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Effects of GLP-1 and Its Analogs on Gastric Physiology in Diabetes Mellitus and Obesity

  • Daniel B. Maselli
  • Michael CamilleriEmail author
Chapter
  • 106 Downloads
Part of the Advances in Experimental Medicine and Biology book series

Abstract

The processing of proglucagon in intestinal L cells results in the formation of glucagon, GLP-1, and GLP-2. The GLP-1 molecule becomes active through the effect of proconvertase 1, and it is inactivated by dipeptidyl peptidase IV (DPP-IV), so that the half-life of endogenous GLP-1 is 2–3 min. GLP-1 stimulates insulin secretion from β cells in the islets of Langerhans. Human studies show that infusion of GLP-1 results in slowing of gastric emptying and increased fasting and postprandial gastric volumes. Retardation of gastric emptying reduces postprandial glycemia. Exendin-4 is a peptide agonist of the GLP-1 receptor that promotes insulin secretion. Chemical modifications of exendin-4 and GLP-1 molecules have been accomplished to prolong the half-life of GLP-1 agonists or analogs. This chapter reviews the effects of GLP-1-related drugs used in treatment of diabetes or obesity on gastric motor functions, chiefly gastric emptying. The literature shows that diverse methods have been used to measure effects of the GLP-1-related drugs on gastric emptying, with most studies using the acetaminophen absorption test which essentially measures gastric emptying of liquids during the first hour and capacity to absorb the drug over 4–6 h, expressed as AUC. The most valid measurements by scintigraphy (solids or liquids) and acetaminophen absorption at 30 or 60 min show that GLP-1-related drugs used in diabetes or obesity retard gastric emptying, and this is associated with reduced glycemia and variable effects on food intake and appetite. GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity. The effects on gastric emptying are reduced with long-acting preparations or long-term use of short-acting preparations as a result of tachyphylaxis. The dual agonists targeting GLP-1 and another receptor (GIP) do not retard gastric emptying, based on reports to date. In summary, GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity, and their effects are mediated, at least in part, by retardation of gastric emptying.

Keywords

Accommodation Albiglutide Appetite Dulaglutide Emptying Exenatide Liraglutide Lixisenatide Semaglutide 

Notes

Acknowledgements

The authors thank Mrs. Cindy Stanislav for excellent secretarial assistance.

References

  1. Acosta A, Camilleri M, Burton D, O’Neill J, Eckert D, Carlson P et al (2015a) Exenatide in obesity with accelerated gastric emptying: a randomized, pharmacodynamics study. Physiol Rep 3(11):e12610Google Scholar
  2. Acosta A, Camilleri M, Shin A, Vazquez-Roque MI, Iturrino J, Burton D et al (2015b) Quantitative gastrointestinal and psychological traits associated with obesity and response to weight-loss therapy. Gastroenterology 148(3):537–546.e4Google Scholar
  3. Adam TCM, Westerterp-Plantenga MS (2005) Glucagon-like peptide-1 release and satiety after a nutrient challenge in normal-weight and obese subjects. Br J Nutr 93(6):845–851Google Scholar
  4. Alvarez E, Martínez MD, Roncero I, Chowen JA, García-Cuartero B, Gispert JD et al (2005) The expression of GLP-1 receptor mRNA and protein allows the effect of GLP-1 on glucose metabolism in the human hypothalamus and brainstem. J Neurochem 92(4):798–806Google Scholar
  5. Ambery P, Parker VE, Stumvoll M, Posch MG, Heise T, Plum-Moerschel L et al (2018) MEDI0382, a GLP-1 and glucagon receptor dual agonist, in obese or overweight patients with type 2 diabetes: a randomised, controlled, double-blind, ascending dose and phase 2a study. Lancet 391(10140):2607–2618Google Scholar
