Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1

Cell Metabolism

Volumn 27, Issue 4, 2018, Pages 740-756

  Drucker, Daniel J ^a  

^a MOUNT SINAI HOSPITAL   (Canada)

Author keywords

body weight; cardiovascular disease; diabetes; drug; G protein coupled receptor; hypertension; incretin; inflammation; metabolism; obesity

Indexed keywords

GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; ANTIDIABETIC AGENT; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; INSULIN;

B LYMPHOCYTE; CARDIOMETABOLIC RISK; CLINICAL OUTCOME; DRUG MECHANISM; DRUG SAFETY; FOOD INTAKE; GASTROINTESTINAL TRACT; GENETIC LINKAGE; GENETIC VARIATION; GLUCOSE HOMEOSTASIS; HUMAN; HYPOTHALAMUS; INFLAMMATION; INSULIN DEPENDENT DIABETES MELLITUS; INSULIN SENSITIVITY; INTESTINE FLORA; LIVER; METABOLIC DISORDER; NONHUMAN; PANCREAS ISLET; REVIEW; RHOMBENCEPHALON; SIGNAL TRANSDUCTION; AGONISTS; ANIMAL; BODY WEIGHT GAIN; DRUG EFFECT; EATING; GLUCOSE BLOOD LEVEL; METABOLISM; MOUSE; NON INSULIN DEPENDENT DIABETES MELLITUS; OBESITY; PHYSIOLOGY; RAT;

ANIMALS; BLOOD GLUCOSE; DIABETES MELLITUS, TYPE 1; DIABETES MELLITUS, TYPE 2; EATING; GLUCAGON-LIKE PEPTIDE 1; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; MICE; OBESITY; RATS; WEIGHT GAIN;

EID: 85044154182     PISSN: 15504131     EISSN: 19327420     Source Type: Journal    
DOI: 10.1016/j.cmet.2018.03.001     Document Type: Review

References (141)

1. Ahrén, B., Hirsch, I.B., Pieber, T.R., Mathieu, C., Gomez-Peralta, F., Hansen, T.K., Philotheou, A., Birch, S., Christiansen, E., Jensen, T.J., et al. Efficacy and safety of liraglutide added to capped insulin treatment in subjects with type 1 diabetes: the ADJUNCT TWO randomized trial. Diabetes Care 39 (2016), 1693–1701.
2. Armstrong, M.J., Gaunt, P., Aithal, G.P., Barton, D., Hull, D., Parker, R., Hazlehurst, J.M., Guo, K.LEAN Trial Team, Abouda, G., Aldersley, M.A., et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet 387 (2016), 679–690.
3. Astrup, A., Rössner, S., Van Gaal, L., Rissanen, A., Niskanen, L., Al Hakim, M., Madsen, J., Rasmussen, M.F., Lean, M.E., NN8022-1807 Study Group. Effects of liraglutide in the treatment of obesity: a randomised, double-blind, placebo-controlled study. Lancet 374 (2009), 1606–1616.
4. Athauda, D., Maclagan, K., Skene, S.S., Bajwa-Joseph, M., Letchford, D., Chowdhury, K., Hibbert, S., Budnik, N., Zampedri, L., Dickson, J., et al. Exenatide once weekly versus placebo in Parkinson's disease: a randomised, double-blind, placebo-controlled trial. Lancet 390 (2017), 1664–1675.
5. Aviles-Olmos, I., Dickson, J., Kefalopoulou, Z., Djamshidian, A., Ell, P., Soderlund, T., Whitton, P., Wyse, R., Isaacs, T., Lees, A., et al. Exenatide and the treatment of patients with Parkinson's disease. J. Clin. Invest. 123 (2013), 2730–2736.
6. Baggio, L.L., Yusta, B., Mulvihill, E.E., Cao, X., Streutker, C.J., Butany, J., Cappola, T.P., Margulies, K.B., Drucker, D.J., GLP-1 receptor expression within the human heart. Endocrinology 159 (2018), 1570–1584.
7. Bethel, M.A., Patel, R.A., Merrill, P., Lokhnygina, Y., Buse, J.B., Mentz, R.J., Pagidipati, N.J., Chan, J.C., Gustavson, S.M., Iqbal, N., et al., EXSCEL Study Group. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 6 (2018), 105–113.
8. Bjerre Knudsen, L., Madsen, L.W., Andersen, S., Almholt, K., de Boer, A.S., Drucker, D.J., Gotfredsen, C., Egerod, F.L., Hegelund, A.C., Jacobsen, H., et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology 151 (2010), 1473–1486.
9. Breton, J., Tennoune, N., Lucas, N., Francois, M., Legrand, R., Jacquemot, J., Goichon, A., Guérin, C., Peltier, J., Pestel-Caron, M., et al. Gut commensal E. coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab. 23 (2016), 324–334.
10. Bunck, M.C., Cornér, A., Eliasson, B., Heine, R.J., Shaginian, R.M., Taskinen, M.R., Smith, U., Yki-Järvinen, H., Diamant, M., Effects of exenatide on measures of beta-cell function after 3 years in metformin-treated patients with type 2 diabetes. Diabetes Care 34 (2011), 2041–2047.
11. Burmeister, M.A., Ayala, J.E., Smouse, H., Landivar-Rocha, A., Brown, J.D., Drucker, D.J., Stoffers, D.A., Sandoval, D.A., Seeley, R.J., Ayala, J.E., The hypothalamic glucagon-like peptide 1 receptor is sufficient but not necessary for the regulation of energy balance and glucose homeostasis in mice. Diabetes 66 (2017), 372–384.
