusion molecule, in overweight or obese patients with type 2 diabetes mellitus. Diabetologia. 2019;62(3):373–86. DOI: 10.1007/s00125-018-4789-6