  6. Bækdal TA, Borregaard J, Hansen CW, Thomsen M, Anderson TW (2019) Effect of Oral Semaglutide on the pharmacokinetics of lisinopril, warfarin, digoxin, and metformin in healthy subjects. Clin Pharmacokinet 58(9):1193–1203Google Scholar
  7. Barrington P, Chien JY, Showalter HDH, Schneck K, Cui S, Tibaldi F et al (2011) A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes Metab 13(5):426–433Google Scholar
  8. Becker RHA, Stechl J, Steinstraesser A, Golor G, Pellissier F (2015) Lixisenatide reduces postprandial hyperglycaemia via gastrostatic and insulinotropic effects. Diabetes Metab Res Rev 31(6):610–618Google Scholar
  9. Bronden A, Alber A, Rohde U, Gasbjerg LS, Rehfeld JF, Holst JJ et al (2018) The bile acid-sequestering resin sevelamer eliminates the acute GLP-1 stimulatory effect of endogenously released bile acids in patients with type 2 diabetes. Diabetes Obes Metab 20(2):362–369Google Scholar
  10. Bunck MC, Diamant M, Cornér A, Eliasson B, Malloy JL, Shaginian RM et al (2009) One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care 32(5):762–768Google Scholar
  11. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD et al (2004) Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27(11):2628–2635Google Scholar
  12. Carr RD, Larsen MO, Jelic K, Lindgren O, Vikman J, Holst JJ et al (2010) Secretion and dipeptidyl peptidase-4-mediated metabolism of incretin hormones after a mixed meal or glucose ingestion in obese compared to lean, nondiabetic men. J Clin Endocrinol Metab 95(2):872–878Google Scholar
  13. Cervera A, Wajcberg E, Sriwijitkamol A, Fernandez M, Zuo P, Triplitt C et al (2008) Mechanism of action of exenatide to reduce postprandial hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab 294(5):E846–E852Google Scholar
  14. Chedid V, Vijayvargiya P, Carlson P, Van Malderen K, Acosta A, Zinsmeister A et al (2018) Allelic variant in the glucagon-like peptide 1 receptor gene associated with greater effect of liraglutide and exenatide on gastric emptying: a pilot pharmacogenetics study. Neurogastroenterol Motil 30(7):e13313-eGoogle Scholar
  15. Coskun T, Sloop KW, Loghin C, Alsina-Fernandez J, Urva S, Bokvist KB et al (2018) LY3298176, a novel dual GIP and GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus: from discovery to clinical proof of concept. Mol Metab 18:3–14Google Scholar
  16. Cummings DE, Overduin J (2007) Gastrointestinal regulation of food intake. J Clin Invest 117(1):13–23Google Scholar
  17. Davies M, Pieber TR, Hartoft-Nielsen M-L, Hansen OKH, Jabbour S, Rosenstock J (2017) 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(15):1460–1470Google Scholar
  18. Deane AM, Nguyen NQ, Stevens JE, Fraser RJL, Holloway RH, Besanko LK et al (2010a) Endogenous glucagon-like peptide-1 slows gastric emptying in healthy subjects, attenuating postprandial glycemia. J Clin Endocrinol Metab 95(1):215–221Google Scholar
  19. Deane AM, Chapman MJ, Fraser RJL, Summers MJ, Zaknic AV, Storey JP et al (2010b) Effects of exogenous glucagon-like peptide-1 on gastric emptying and glucose absorption in the critically ill: relationship to glycemia. Crit Care Med 38(5):1261–1269Google Scholar
  20. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD (2005) Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 28(5):1092–1100Google Scholar
  21. DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcombe JH, MacConell L (2008) Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagon secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin 24(10):2943–2952Google Scholar
  22. Degen L, Oesch S, Matzinger D, Drewe J, Knupp M, Zimmerli F et al (2006) Effects of a preload on reduction of food intake by GLP-1 in healthy subjects. Digestion 74(2):78–84Google Scholar