12. Campbell, J.E., Drucker, D.J., Pharmacology, physiology, and mechanisms of incretin hormone action. Cell Metab. 17 (2013), 819–837.
13. Carmody, J.S., Muñoz, R., Yin, H., Kaplan, L.M., Peripheral, but not central, GLP-1 receptor signaling is required for improvement in glucose tolerance after Roux-en-Y gastric bypass in mice. Am. J. Physiol. Endocrinol. Metab. 310 (2016), E855–E861.
14. Chadwick, K.D., Fletcher, A.M., Parrula, M.C., Bonner-Weir, S., Mangipudy, R.S., Janovitz, E., Graziano, M.J., Roy, D., Reilly, T.P., Occurrence of spontaneous pancreatic lesions in normal and diabetic rats: a potential confounding factor in the nonclinical assessment of GLP-1-based therapies. Diabetes 63 (2014), 1303–1314.
15. Chimerel, C., Emery, E., Summers, D.K., Keyser, U., Gribble, F.M., Reimann, F., Bacterial metabolite indole modulates incretin secretion from intestinal enteroendocrine L cells. Cell Rep. 9 (2014), 1202–1208.
16. Cohen, L.J., Esterhazy, D., Kim, S.H., Lemetre, C., Aguilar, R.R., Gordon, E.A., Pickard, A.J., Cross, J.R., Emiliano, A.B., Han, S.M., et al. Commensal bacteria make GPCR ligands that mimic human signalling molecules. Nature 549 (2017), 48–53.
17. Dai, C., Hang, Y., Shostak, A., Poffenberger, G., Hart, N., Prasad, N., Phillips, N., Levy, S.E., Greiner, D.L., Shultz, L.D., et al. Age-dependent human beta cell proliferation induced by glucagon-like peptide 1 and calcineurin signaling. J. Clin. Invest. 127 (2017), 3835–3844.
18. Davies, M., Pieber, T.R., Hartoft-Nielsen, M.L., Hansen, O.K.H., Jabbour, S., Rosenstock, J., Effect of oral semaglutide compared with placebo and subcutaneous semaglutide on glycemic control in patients with type 2 diabetes: a randomized clinical trial. JAMA 318 (2017), 1460–1470.
19. de Heer, J., Rasmussen, C., Coy, D.H., Holst, J.J., Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia 51 (2008), 2263–2270.
20. DeFronzo, R.A., Buse, J.B., Kim, T., Burns, C., Skare, S., Baron, A., Fineman, M., Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia 59 (2016), 1645–1654.
21. Drucker, D.J., Incretin action in the pancreas: potential promise, possible perils, and pathological pitfalls. Diabetes 62 (2013), 3316–3323.
22. Drucker, D.J., The cardiovascular biology of glucagon-like peptide-1. Cell Metab. 24 (2016), 15–30.
23. Drucker, D.J., Evolving concepts and translational relevance of enteroendocrine cell biology. J. Clin. Endocrinol. Metab. 101 (2016), 778–786.
24. Drucker, D.J., Habener, J.F., Holst, J.J., Discovery, characterization, and clinical development of the glucagon-like peptides. J. Clin. Invest. 127 (2017), 4217–4227.
25. Drucker, D.J., Nauck, M.A., The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368 (2006), 1696–1705.
26. Drucker, D.J., Yusta, B., Physiology and pharmacology of the enteroendocrine hormone glucagon-like peptide-2. Annu. Rev. Physiol. 76 (2014), 561–583.
27. Edwards, C.M., Todd, J.F., Mahmoudi, M., Wang, Z., Wang, R.M., Ghatei, M.A., Bloom, S.R., Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39. Diabetes 48 (1999), 86–93.
28. Egan, A.G., Blind, E., Dunder, K., de Graeff, P.A., Hummer, B.T., Bourcier, T., Rosebraugh, C., Pancreatic safety of incretin-based drugs—FDA and EMA assessment. N. Engl. J. Med. 370 (2014), 794–797.
29. Ellingsgaard, H., Hauselmann, I., Schuler, B., Habib, A.M., Baggio, L.L., Meier, D.T., Eppler, E., Bouzakri, K., Wueest, S., Muller, Y.D., et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat. Med. 17 (2011), 1481–1489.
30. Faillie, J.L., Yu, O.H., Yin, H., Hillaire-Buys, D., Barkun, A., Azoulay, L., Association of bile duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes mellitus. JAMA Intern. Med. 176 (2016), 1474–1481.
31. Finan, B., Ma, T., Ottaway, N., Muller, T.D., Habegger, K.M., Heppner, K.M., Kirchner, H., Holland, J., Hembree, J., Raver, C., et al. Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci. Transl. Med., 5, 2013, 209ra151.
32. Finan, B., Yang, B., Ottaway, N., Smiley, D.L., Ma, T., Clemmensen, C., Chabenne, J., Zhang, L., Habegger, K.M., Fischer, K., et al. A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat. Med. 21 (2015), 27–36.
33. Flock, G., Baggio, L.L., Longuet, C., Drucker, D.J., Incretin receptors for glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide are essential for the sustained metabolic actions of vildagliptin in mice. Diabetes 56 (2007), 3006–3013.
34. Frias, J.P., Bastyr, E.J. 3rd, Vignati, L., Tschop, M.H., Schmitt, C., Owen, K., Christensen, R.H., DiMarchi, R.D., The sustained effects of a dual GIP/GLP-1 receptor agonist, NNC0090-2746, in patients with type 2 diabetes. Cell Metab. 26 (2017), 343–352.e2.
