Metabolic Messengers: glucagon-like peptide 1

Abstract

Glucagon like peptide-1 (GLP-1), a peptide hormone from the intestinal tract, plays a central role in the coordination of postprandial glucose homeostasis through actions on insulin secretion, food intake and gut motility. GLP-1 forms the basis for a variety of current drugs for the treatment of type 2 diabetes and obesity, as well as new agents currently being developed. Here, we provide a concise overview of the core physiology of GLP-1 secretion and action, and the role of the peptide in human health, disease and therapeutics.

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Fig. 1: Timeline of GLP-1 discovery and clinical development.
Fig. 2: Food-dependent stimulation of GLP-1 release from small intestine L-cells.
Fig. 3: Major GLP-1 targets.

References

  1. 1.

    Moore, B. On the treatment of diabetus mellitus by acid extract of duodenal mucous membrane. Biochem. J. 1, 28–38 (1906).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Holst, J. J. The physiology of glucagon-like peptide 1. Physiol. Rev. 87, 1409–1439 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Thorens, B. Expression cloning of the pancreatic beta cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc. Natl. Acad. Sci. USA 89, 8641–8645 (1992).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Nauck, M. A. et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36, 741–744 (1993).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Gribble, F. M. & Reimann, F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism. Nat. Rev. Endocrinol. 15, 226–237 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Sjölund, K., Sandén, G., Håkanson, R. & Sundler, F. Endocrine cells in human intestine: an immunocytochemical study. Gastroenterology 85, 1120–1130 (1983).

    PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Lewis, J. E. et al. Selective stimulation of colonic L cells improves metabolic outcomes in mice. Diabetologia 63, 1396–1407 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Batterham, R. L. et al. Inhibition of food intake in obese subjects by peptide YY3-36. N. Engl. J. Med. 349, 941–948 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Gribble, F. M. & Reimann, F. Enteroendocrine cells: chemosensors in the intestinal epithelium. Annu. Rev. Physiol. 78, 277–299 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

    Brubaker, P. L., Schloos, J. & Drucker, D. J. Regulation of glucagon-like peptide-1 synthesis and secretion in the GLUTag enteroendocrine cell line. Endocrinology 139, 4108–4114 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Edfalk, S., Steneberg, P. & Edlund, H. Gpr40 is expressed in enteroendocrine cells and mediates free fatty acid stimulation of incretin secretion. Diabetes 57, 2280–2287 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  12. 12.

    Chu, Z. L. et al. A role for intestinal endocrine cell-expressed G protein-coupled receptor 119 in glycemic control by enhancing glucagon-like peptide-1 and glucose-dependent insulinotropic peptide release. Endocrinology 149, 2038–2047 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Hansen, K. B. et al. 2-Oleoyl glycerol is a GPR119 agonist and signals GLP-1 release in humans. J. Clin. Endocrinol. Metab. 96, E1409–E1417 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Mace, O. J., Schindler, M. & Patel, S. The regulation of K- and L-cell activity by GLUT2 and CasR in rat small intestine. J. Physiol. 590, 2917–2936 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  15. 15.

    Thomas, C. et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab 10, 167–177 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Bolognini, D., Tobin, A. B., Milligan, G. & Moss, C. E. The pharmacology and function of receptors for short-chain fatty acids. Mol. Pharmacol. 89, 388–398 (2016).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  17. 17.

    Pais, R., Rievaj, J., Larraufie, P., Gribble, F. & Reimann, F. Angiotensin II type 1 receptor-dependent GLP-1 and PYY secretion in mice and humans. Endocrinology 157, 3821–3831 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Pais, R. et al. Role of enteroendocrine L-cells in arginine vasopressin-mediated inhibition of colonic anion secretion. J. Physiol. (Lond.) 594, 4865–4878 (2016).

    CAS  Article  Google Scholar 

  19. 19.

    Psichas, A., Glass, L. L., Sharp, S. J., Reimann, F. & Gribble, F. M. Galanin inhibits GLP-1 and GIP secretion via the GAL1 receptor in enteroendocrine L and K cells. Br. J. Pharmacol. 173, 888–898 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Roberge, J. N., Gronau, K. A. & Brubaker, P. L. Gastrin-releasing peptide is a novel mediator of proximal nutrient-induced proglucagon-derived peptide secretion from the distal gut. Endocrinology 137, 2383–2388 (1996).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Jang, H. J. et al. Gut-expressed gustducin and taste receptors regulate secretion of glucagon-like peptide-1. Proc. Natl Acad. Sci. USA 104, 15069–15074 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  22. 22.

    Saltiel, M. Y. et al. Sweet taste receptor activation in the gut is of limited importance for glucose-stimulated GLP-1 and GIP secretion. Nutrients 9, E418 (2017).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  23. 23.