  23. Degn KB, Juhl CB, Sturis J, Jakobsen G, Brock B, Chandramouli V et al (2004) One week’s treatment with the long-acting glucagon-like peptide 1 derivative liraglutide (NN2211) markedly improves 24-h glycemia and alpha- and beta-cell function and reduces endogenous glucose release in patients with type 2 diabetes. Diabetes 53(5):1187–1194Google Scholar
  24. Dejgaard TF, Frandsen CS, Hansen TS, Almdal T, Urhammer S, Pedersen-Bjergaard U et al (2016) Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 4(3):221–232Google Scholar
  25. Delgado-Aros S, Kim D-Y, Burton DD, Thomforde GM, Stephens D, Brinkmann BH et al (2002) Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans. Am J Physiol Gastrointest Liver Physiol 282(3):G424–GG31Google Scholar
  26. Delgado-Aros S, Vella A, Camilleri M, Low PA, Burton DD, Thomforde GM et al (2003) Effects of glucagon-like peptide-1 and feeding on gastric volumes in diabetes mellitus with cardio-vagal dysfunction. Neurogastroenterol Motil 15(4):435–443Google Scholar
  27. Diakogiannaki E, Gribble FM, Reimann F (2012) Nutrient detection by incretin hormone secreting cells. Physiol Behav 106(3):387–393Google Scholar
  28. Drucker DJ (2003) Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol 17(2):161–171Google Scholar
  29. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D et al (2008) Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372(9645):1240–1250Google Scholar
  30. Fineman MS, Mace KF, Diamant M, Darsow T, Cirincione BB, Booker Porter TK et al (2012) Clinical relevance of anti-exenatide antibodies: safety, efficacy and cross-reactivity with long-term treatment. Diabetes Obes Metab 14(6):546–554Google Scholar
  31. Flint A, Raben A, Astrup A, Holst JJ (1998) Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest 101(3):515–520Google Scholar
  32. Flint A, Raben A, Ersbøll AK, Holst JJ, Astrup A (2001) The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord 25(6):781–792Google Scholar
  33. Flint A, Kapitza C, Hindsberger C, Zdravkovic M (2011) The once-daily human glucagon-like peptide-1 (GLP-1) analog liraglutide improves postprandial glucose levels in type 2 diabetes patients. Adv Ther 28(3):213–226Google Scholar
  34. Frias JP, Nauck MA, Van J, Kutner ME, Cui X, Benson C et al (2018) 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(10160):2180–2193Google Scholar
  35. Garber AJ (2011) Long-acting glucagon-like peptide 1 receptor agonists: a review of their efficacy and tolerability. Diabetes Care 34(Suppl 2):S279–SS84Google Scholar
  36. Garber A, Henry RR, Ratner R, Hale P, Chang CT, Bode B et al (2011) Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab 13(4):348–356Google Scholar
  37. Gasbjerg LS, Helsted MM, Hartmann B, Jensen MH, Gabe MBN, Sparre-Ulrich AH et al (2019) Separate and combined glucometabolic effects of endogenous glucose-dependent Insulinotropic polypeptide and glucagon-like peptide 1 in healthy individuals. Diabetes 68(5):906–917Google Scholar
  38. Gentilella R, Pechtner V, Corcos A, Consoli A (2019) Glucagon-like peptide-1 receptor agonists in type 2 diabetes treatment: are they all the same? Diabetes Metab Res Rev 35(1):e3070-eGoogle Scholar
  39. Gibbs J, Young RC, Smith GP (1973) Cholecystokinin decreases food intake in rats. J Comp Physiol Psychol 84(3):488–495Google Scholar
  40. Gutzwiller JP, Drewe J, Göke B, Schmidt H, Rohrer B, Lareida J et al (1999) Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Phys 276(5):R1541–R15R4Google Scholar
  41. Halawi H, Khemani D, Eckert D, O’Neill J, Kadouh H, Grothe K et al (2017) Effects of liraglutide on weight, satiation, and gastric functions in obesity: a randomised, placebo-controlled pilot trial. Lancet Gastroenterol Hepatol 2(12):890–899Google Scholar