35. Garibay, D., McGavigan, A.K., Lee, S.A., Ficorilli, J.V., Cox, A.L., Michael, M.D., Sloop, K.W., Cummings, B.P., Beta-cell glucagon-like peptide-1 receptor contributes to improved glucose tolerance after vertical sleeve gastrectomy. Endocrinology 157 (2016), 3405–3409.
36. Gaykema, R.P., Newmyer, B.A., Ottolini, M., Raje, V., Warthen, D.M., Lambeth, P.S., Niccum, M., Yao, T., Huang, Y., Schulman, I.G., et al. Activation of murine pre-proglucagon-producing neurons reduces food intake and body weight. J. Clin. Invest. 127 (2017), 1031–1045.
37. Graaf, C., Donnelly, D., Wootten, D., Lau, J., Sexton, P.M., Miller, L.J., Ahn, J.M., Liao, J., Fletcher, M.M., Yang, D., et al. Glucagon-like peptide-1 and its class B G protein-coupled receptors: a long march to therapeutic successes. Pharmacol. Rev. 68 (2016), 954–1013.
38. Grasset, E., Puel, A., Charpentier, J., Collet, X., Christensen, J.E., Tercé, F., Burcelin, R., A specific gut microbiota dysbiosis of type 2 diabetic mice induces GLP-1 resistance through an enteric NO-dependent and gut-brain axis mechanism. Cell Metab. 25 (2017), 1075–1090.e5.
39. Hansotia, T., Maida, A., Flock, G., Yamada, Y., Tsukiyama, K., Seino, Y., Drucker, D.J., Extrapancreatic incretin receptors modulate glucose homeostasis, body weight, and energy expenditure. J. Clin. Invest. 117 (2007), 143–152.
40. Hayes, M.R., Bradley, L., Grill, H.J., Endogenous hindbrain glucagon-like peptide-1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling. Endocrinology 150 (2009), 2654–2659.
41. Hayes, M.R., Leichner, T.M., Zhao, S., Lee, G.S., Chowansky, A., Zimmer, D., De Jonghe, B.C., Kanoski, S.E., Grill, H.J., Bence, K.K., Intracellular signals mediating the food intake-suppressive effects of hindbrain glucagon-like peptide-1 receptor activation. Cell Metab. 13 (2011), 320–330.
42. Hegedüs, L., Moses, A.C., Zdravkovic, M., Thi, T.L., Daniels, G.H., GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J. Clin. Endocrinol. Metab. 96 (2011), 853–860.
43. Holman, R.R., Bethel, M.A., Mentz, R.J., Thompson, V.P., Lokhnygina, Y., Buse, J.B., Chan, J.C., Choi, J., Gustavson, S.M., Iqbal, N., et al., EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 377 (2017), 1228–1239.
44. Hou, Y., Ernst, S.A., Heidenreich, K., Williams, J.A., Glucagon-like peptide-1 receptor is present in pancreatic acinar cells and regulates amylase secretion through cAMP. Am. J. Physiol. Gastrointest. Liver Physiol. 310 (2016), G26–G33.
45. Hsieh, J., Longuet, C., Baker, C.L., Qin, B., Federico, L.M., Drucker, D.J., Adeli, K., The glucagon-like peptide 1 receptor is essential for postprandial lipoprotein synthesis and secretion in hamsters and mice. Diabetologia 53 (2010), 552–561.
46. Hwang, I., Park, Y.J., Kim, Y.R., Kim, Y.N., Ka, S., Lee, H.Y., Seong, J.K., Seok, Y.J., Kim, J.B., Alteration of gut microbiota by vancomycin and bacitracin improves insulin resistance via glucagon-like peptide 1 in diet-induced obesity. FASEB J. 29 (2015), 2397–2411.
47. Hyltén-Cavallius, L., Iepsen, E.W., Wewer Albrechtsen, N.J., Svendstrup, M., Lubberding, A.F., Hartmann, B., Jespersen, T., Linneberg, A., Christiansen, M., Vestergaard, H., et al. Patients with long-QT syndrome caused by impaired hERG-encoded Kv11.1 potassium channel have exaggerated endocrine pancreatic and incretin function associated with reactive hypoglycemia. Circulation 135 (2017), 1705–1719.
48. Iwasaki, Y., Sendo, M., Dezaki, K., Hira, T., Sato, T., Nakata, M., Goswami, C., Aoki, R., Arai, T., Kumari, P., et al. GLP-1 release and vagal afferent activation mediate the beneficial metabolic and chronotherapeutic effects of D-allulose. Nat. Commun., 9, 2018, 113.
49. Jazayeri, A., Rappas, M., Brown, A.J.H., Kean, J., Errey, J.C., Robertson, N.J., Fiez-Vandal, C., Andrews, S.P., Congreve, M., Bortolato, A., et al. Crystal structure of the GLP-1 receptor bound to a peptide agonist. Nature 546 (2017), 254–258.
50. Jorsal, A., Kistorp, C., Holmager, P., Tougaard, R.S., Nielsen, R., Hänselmann, A., Nilsson, B., Møller, J.E., Hjort, J., Rasmussen, J., et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial. Eur. J. Heart Fail. 19 (2017), 69–77.
51. Keller, J., Trautmann, M.E., Haber, H., Tham, L.S., Hunt, T., Mace, K., Linnebjerg, H., Effect of exenatide on cholecystokinin-induced gallbladder emptying in fasting healthy subjects. Regul. Pept. 179 (2012), 77–83.