    Reimann, F. et al. Glucose sensing in L cells: a primary cell study. Cell Metab. 8, 532–539 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Gribble, F. M., Williams, L., Simpson, A. K. & Reimann, F. A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line. Diabetes 52, 1147–1154 (2003).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Gorboulev, V. et al. Na+-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion. Diabetes 61, 187–196 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Reimann, F., Williams, L., da Silva Xavier, G., Rutter, G. A. & Gribble, F. M. Glutamine potently stimulates glucagon-like peptide-1 secretion from GLUTag cells. Diabetologia 47, 1592–1601 (2004).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Matsumura, K., Miki, T., Jhomori, T., Gonoi, T. & Seino, S. Possible role of PEPT1 in gastrointestinal hormone secretion. Biochem. Biophys. Res. Commun. 336, 1028–1032 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Diakogiannaki, E. et al. Oligopeptides stimulate glucagon-like peptide-1 secretion in mice through proton-coupled uptake and the calcium-sensing receptor. Diabetologia 56, 2688–2696 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Parker, H. E. et al. Predominant role of active versus facilitative glucose transport for glucagon-like peptide-1 secretion. Diabetologia 55, 2445–2455 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Powell, D. R. et al. LX4211 increases serum glucagon-like peptide 1 and peptide YY levels by reducing sodium/glucose cotransporter 1 (SGLT1)-mediated absorption of intestinal glucose. J. Pharmacol. Exp. Ther. 345, 250–259 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Christiansen, C. B. et al. The impact of short-chain fatty acids on GLP-1 and PYY secretion from the isolated perfused rat colon. Am. J. Physiol. Gastrointest. Liver Physiol. 315, G53–G65 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Jørgensen, N. B. et al. Acute and long-term effects of Roux-en-Y gastric bypass on glucose metabolism in subjects with type 2 diabetes and normal glucose tolerance. Am. J. Physiol. Endocrinol. Metab. 303, E122–E131 (2012).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  33. 33.

    Martinussen, C. et al. The effect of acute dual SGLT1/SGLT2 inhibition on incretin release and glucose metabolism after gastric bypass surgery. Am. J. Physiol. Endocrinol. Metab. 318, E956–E964 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    El-Ouaghlidi, A. et al. The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion. J. Clin. Endocrinol. Metab. 92, 4165–4171 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  35. 35.

    Reimann, F., Tolhurst, G. & Gribble, F. M. G-protein-coupled receptors in intestinal chemosensation. Cell Metab. 15, 421–431 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Goldspink, D. A. et al. Mechanistic insights into the detection of free fatty and bile acids by ileal glucagon-like peptide-1 secreting cells. Mol. Metab. 7, 90–101 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Goldspink, D. A. et al. Labeling and characterization of human GLP-1-secreting L-cells in primary ileal organoid culture. Cell Rep. 31, 107833 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Brighton, C. A. et al. Bile acids trigger GLP-1 release predominantly by accessing basolaterally located G protein-coupled bile acid receptors. Endocrinology 156, 3961–3970 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Christensen, L. W., Kuhre, R. E., Janus, C., Svendsen, B. & Holst, J. J. Vascular, but not luminal, activation of FFAR1 (GPR40) stimulates GLP-1 secretion from isolated perfused rat small intestine. Physiol. Rep. 3, e12551 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Modvig, I. M., Kuhre, R. E. & Holst, J. J. Peptone-mediated glucagon-like peptide-1 secretion depends on intestinal absorption and activation of basolaterally located calcium-sensing receptors. Physiol. Rep. 7, e14056 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  41. 41.

    Llewellyn-Smith, I. J., Reimann, F., Gribble, F. M. & Trapp, S. Preproglucagon neurons project widely to autonomic control areas in the mouse brain. Neuroscience 180, 111–121 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  42. 42.

    Orskov, C., Holst, J. J., Poulsen, S. S. & Kirkegaard, P. Pancreatic and intestinal processing of proglucagon in man. Diabetologia 30, 874–881 (1987).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Rouillé, Y. et al. Proteolytic processing mechanisms in the biosynthesis of neuroendocrine peptides: the subtilisin-like proprotein convertases. Front. Neuroendocrinol. 16, 322–361 (1995).

    PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Larraufie, P. et al. Important role of the GLP-1 axis for glucose homeostasis after bariatric surgery. Cell Rep. 26, 1399–1408.e6 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Song, Y. et al. Gut-proglucagon-derived peptides are essential for regulating glucose homeostasis in mice. Cell Metab. 30, 976–986.e3 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  46. 46.

    Ban, K. et al. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation 117, 2340–2350 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  47. 47.

    Richards, P. et al. Identification and characterization of GLP-1 receptor-expressing cells using a new transgenic mouse model. Diabetes 63, 1224–1233 (2014).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  48. 48.