  42. Halim MA, Degerblad M, Sundbom M, Karlbom U, Holst JJ, Webb D-L et al (2018) Glucagon-like peptide-1 inhibits prandial gastrointestinal motility through myenteric neuronal mechanisms in humans. J Clin Endocrinol Metab 103(2):575–585Google Scholar
  43. Hayes MR, Bradley L, Grill HJ (2009) Endogenous hindbrain glucagon-like peptide-1 receptor activation contributes to the control of food intake by mediating gastric satiation signaling. Endocrinology 150(6):2654–2659Google Scholar
  44. Hjerpsted JB, Flint A, Brooks A, Axelsen MB, Kvist T, Blundell J (2018) Semaglutide improves postprandial glucose and lipid metabolism, and delays first-hour gastric emptying in subjects with obesity. Diabetes Obes Metab 20(3):610–619Google Scholar
  45. Holst JJ (2013) Incretin hormones and the satiation signal. Int J Obes 37(9):1161–1168Google Scholar
  46. Holst JJ (2019) From the incretin concept and the discovery of GLP-1 to today’s diabetes therapy. Front Endocrinol (Lausanne) 10:260Google Scholar
  47. Holst JJ, Gribble F, Horowitz M, Rayner CK (2016) Roles of the gut in glucose homeostasis. Diabetes Care 39(6):884–892Google Scholar
  48. Horowitz M, Flint A, Jones KL, Hindsberger C, Rasmussen MF, Kapitza C et al (2012) Effect of the once-daily human GLP-1 analogue liraglutide on appetite, energy intake, energy expenditure and gastric emptying in type 2 diabetes. Diabetes Res Clin Pract 97(2):258–266Google Scholar
  49. Horowitz M, Rayner CK, Jones KL (2013) Mechanisms and clinical efficacy of lixisenatide for the management of type 2 diabetes. Adv Ther 30(2):81–101Google Scholar
  50. Imeryüz N, Yeğen BC, Bozkurt A, Coşkun T, Villanueva-Peñacarrillo ML, Ulusoy NB (1997) Glucagon-like peptide-1 inhibits gastric emptying via vagal afferent-mediated central mechanisms. Am J Phys 273(4):G920–G9G7Google Scholar
  51. Jones KL, Rigda RS, Buttfield MDM, Hatzinikolas S, Pham HT, Marathe CS et al (2019) Effects of lixisenatide on postprandial blood pressure, gastric emptying and glycaemia in healthy people and people with type 2 diabetes. Diabetes Obes Metab 21(5):1158–1167Google Scholar
  52. Jones KL, Huynh LQ, Hatzinikolas S, Rigda RS, Phillips LK, Pham HT et al (2020) Exenatide once weekly slows gastric emptying of solids and liquids in healthy, overweight, subjects under steady-state concentrations. Diabetes Obes Metab.  https://doi.org/10.1111/dom.13956
  53. Kolterman OG, Kim DD, Shen L, Ruggles JA, Nielsen LL, Fineman MS et al (2005) Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm 62(2):173–181Google Scholar
  54. Kothare PA, Soon DKW, Linnebjerg H, Park S, Chan C, Yeo A et al (2005) Effect of exenatide on the steady-state pharmacokinetics of digoxin. J Clin Pharmacol 45(9):1032–1037Google Scholar
  55. Kothare PA, Linnebjerg H, Skrivanek Z, Reddy S, Mace K, Pena A et al (2007) Exenatide effects on statin pharmacokinetics and lipid response. Int J Clin Pharmacol Ther 45(2):114–120Google Scholar
  56. le Roux CW, Astrup A, Fujioka K, Greenway F, Lau DCW, Van Gaal L et al (2017) 3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial. Lancet 389(10077):1399–1409Google Scholar
  57. Linnebjerg H, Park S, Kothare PA, Trautmann ME, Mace K, Fineman M et al (2008) Effect of exenatide on gastric emptying and relationship to postprandial glycemia in type 2 diabetes. Regul Pept 151(1–3):123–129Google Scholar
  58. Linnebjerg H, Kothare P, Park S, Mace K, Mitchell M (2009) The effect of exenatide on lisinopril pharmacodynamics and pharmacokinetics in patients with hypertension. Int J Clin Pharmacol Ther 47(11):651–658Google Scholar