52. Kim, M., Platt, M., Shibasaki, T., Quaggin, S., Backx, P.H., Seino, S., Simpson, J., Drucker, D.J., GLP-1 receptor activation and Epac2 link atrial natriuretic peptide secretion to control of blood pressure. Nat. Med. 19 (2013), 567–575.
53. Kinzig, K.P., D'Alessio, D.A., Seeley, R.J., The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J. Neurosci. 22 (2002), 10470–10476.
54. Kirk, R.K., Pyke, C., von Herrath, M.G., Hasselby, J.P., Pedersen, L., Mortensen, P.G., Knudsen, L.B., Coppieters, K., Immunohistochemical assessment of glucagon-like peptide 1 receptor (GLP-1R) expression in the pancreas of patients with type 2 diabetes. Diabetes Obes. Metab. 19 (2017), 705–712.
55. Koehler, J.A., Baggio, L.L., Cao, X., Abdulla, T., Campbell, J.E., Secher, T., Jelsing, J., Larsen, B., Drucker, D.J., Glucagon-like peptide-1 receptor agonists increase pancreatic mass by induction of protein synthesis. Diabetes 64 (2015), 1046–1056.
56. Koehler, J.A., Baggio, L.L., Yusta, B., Longuet, C., Rowland, K.J., Cao, X., Holland, D., Brubaker, P.L., Drucker, D.J., GLP-1R agonists promote normal and neoplastic intestinal growth through mechanisms requiring Fgf7. Cell Metab. 21 (2015), 379–391.
57. Krieger, J.P., Arnold, M., Pettersen, K.G., Lossel, P., Langhans, W., Lee, S.J., Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia. Diabetes 65 (2016), 34–43.
58. Lamont, B.J., Li, Y., Kwan, E., Brown, T.J., Gaisano, H., Drucker, D.J., Pancreatic GLP-1 receptor activation is sufficient for incretin control of glucose metabolism in mice. J. Clin. Invest. 122 (2012), 388–402.
59. Landgraf, D., Tsang, A.H., Leliavski, A., Koch, C.E., Barclay, J.L., Drucker, D.J., Oster, H., Oxyntomodulin regulates resetting of the liver circadian clock by food. Elife, 4, 2015, e06253.
60. Lebherz, C., Schlieper, G., Mollmann, J., Kahles, F., Schwarz, M., Brunsing, J., Dimkovic, N., Koch, A., Trautwein, C., Floge, J., et al. GLP-1 levels predict mortality in patients with critical illness as well as end-stage renal disease. Am. J. Med. 130 (2017), 833–841.e3.
61. Lebrun, L.J., Lenaerts, K., Kiers, D., Pais de Barros, J.P., Le Guern, N., Plesnik, J., Thomas, C., Bourgeois, T., Dejong, C.H.C., Kox, M., et al. Enteroendocrine L cells sense LPS after gut barrier injury to enhance GLP-1 secretion. Cell Rep. 21 (2017), 1160–1168.
62. Liu, J., Conde, K., Zhang, P., Lilascharoen, V., Xu, Z., Lim, B.K., Seeley, R.J., Zhu, J.J., Scott, M.M., Pang, Z.P., Enhanced AMPA receptor trafficking mediates the anorexigenic effect of endogenous glucagon-like peptide-1 in the paraventricular hypothalamus. Neuron 96 (2017), 897–909.e5.
63. López-Ferreras, L., Richard, J.E., Noble, E.E., Eerola, K., Anderberg, R.H., Olandersson, K., Taing, L., Kanoski, S.E., Hayes, M.R., Skibicka, K.P., Lateral hypothalamic GLP-1 receptors are critical for the control of food reinforcement, ingestive behavior and body weight. Mol. Psychiatry, 2017, 10.1038/mp.2017.187 Published online September 12, 2017.
64. Lynch, L., Hogan, A.E., Duquette, D., Lester, C., Banks, A., LeClair, K., Cohen, D.E., Ghosh, A., Lu, B., Corrigan, M., et al. iNKT cells induce FGF21 for thermogenesis and are required for maximal weight loss in GLP1 therapy. Cell Metab. 24 (2016), 510–519.
65. Madsbad, S., Dirksen, C., Holst, J.J., Mechanisms of changes in glucose metabolism and bodyweight after bariatric surgery. Lancet Diabetes Endocrinol. 2 (2014), 152–164.
66. Maida, A., Lamont, B.J., Cao, X., Drucker, D.J., Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia 54 (2011), 339–349.
67. Margulies, K.B., Hernandez, A.F., Redfield, M.M., Givertz, M.M., Oliveira, G.H., Cole, R., Mann, D.L., Whellan, D.J., Kiernan, M.S., Felker, G.M., et al., NHLBI Heart Failure Clinical Research Network. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA 316 (2016), 500–508.
68. Marso, S.P., Bain, S.C., Consoli, A., Eliaschewitz, F.G., Jodar, E., Leiter, L.A., Lingvay, I., Rosenstock, J., Seufert, J., Warren, M.L., et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 375 (2016), 1834–1844.
69. Marso, S.P., Daniels, G.H., Brown-Frandsen, K., Kristensen, P., Mann, J.F., Nauck, M.A., Nissen, S.E., Pocock, S., Poulter, N.R., Ravn, L.S., et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 375 (2016), 311–322.
70. Mathieu, C., Zinman, B., Hemmingsson, J.U., Woo, V., Colman, P., Christiansen, E., Linder, M., Bode, B., ADJUNCT ONE Investigators. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: the ADJUNCT ONE treat-to-target randomized trial. Diabetes Care 39 (2016), 1702–1710.