    Pyke, C. et al. GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. Endocrinology 155, 1280–1290 (2014).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  49. 49.

    He, S. et al. Gut intraepithelial T cells calibrate metabolism and accelerate cardiovascular disease. Nature 566, 115–119 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Baggio, L. L. et al. GLP-1 receptor expression within the human heart. Endocrinology 159, 1570–1584 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    Dhir, G. & Cusi, K. Glucagon like peptide-1 receptor agonists for the management of obesity and non-alcoholic fatty liver disease: a novel therapeutic option. J. Investig. Med. 66, 7–10 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  52. 52.

    Gromada, J., Holst, J. J. & Rorsman, P. Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1. Pflugers Arch. 435, 583–594 (1998).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Creutzfeldt, W. The [pre-] history of the incretin concept. Regul. Pept. 128, 87–91 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  54. 54.

    Nauck, M. A., Bartels, E., Orskov, C., Ebert, R. & Creutzfeldt, W. 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, 912–917 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Gasbjerg, L. S. et al. Separate and combined glucometabolic effects of endogenous glucose-dependent insulinotropic polypeptide and glucagon-like peptide 1 in healthy individuals. Diabetes 68, 906–917 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  56. 56.

    Jørgensen, N. B. et al. Exaggerated glucagon-like peptide 1 response is important for improved β-cell function and glucose tolerance after Roux-en-Y gastric bypass in patients with type 2 diabetes. Diabetes 62, 3044–3052 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Hansen, L., Deacon, C. F., Orskov, C. & Holst, J. J. 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, 5356–5363 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  58. 58.

    Vahl, T. P. et al. Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. Endocrinology 148, 4965–4973 (2007).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  59. 59.

    Woerle, H. J., Carneiro, L., Derani, A., Göke, B. & Schirra, J. The role of endogenous incretin secretion as amplifier of glucose-stimulated insulin secretion in healthy subjects and patients with type 2 diabetes. Diabetes 61, 2349–2358 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Chambers, A. P. et al. The role of pancreatic preproglucagon in glucose homeostasis in mice. Cell Metab. 25, 927–934.e3 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Svendsen, B. et al. Insulin secretion depends on intra-islet glucagon signaling. Cell Rep. 25, 1127–1134.e2 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    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, 2263–2270 (2008).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  63. 63.

    Gasbjerg, L. S. et al. Evaluation of the incretin effect in humans using GIP and GLP-1 receptor antagonists. Peptides 125, 170183 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  64. 64.

    Wu, T., Rayner, C. K., Young, R. L. & Horowitz, M. Gut motility and enteroendocrine secretion. Curr. Opin. Pharmacol. 13, 928–934 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  65. 65.

    Meier, J. J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728–742 (2012).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Krieger, J. P. et al. Knockdown of GLP-1 receptors in vagal afferents affects normal food intake and glycemia. Diabetes 65, 34–43 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Nauck, M. A., Quast, D. R., Wefers, J. & Meier, J. J. GLP-1 receptor agonists in the treatment of type 2 diabetes: state-of-the-art. Mol. Metab. https://doi.org/10.1016/j.molmet.2020.101102 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Knudsen, L. B. & Lau, J. The discovery and development of liraglutide and semaglutide. Front. Endocrinol. (Lausanne) 10, 155 (2019).

    Article  Google Scholar 

  69. 69.

    Jepsen, S. L. et al. Paracrine crosstalk between intestinal L- and D-cells controls secretion of glucagon-like peptide-1 in mice. Am. J. Physiol. Endocrinol. Metab. 317, E1081–E1093 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Svane, M. S. et al. Peptide YY and glucagon-like peptide-1 contribute to decreased food intake after Roux-en-Y gastric bypass surgery. Int. J. Obes. (Lond) 40, 1699–1706 (2016).

    CAS  Article  Google Scholar 

  71. 71.

    Williams, E. K. et al. Sensory neurons that detect stretch and nutrients in the digestive system. Cell 166, 209–221 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Lu, V. B. et al. Adenosine triphosphate is co-secreted with glucagon-like peptide-1 to modulate intestinal enterocytes and afferent neurons. Nat. Commun. 10, 1029 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  73. 73.

    Trapp, S. & Cork, S. C. PPG neurons of the lower brain stem and their role in brain GLP-1 receptor activation. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309, R795–R804 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    Kreisler, A. D. & Rinaman, L. Hindbrain glucagon-like peptide-1 neurons track intake volume and contribute to injection stress-induced hypophagia in meal-entrained rats. Am. J. Physiol. Regul. Integr. Comp. Physiol. 310, R906–R916 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Holt, M. K. et al. 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 68, 21–33 (2019).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  76. 76.