  59. Little TJ, Pilichiewicz AN, Russo A, Phillips L, Jones KL, Nauck MA et al (2006) Effects of intravenous glucagon-like peptide-1 on gastric emptying and intragastric distribution in healthy subjects: relationships with postprandial glycemic and insulinemic responses. J Clin Endocrinol Metab 91(5):1916–1923Google Scholar
  60. Lorenz M, Pfeiffer C, Steinstrasser A, Becker RH, Rutten H, Ruus P et al (2013) Effects of lixisenatide once daily on gastric emptying in type 2 diabetes--relationship to postprandial glycemia. Regul Pept 185:1–8Google Scholar
  61. Lu WJ, Yang Q, Sun W, Woods SC, D’Alessio D, Tso P (2007) The regulation of the lymphatic secretion of glucagon-like peptide-1 (GLP-1) by intestinal absorption of fat and carbohydrate. Am J Physiol Gastrointest Liver Physiol 293(5):G963–GG71Google Scholar
  62. Madsbad S (2016) Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obes Metab 18(4):317–332Google Scholar
  63. Marathe CS, Rayner CK, Jones KL, Horowitz M (2011) Effects of GLP-1 and incretin-based therapies on gastrointestinal motor function. Exp Diabetes Res 2011:279530Google Scholar
  64. Marathe CS, Rayner CK, Wu T, Jones KL, Horowitz M (2018) Gastric emptying and the personalized management of type 1 diabetes. J Clin Endocrinol Metab 103(9):3503–3506Google Scholar
  65. Mathiesen DS, Bagger JI, Bergmann NC, Lund A, Christensen MB, Vilsbøll T et al (2019) The effects of dual GLP-1/GIP receptor agonism on glucagon secretion-a review. Int J Mol Sci 20(17):4092Google Scholar
  66. Meier JJ (2012) GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol 8(12):728–742Google Scholar
  67. Meier JJ, Kemmeries G, Holst JJ, Nauck MA (2005) Erythromycin antagonizes the deceleration of gastric emptying by glucagon-like peptide 1 and unmasks its insulinotropic effect in healthy subjects. Diabetes 54(7):2212–2218Google Scholar
  68. Meier JJ, Rosenstock J, Hincelin-Mery A, Roy-Duval C, Delfolie A, Coester HV et al (2015) Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on Optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care 38(7):1263–1273Google Scholar
  69. Moller DE (2001) New drug targets for type 2 diabetes and the metabolic syndrome. Nature 414(6865):821–827Google Scholar
  70. Monnier L, Lapinski H, Colette C (2003) Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). Diabetes Care 26(3):881–885Google Scholar
  71. Nakatani Y, Maeda M, Matsumura M, Shimizu R, Banba N, Aso Y et al (2017) Effect of GLP-1 receptor agonist on gastrointestinal tract motility and residue rates as evaluated by capsule endoscopy. Diabetes Metab 43(5):430–437Google Scholar
  72. Näslund E, Barkeling B, King N, Gutniak M, Blundell JE, Holst JJ et al (1999) Energy intake and appetite are suppressed by glucagon-like peptide-1 (GLP-1) in obese men. Int J Obes Relat Metab Disord 23(3):304–311Google Scholar
  73. Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R et al (1997) Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Phys 273(5):E981–E9E8Google Scholar
  74. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH et al (2009) Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care 32(1):84–90Google Scholar
  75. Nauck MA, Kemmeries G, Holst JJ, Meier JJ (2011) Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes 60(5):1561–1565Google Scholar
  76. Odunsi ST, Camilleri M (2009) Selected interventions in nuclear medicine: gastrointestinal motor functions. Semin Nucl Med 39(3):186–194Google Scholar
  77. Odunsi ST, Camilleri M, Szarka LA, Zinsmeister AR (2009) Optimizing analysis of stable isotope breath tests to estimate gastric emptying of solids. Neurogastroenterol Motil 21(7):706–e38Google Scholar