71. Mayo, K.E., Miller, L.J., Bataille, D., Dalle, S., Göke, B., Thorens, B., Drucker, D.J., International union of pharmacology. XXXV. The glucagon receptor family. Pharmacol. Rev. 55 (2003), 167–194.
72. Meeran, K., O'Shea, D., Edwards, C.M., Turton, M.D., Heath, M.M., Gunn, I., Abusnana, S., Rossi, M., Small, C.J., Goldstone, A.P., et al. Repeated intracerebroventricular administration of glucagon-like peptide-1-(7-36) amide or exendin-(9-39) alters body weight in the rat. Endocrinology 140 (1999), 244–250.
73. Migoya, E.M., Bergeron, R., Miller, J.L., Snyder, R.N., Tanen, M., Hilliard, D., Weiss, B., Larson, P., Gutierrez, M., Jiang, G., et al. Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1. Clin. Pharmacol. Ther. 88 (2010), 801–808.
74. Mikkelsen, K.H., Frost, M., Bahl, M.I., Licht, T.R., Jensen, U.S., Rosenberg, J., Pedersen, O., Hansen, T., Rehfeld, J.F., Holst, J.J., et al. Effect of antibiotics on gut microbiota, gut hormones and glucose metabolism. PLoS One, 10, 2015, e0142352.
75. Mokadem, M., Zechner, J.F., Margolskee, R.F., Drucker, D.J., Aguirre, V., Effects of Roux-en-Y gastric bypass on energy and glucose homeostasis are preserved in two mouse models of functional glucagon-like peptide-1 deficiency. Mol. Metab. 3 (2014), 191–201.
76. Muraro, M.J., Dharmadhikari, G., Grun, D., Groen, N., Dielen, T., Jansen, E., van Gurp, L., Engelse, M.A., Carlotti, F., de Koning, E.J., van Oudenaarden, A., A single-cell transcriptome atlas of the human pancreas. Cell Syst. 3 (2016), 385–394.e3.
77. Napolitano, A., Miller, S., Nicholls, A.W., Baker, D., Van Horn, S., Thomas, E., Rajpal, D., Spivak, A., Brown, J.R., Nunez, D.J., Novel gut-based pharmacology of metformin in patients with type 2 diabetes mellitus. PLoS One, 9, 2014, e100778.
78. Nauck, M.A., Kemmeries, G., Holst, J.J., Meier, J.J., Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60 (2011), 1561–1565.
79. Nauck, M.A., Sauerwald, A., Ritzel, R., Holst, J.J., Schmiegel, W., Influence of glucagon-like peptide 1 on fasting glycemia in type 2 diabetic patients treated with insulin after sulfonylurea secondary failure. Diabetes Care 21 (1998), 1925–1931.
80. Nguyen, A.T., Mandard, S., Dray, C., Deckert, V., Valet, P., Besnard, P., Drucker, D.J., Lagrost, L., Grober, J., Lipopolysaccharides-mediated increase in glucose-stimulated insulin secretion: involvement of the GLP-1 pathway. Diabetes 63 (2014), 471–482.
81. Nogueiras, R., Pérez-Tilve, D., Veyrat-Durebex, C., Morgan, D.A., Varela, L., Haynes, W.G., Patterson, J.T., Disse, E., Pfluger, P.T., Lopez, M., et al. Direct control of peripheral lipid deposition by CNS GLP-1 receptor signaling is mediated by the sympathetic nervous system and blunted in diet-induced obesity. J. Neurosci. 29 (2009), 5916–5925.
82. Panjwani, N., Mulvihill, E.E., Longuet, C., Yusta, B., Campbell, J.E., Brown, T.J., Streutker, C., Holland, D., Cao, X., Baggio, L.L., Drucker, D.J., GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE-/- mice. Endocrinology 154 (2013), 127–139.
83. Parks, M., Rosebraugh, C., Weighing risks and benefits of liraglutide—the FDA's review of a new antidiabetic therapy. N. Engl. J. Med. 362 (2010), 774–777.
84. Patterson, J.T., Ottaway, N., Gelfanov, V.M., Smiley, D.L., Perez-Tilve, D., Pfluger, P.T., Tschöp, M.H., Dimarchi, R.D., A novel human-based receptor antagonist of sustained action reveals body weight control by endogenous GLP-1. ACS Chem. Biol. 6 (2011), 135–145.
85. Pfeffer, M.A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H.C., Kober, L.V., Lawson, F.C., Ping, L., Wei, X., Lewis, E.F., et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373 (2015), 2247–2257.
86. Plamboeck, A., Veedfald, S., Deacon, C.F., Hartmann, B., Vilsbøll, T., Knop, F.K., Holst, J.J., The role of efferent cholinergic transmission for the insulinotropic and glucagonostatic effects of GLP-1. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309 (2015), R544–R551.
87. Plamboeck, A., Veedfald, S., Deacon, C.F., Hartmann, B., Wettergren, A., Svendsen, L.B., Meisner, S., Hovendal, C., Vilsbøll, T., Knop, F.K., Holst, J.J., The effect of exogenous GLP-1 on food intake is lost in male truncally vagotomized subjects with pyloroplasty. Am. J. Physiol. Gastrointest. Liver Physiol. 304 (2013), G1117–G1127.
88. Preiss, D., Dawed, A., Welsh, P., Heggie, A., Jones, A.G., Dekker, J., Koivula, R., Hansen, T.H., Stewart, C., Holman, R.R., et al. Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes. Diabetes Obes. Metab. 19 (2017), 356–363.