    Cheng, W. et al. Leptin receptor-expressing nucleus tractus solitarius neurons suppress food intake independently of GLP1 in mice. JCI Insight 5, 134359 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  77. 77.

    Sun, F. et al. 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. 110, 26–37 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Giblett, J. P., Clarke, S. J., Dutka, D. P. & Hoole, S. P. Glucagon-like peptide-1: a promising agent for cardioprotection during myocardial ischemia. JACC Basic Transl. Sci. 1, 267–276 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Holt, M. K. et al. PPG neurons in the nucleus of the solitary tract modulate heart rate but do not mediate GLP-1 receptor agonist-induced tachycardia in mice. Mol. Metab. 39, 101024 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Müller, T. D. et al. Glucagon-like peptide 1 (GLP-1). Mol. Metab. 30, 72–130 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. 81.

    Cheng, H. & Leblond, C. P. Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. III. Entero-endocrine cells. Am. J. Anat. 141, 503–519 (1974).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Mumphrey, M. B., Patterson, L. M., Zheng, H. & Berthoud, H. R. Roux-en-Y gastric bypass surgery increases number but not density of CCK-, GLP-1-, 5-HT-, and neurotensin-expressing enteroendocrine cells in rats. Neurogastroenterol. Motil. 25, e70–e79 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Nauck, M., Stöckmann, F., Ebert, R. & Creutzfeldt, W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia 29, 46–52 (1986).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  84. 84.

    Vollmer, K. et al. Hyperglycemia acutely lowers the postprandial excursions of glucagon-like peptide-1 and gastric inhibitory polypeptide in humans. J. Clin. Endocrinol. Metab. 94, 1379–1385 (2009).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  85. 85.

    Wang, J. et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N. Engl. J. Med. 355, 270–280 (2006).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Jackson, R. S. et al. Small-intestinal dysfunction accompanies the complex endocrinopathy of human proprotein convertase 1 deficiency. J. Clin. Invest. 112, 1550–1560 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Kay, R. G. et al. Peptidomic analysis of endogenous plasma peptides from patients with pancreatic neuroendocrine tumours. Rapid Commun. Mass Spectrom. 32, 1414–1424 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Tan, M., Lamendola, C., Luong, R., McLaughlin, T. & Craig, C. Safety, efficacy and pharmacokinetics of repeat subcutaneous dosing of avexitide (exendin 9-39) for treatment of post-bariatric hypoglycaemia. Diabetes Obes. Metab. 22, 1406–1416 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  89. 89.

    Deacon, C. F. Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes. Peptides 100, 150–157 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Thethi, T. K., Pratley, R. & Meier, J. J. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme. Diabetes Obes. Metab. 22, 1263–1277 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Zhang, X. et al. Differential GLP-1R binding and activation by peptide and non-peptide agonists. Mol. Cell 80, 485–500.e7 (2020).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  92. 92.

    Lucey, M. et al. Disconnect between signalling potency and in vivo efficacy of pharmacokinetically optimised biased glucagon-like peptide-1 receptor agonists. Mol. Metab. 37, 100991 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Tschöp, M. H. et al. Unimolecular polypharmacy for treatment of diabetes and obesity. Cell Metab. 24, 51–62 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  94. 94.

    Frias, J. P. et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomised, placebo-controlled and active comparator-controlled phase 2 trial. Lancet 392, 2180–2193 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  95. 95.

    Parker, V. E. R. et al. Efficacy, safety, and mechanistic insights of cotadutide, a dual receptor glucagon-like peptide-1 and glucagon agonist. J. Clin. Endocrinol. Metab. 105, dgz047 (2020).

    PubMed  Article  PubMed Central  Google Scholar 

  96. 96.

    Ämmälä, C. et al. Targeted delivery of antisense oligonucleotides to pancreatic β-cells. Sci. Adv. 4, eaat3386 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    Reiner, T. et al. Accurate measurement of pancreatic islet beta-cell mass using a second-generation fluorescent exendin-4 analog. Proc. Natl. Acad. Sci. USA 108, 12815–12820 (2011).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

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Acknowledgements

Research in the laboratories of F.M.G. and F.R. is primarily supported by Wellcome (106262/Z/14/Z and 106263/Z/14/Z) and MRC-UK (MRC_MC_UU_12012/3) funding.

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F.M.G. and F.R. co-wrote the article.

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Correspondence to Fiona M. Gribble or Frank Reimann.

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F.M.G. is a consultant for Kallyope, and the laboratories of F.M.G. and F.R. receive additional research funding from AstraZeneca, Eli Lilly and LGC.

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Peer review information Primary Handling Editor: Christoph Schmitt. Nature Metabolism thanks Brian Finan and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Gribble, F.M., Reimann, F. Metabolic Messengers: glucagon-like peptide 1. Nat Metab (2021). https://doi.org/10.1038/s42255-020-00327-x

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