  78. Parker VER, Robertson D, Wang T, Hornigold DC, Petrone M, Cooper AT et al (2019) Efficacy, safety, and mechanistic insights of cotadutide a dual receptor glucagon-like peptide-1 and glucagon agonist. J Clin Endocrinol Metab.  https://doi.org/10.1210/clinem/dgz047
  79. Pi-Sunyer X, Astrup A, Fujioka K, Greenway F, Halpern A, Krempf M et al (2015) A randomized, controlled trial of 3.0 mg of Liraglutide in weight management. N Engl J Med 373(1):11–22Google Scholar
  80. Ramesh N, Mortazavi S, Unniappan S (2016) Nesfatin-1 stimulates cholecystokinin and suppresses peptide YY expression and secretion in mice. Biochem Biophys Res Commun 472(1):201–208Google Scholar
  81. Read NW, McFarlane A, Kinsman RI, Bates TE, Blackhall NW, Farrar GB et al (1984) Effect of infusion of nutrient solutions into the ileum on gastrointestinal transit and plasma levels of neurotensin and enteroglucagon. Gastroenterology 86(2):274–280Google Scholar
  82. Ritzel R, Orskov C, Holst JJ, Nauck MA (1995) Pharmacokinetic, insulinotropic, and glucagonostatic properties of GLP-1 [7-36 amide] after subcutaneous injection in healthy volunteers. Dose-response-relationships. Diabetologia 38(6):720–725Google Scholar
  83. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S et al (2009) Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomised controlled trial. Diabetologia 52(10):2046–2055Google Scholar
  84. Schirra J, Göke B (2005) The physiological role of GLP-1 in human: incretin, ileal brake or more? Regul Pept 128(2):109–115Google Scholar
  85. Schirra J, Wank U, Arnold R, Göke B, Katschinski M (2002) Effects of glucagon-like peptide-1(7-36)amide on motility and sensation of the proximal stomach in humans. Gut 50(3):341–348Google Scholar
  86. Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle HJ et al (2006) Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut 55(2):243–251Google Scholar
  87. Schirra J, Nicolaus M, Woerle HJ, Struckmeier C, Katschinski M, Göke B (2009) GLP-1 regulates gastroduodenal motility involving cholinergic pathways. Neurogastroenterol Motil 21(6):609–e22Google Scholar
  88. Schmitt C, Portron A, Jadidi S, Sarkar N, DiMarchi R (2017) Pharmacodynamics, pharmacokinetics and safety of multiple ascending doses of the novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 agonist RG7697 in people with type 2 diabetes mellitus. Diabetes Obes Metab 19(10):1436–1445Google Scholar
  89. Soon D, Kothare PA, Linnebjerg H, Park S, Yuen E, Mace KF et al (2006) Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men. J Clin Pharmacol 46(10):1179–1187Google Scholar
  90. Steinert RE, Meyer-Gerspach AC, Beglinger C (2012) The role of the stomach in the control of appetite and the secretion of satiation peptides. Am J Physiol Endocrinol Metab 302(6):E666–EE73Google Scholar
  91. Steinert RE, Beglinger C, Langhans W (2016) Intestinal GLP-1 and satiation: from man to rodents and back. Int J Obes 40(2):198–205Google Scholar
  92. Steinert RE, Feinle-Bisset C, Asarian L, Horowitz M, Beglinger C, Geary N (2017) Ghrelin, CCK, GLP-1, and PYY(3-36): secretory controls and physiological roles in eating and Glycemia in health, obesity, and after RYGB. Physiol Rev 97(1):411–463Google Scholar
  93. Stevens JE, Horowitz M, Deacon CF, Nauck M, Rayner CK, Jones KL (2012) The effects of sitagliptin on gastric emptying in healthy humans – a randomised, controlled study. Aliment Pharmacol Ther 36(4):379–390Google Scholar
  94. Szarka LA, Camilleri M (2009) Methods for measurement of gastric motility. Am J Physiol Gastrointest Liver Physiol 296(3):G461–G475Google Scholar
  95. Szarka LA, Camilleri M, Vella A, Burton D, Baxter K, Simonson J et al (2008) A stable isotope breath test with a standard meal for abnormal gastric emptying of solids in the clinic and in research. Clin Gastroenterol Hepatol 6(6):635–643.e1Google Scholar