89. Pyke, C., Heller, R.S., Kirk, R.K., Ørskov, C., Reedtz-Runge, S., Kaastrup, P., Hvelplund, A., Bardram, L., Calatayud, D., Knudsen, L.B., GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155 (2014), 1280–1290.
90. Rankin, M.M., Kushner, J.A., Adaptive beta cell proliferation is severely restricted with advanced age. Diabetes 58 (2009), 1365–1372.
91. Reijnders, D., Goossens, G.H., Hermes, G.D., Neis, E.P., van der Beek, C.M., Most, J., Holst, J.J., Lenaerts, K., Kootte, R.S., Nieuwdorp, M., et al. Effects of gut microbiota manipulation by antibiotics on host metabolism in obese humans: a randomized double-blind placebo-controlled trial. Cell Metab. 24 (2016), 63–74.
92. Reiner, D.J., Mietlicki-Baase, E.G., McGrath, L.E., Zimmer, D.J., Bence, K.K., Sousa, G.L., Konanur, V.R., Krawczyk, J., Burk, D.H., Kanoski, S.E., et al. Astrocytes regulate GLP-1 receptor-mediated effects on energy balance. J. Neurosci. 36 (2016), 3531–3540.
93. Retnakaran, R., Kramer, C.K., Choi, H., Swaminathan, B., Zinman, B., Liraglutide and the preservation of pancreatic beta-cell function in early type 2 diabetes: the LIBRA trial. Diabetes Care 37 (2014), 3270–3278.
94. Richards, P., Parker, H.E., Adriaenssens, A.E., Hodgson, J.M., Cork, S.C., Trapp, S., Gribble, F.M., Reimann, F., Identification and characterisation of glucagon-like peptide-1 receptor expressing cells using a new transgenic mouse model. Diabetes 63 (2014), 1224–1233.
95. Rother, K.I., Spain, L.M., Wesley, R.A., Digon, B.J. 3rd, Baron, A., Chen, K., Nelson, P., Dosch, H.M., Palmer, J.P., Brooks-Worrell, B., et al. Effects of exenatide alone and in combination with daclizumab on beta-cell function in long-standing type 1 diabetes. Diabetes Care 32 (2009), 2251–2257.
96. Sadry, S.A., Drucker, D.J., Emerging combinatorial hormone therapies for the treatment of obesity and T2DM. Nat. Rev. Endocrinol. 9 (2013), 425–433.
97. Salehi, M., Gastaldelli, A., D'Alessio, D.A., Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology 146 (2014), 669–680.e2.
98. Sandoval, D.A., Bagnol, D., Woods, S.C., D'Alessio, D.A., Seeley, R.J., Arcuate glucagon-like peptide 1 receptors regulate glucose homeostasis but not food intake. Diabetes 57 (2008), 2046–2054.
99. Scott, R.A., Freitag, D.F., Li, L., Chu, A.Y., Surendran, P., Young, R., Grarup, N., Stancáková, A., Chen, Y., Varga, T.V., et al. A genomic approach to therapeutic target validation identifies a glucose-lowering GLP1R variant protective for coronary heart disease. Sci. Transl. Med., 8, 2016, 341ra376.
100. Scrocchi, L.A., Brown, T.J., MacLusky, N., Brubaker, P.L., Auerbach, A.B., Joyner, A.L., Drucker, D.J., Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide receptor gene. Nat. Med. 2 (1996), 1254–1258.
101. Secher, A., Jelsing, J., Baquero, A.F., Hecksher-Sørensen, J., Cowley, M.A., Dalbøge, L.S., Hansen, G., Grove, K.L., Pyke, C., Raun, K., et al. The arcuate nucleus mediates GLP-1 receptor agonist liraglutide-dependent weight loss. J. Clin. Invest. 124 (2014), 4473–4488.
102. Segerstolpe, A., Palasantza, A., Eliasson, P., Andersson, E.M., Andreasson, A.C., Sun, X., Picelli, S., Sabirsh, A., Clausen, M., Bjursell, M.K., et al. Single-cell transcriptome profiling of human pancreatic islets in health and type 2 diabetes. Cell Metab. 24 (2016), 593–607.
103. Shaddinger, B.C., Young, M.A., Billiard, J., Collins, D.A., Hussaini, A., Nino, A., Effect of albiglutide on cholecystokinin-induced gallbladder emptying in healthy individuals: a randomized crossover study. J. Clin. Pharmacol. 57 (2017), 1322–1329.
104. Shah, H.S., Morieri, M.L., Marcovina, S.M., Sigal, R.J., Gerstein, H.C., Wagner, M.J., Motsinger-Reif, A.A., Buse, J.B., Kraft, P., Mychaleckyj, J.C., Doria, A., Modulation of GLP-1 levels by a genetic variant that regulates the cardiovascular effects of intensive glycemic control in ACCORD. Diabetes Care 41 (2018), 348–355.
105. Shah, M., Law, J.H., Micheletto, F., Sathananthan, M., Dalla Man, C., Cobelli, C., Rizza, R.A., Camilleri, M., Zinsmeister, A.R., Vella, A., Contribution of endogenous glucagon-like peptide 1 to glucose metabolism after Roux-en-Y gastric bypass. Diabetes 63 (2014), 483–493.
106. Simon, M.C., Strassburger, K., Nowotny, B., Kolb, H., Nowotny, P., Burkart, V., Zivehe, F., Hwang, J.H., Stehle, P., Pacini, G., et al. Intake of Lactobacillus reuteri improves incretin and insulin secretion in glucose-tolerant humans: a proof of concept. Diabetes Care 38 (2015), 1827–1834.