  96. Szayna M, Doyle ME, Betkey JA, Holloway HW, Spencer RG, Greig NH et al (2000) Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology 141(6):1936–1941Google Scholar
  97. Tibble CA, Cavaiola TS, Henry RR (2013) Longer acting GLP-1 receptor agonists and the potential for improved cardiovascular outcomes: a review of current literature. Expert Rev Endocrinol Metab 8(3):247–259Google Scholar
  98. Trujillo JM, Nuffer W (2014) Albiglutide: a new GLP-1 receptor agonist for the treatment of type 2 diabetes. Ann Pharmacother 48(11):1494–1501Google Scholar
  99. Uccellatore A, Genovese S, Dicembrini I, Mannucci E, Ceriello A (2015) Comparison review of short-acting and long-acting glucagon-like peptide-1 receptor agonists. Diabetes Ther 6(3):239–256Google Scholar
  100. Umapathysivam MM, Lee MY, Jones KL, Annink CE, Cousins CE, Trahair LG et al (2014) Comparative effects of prolonged and intermittent stimulation of the glucagon-like peptide 1 receptor on gastric emptying and glycemia. Diabetes 63(2):785–790Google Scholar
  101. Urva S, Nauck MA, Coskun T, Cui X, Haupt A, Benson C et al (2019) 58-OR: the novel dual GIP and GLP-1 receptor agonist tirzepatide transiently delays gastric emptying similarly to a selective long-acting GLP-1 receptor agonist. Diabetes 68(Supplement 1):58-ORGoogle Scholar
  102. van Can J, Sloth B, Jensen CB, Flint A, Blaak EE, Saris WHM (2014) 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 38(6):784–793Google Scholar
  103. Vella A, Bock G, Giesler PD, Burton DB, Serra DB, Saylan ML et al (2007) Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes. Diabetes 56(5):1475–1480Google Scholar
  104. Vella A, Bock G, Giesler PD, Burton DB, Serra DB, Saylan ML et al (2008) The effect of dipeptidyl peptidase-4 inhibition on gastric volume, satiation and enteroendocrine secretion in type 2 diabetes: a double-blind, placebo-controlled crossover study. Clin Endocrinol 69(5):737–744Google Scholar
  105. Verdich C, Toubro S, Buemann B, Lysgård Madsen J, Juul Holst J, Astrup A (2001) The role of postprandial releases of insulin and incretin hormones in meal-induced satiety--effect of obesity and weight reduction. Int J Obes Relat Metab Disord 25(8):1206–1214Google Scholar
  106. Vilsbøll T, Agersø H, Lauritsen T, Deacon CF, Aaboe K, Madsbad S et al (2006) The elimination rates of intact GIP as well as its primary metabolite, GIP 3-42, are similar in type 2 diabetic patients and healthy subjects. Regul Pept 137(3):168–172Google Scholar
  107. Vrang N, Larsen PJ (2010) Preproglucagon derived peptides GLP-1, GLP-2 and oxyntomodulin in the CNS: role of peripherally secreted and centrally produced peptides. Prog Neurobiol 92(3):442–462Google Scholar
  108. Vrang N, Phifer CB, Corkern MM, Berthoud H-R (2003) Gastric distension induces c-Fos in medullary GLP-1/2-containing neurons. Am J Physiol Regul Integr Comp Physiol 285(2):R470–R4R8Google Scholar
  109. Wettergren A, Wøjdemann M, Holst JJ (1998) Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Phys 275(5):G984–GG92Google Scholar
  110. Willms B, Werner J, Holst JJ, Orskov C, Creutzfeldt W, Nauck MA (1996) Gastric emptying, glucose responses, and insulin secretion after a liquid test meal: effects of exogenous glucagon-like peptide-1 (GLP-1)-(7-36) amide in type 2 (noninsulin-dependent) diabetic patients. J Clin Endocrinol Metab 81(1):327–332Google Scholar
  111. Zinman B, Hoogwerf BJ, Durán García S, Milton DR, Giaconia JM, Kim DD et al (2007) The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med 146(7):477–485Google Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.), Division of Gastroenterology and HepatologyMayo ClinicRochesterUSA

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