107. Simonsen, L., Pilgaard, S., Orskov, C., Rosenkilde, M.M., Hartmann, B., Holst, J.J., Deacon, C.F., Exendin-4, but not dipeptidyl peptidase IV inhibition, increases small intestinal mass in GK rats. Am. J. Physiol. Gastrointest. Liver Physiol. 293 (2007), G288–G295.
108. Sisley, S., Gutierrez-Aguilar, R., Scott, M., D'Alessio, D.A., Sandoval, D.A., Seeley, R.J., Neuronal GLP1R mediates liraglutide's anorectic but not glucose-lowering effect. J. Clin. Invest. 124 (2014), 2456–2463.
109. Sjoberg, K.A., Holst, J.J., Rattigan, S., Richter, E.A., Kiens, B., GLP-1 increases microvascular recruitment but not glucose uptake in human and rat skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 306 (2014), E355–E362.
110. Smith, E.P., An, Z., Wagner, C., Lewis, A.G., Cohen, E.B., Li, B., Mahbod, P., Sandoval, D., Perez-Tilve, D., Tamarina, N., et al. The role of beta cell glucagon-like peptide-1 signaling in glucose regulation and response to diabetes drugs. Cell Metab. 19 (2014), 1050–1057.
111. Smits, M.M., Tonneijck, L., Muskiet, M.H., Hoekstra, T., Kramer, M.H., Diamant, M., Nieuwdorp, M., Groen, A.K., Cahen, D.L., van Raalte, D.H., Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients. Diabetes Obes. Metab. 18 (2016), 1217–1225.
112. Smits, M.M., Tonneijck, L., Muskiet, M.H., Hoekstra, T., Kramer, M.H., Diamant, M., Serne, E.H., van Raalte, D.H., GLP-1-based therapies have no microvascular effects in type 2 diabetes mellitus: an acute and 12-week randomized, double-blind, placebo-controlled trial. Arterioscler. Thromb. Vasc. Biol. 36 (2016), 2125–2132.
113. Smushkin, G., Sathananthan, M., Sathananthan, A., Dalla Man, C., Micheletto, F., Zinsmeister, A.R., Cobelli, C., Vella, A., Diabetes-associated common genetic variation and its association with GLP-1 concentrations and response to exogenous GLP-1. Diabetes 61 (2012), 1082–1089.
114. Song, G., Yang, D., Wang, Y., de Graaf, C., Zhou, Q., Jiang, S., Liu, K., Cai, X., Dai, A., Lin, G., et al. Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators. Nature 546 (2017), 312–315.
115. Steinberg, W.M., Rosenstock, J., Wadden, T.A., Donsmark, M., Jensen, C.B., DeVries, J.H., Impact of liraglutide on amylase, lipase, and acute pancreatitis in participants with overweight/obesity and normoglycemia, prediabetes, or type 2 diabetes: secondary analyses of pooled data from the SCALE clinical development program. Diabetes Care 40 (2017), 839–848.
116. ten Kulve, J.S., Veltman, D.J., van Bloemendaal, L., Barkhof, F., Deacon, C.F., Holst, J.J., Konrad, R.J., Sloan, J.H., Drent, M.L., Diamant, M., et al. Endogenous GLP-1 mediates postprandial reductions in activation in central reward and satiety areas in patients with type 2 diabetes. Diabetologia 58 (2015), 2688–2698.
117. Ten Kulve, J.S., Veltman, D.J., Gerdes, V.E.A., van Bloemendaal, L., Barkhof, F., Deacon, C.F., Holst, J.J., Drent, M.L., Diamant, M., IJzerman, R.G., Elevated postoperative endogenous GLP-1 levels mediate effects of Roux-en-Y gastric bypass on neural responsivity to food cues. Diabetes Care 40 (2017), 1522–1529.
118. Tschen, S.I., Georgia, S., Dhawan, S., Bhushan, A., Skp2 is required for incretin hormone-mediated beta-cell proliferation. Mol. Endocrinol. 25 (2011), 2134–2143.
119. Ussher, J.R., Drucker, D.J., Cardiovascular actions of incretin-based therapies. Circ. Res. 114 (2014), 1788–1803.
120. Vahle, J.L., Byrd, R.A., Blackbourne, J.L., Martin, J.A., Sorden, S.D., Ryan, T., Pienkowski, T., Wijsman, J.A., Smith, H.W., Rosol, T.J., Effects of dulaglutide on thyroid C cells and serum calcitonin in male monkeys. Endocrinology 156 (2015), 2409–2416.
121. van Can, J., Sloth, B., Jensen, C.B., Flint, A., Blaak, E.E., Saris, W.H., Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int. J. Obes. (Lond.) 38 (2014), 784–793.
122. Vetter, M.L., Wadden, T.A., Teff, K.L., Khan, Z.F., Carvajal, R., Ritter, S., Moore, R.H., Chittams, J.L., Iagnocco, A., Murayama, K., et al. GLP-1 plays a limited role in improved glycemia shortly after Roux-en-Y gastric bypass: a comparison with intensive lifestyle modification. Diabetes 64 (2015), 434–446.
123. Wallner, M., Kolesnik, E., Ablasser, K., Khafaga, M., Wakula, P., Ljubojevic, S., Thon-Gutschi, E.M., Sourij, H., Kapl, M., Edmunds, N.J., et al. Exenatide exerts a PKA-dependent positive inotropic effect in human atrial myocardium: GLP-1R mediated effects in human myocardium. J. Mol. Cell. Cardiol. 89 (2015), 365–375.
124. Wang, X.F., Liu, J.J., Xia, J., Liu, J., Mirabella, V., Pang, Z.P., Endogenous glucagon-like peptide-1 suppresses high-fat food intake by reducing synaptic drive onto mesolimbic dopamine neurons. Cell Rep. 12 (2015), 726–733.
125. Waser, B., Blank, A., Karamitopoulou, E., Perren, A., Reubi, J.C., Glucagon-like-peptide-1 receptor expression in normal and diseased human thyroid and pancreas. Mod. Pathol. 28 (2015), 391–402.
126. Wessel, J., Chu, A.Y., Willems, S.M., Wang, S., Yaghootkar, H., Brody, J.A., Dauriz, M., Hivert, M.F., Raghavan, S., Lipovich, L., et al. Low-frequency and rare exome chip variants associate with fasting glucose and type 2 diabetes susceptibility. Nat. Commun., 6, 2015, 5897.
127. Wichmann, A., Allahyar, A., Greiner, T.U., Plovier, H., Lundén, G.Ö., Larsson, T., Drucker, D.J., Delzenne, N.M., Cani, P.D., Bäckhed, F., Microbial modulation of energy availability in the colon regulates intestinal transit. Cell Host Microbe 14 (2013), 582–590.
128. Williams, E.K., Chang, R.B., Strochlic, D.E., Umans, B.D., Lowell, B.B., Liberles, S.D., Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166 (2016), 209–221.
129. Wilson-Pérez, H.E., Chambers, A.P., Ryan, K.K., Li, B., Sandoval, D.A., Stoffers, D., Drucker, D.J., Pérez-Tilve, D., Seeley, R.J., Vertical sleeve gastrectomy is effective in two genetic mouse models of glucagon-like peptide-1 receptor deficiency. Diabetes 62 (2013), 2380–2385.
130. Wootten, D., Reynolds, C.A., Smith, K.J., Mobarec, J.C., Koole, C., Savage, E.E., Pabreja, K., Simms, J., Sridhar, R., Furness, S.G.B., et al. The extracellular surface of the GLP-1 receptor is a molecular trigger for biased agonism. Cell 165 (2016), 1632–1643.
131. Wu, H., Esteve, E., Tremaroli, V., Khan, M.T., Caesar, R., Mannerås-Holm, L., Stahlman, M., Olsson, L.M., Serino, M., Planas-Fèlix, M., et al. Metformin alters the gut microbiome of individuals with treatment-naive type 2 diabetes, contributing to the therapeutic effects of the drug. Nat. Med. 23 (2017), 850–858.
132. Wynne, K., Park, A.J., Small, C.J., Meeran, K., Ghatei, M.A., Frost, G.S., Bloom, S.R., Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int. J. Obes. (Lond) 30 (2006), 1729–1736.
133. Wynne, K., Park, A.J., Small, C.J., Patterson, M., Ellis, S.M., Murphy, K.G., Wren, A.M., Frost, G.S., Meeran, K., Ghatei, M.A., Bloom, S.R., Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 54 (2005), 2390–2395.
134. Xiao, C., Bandsma, R.H., Dash, S., Szeto, L., Lewis, G.F., Exenatide, a glucagon-like peptide receptor agonist, acutely inhibits intestinal lipoprotein production in healthy humans. Arterioscler. Thromb. Vasc. Biol. 32 (2012), 1513–1519.
135. Yamada, C., Yamada, Y., Tsukiyama, K., Yamada, K., Udagawa, N., Takahashi, N., Tanaka, K., Drucker, D.J., Seino, Y., Inagaki, N., The murine glucagon-like peptide-1 receptor is essential for control of bone resorption. Endocrinology 149 (2008), 574–579.
136. Ye, J., Hao, Z., Mumphrey, M.B., Townsend, R.L., Patterson, L.M., Stylopoulos, N., Munzberg, H., Morrison, C.D., Drucker, D.J., Berthoud, H.R., GLP-1 receptor signaling is not required for reduced body weight after RYGB in rodents. Am. J. Physiol. Regul. Integr. Comp. Physiol. 306 (2014), R352–R362.
137. Yusta, B., Baggio, L.L., Estall, J.E., Koehler, J.A., Holland, D.P., Li, H., Pipeleers, D., Ling, Z., Drucker, D.J., GLP-1 receptor activation improves β-cell function and survival following induction of endoplasmic reticulum stress. Cell Metab. 4 (2006), 391–406.
138. Yusta, B., Baggio, L.L., Koehler, J., Holland, D., Cao, X., Pinnell, L.J., Johnson-Henry, K.C., Yeung, W., Surette, M.G., Bang, K.A., et al. GLP-1R agonists modulate enteric immune responses through the intestinal intraepithelial lymphocyte (IEL) GLP-1R. Diabetes 64 (2015), 2537–2549.
139. Yusta, B., Matthews, D., Flock, G.B., Ussher, J.R., Lavoie, B., Mawe, G.M., Drucker, D.J., Glucagon-like peptide-2 promotes gallbladder refilling via a TGR5-independent, GLP-2R-dependent pathway. Mol. Metab. 6 (2017), 503–511.
140. Zhang, H., Sturchler, E., Zhu, J., Nieto, A., Cistrone, P.A., Xie, J., He, L., Yea, K., Jones, T., Turn, R., et al. Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects. Nat. Commun., 6, 2015, 8918.
141. Zhang, Y., Sun, B., Feng, D., Hu, H., Chu, M., Qu, Q., Tarrasch, J.T., Li, S., Sun Kobilka, T., Kobilka, B.K., Skiniotis, G., Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature 546 (2017), 248–253.