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Discovery of the GI Effects of GLP-1: An Historical Perspective

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A DDS Citation Classics to this article was published on 30 May 2022

Abstract

In 1993, my laboratory published an article in Digestive Diseases and Sciences that clearly demonstrated the pronounced effects of the newly discovered intestinal hormone, glucagon-like peptide-1 (GLP-1), on a number of gastrointestinal functions, including gastric emptying rate, gastric acid secretion, and pancreatic enzyme secretion. The gut hormone is released in response to nutrient intake, and in further experiments, its release from the ileum paralleled inhibition of both gastric and pancreatic secretions. Based on these studies, it was concluded that GLP-1 is an important regulator of the so-called ileal brake, a term given for the observation that ileal perfusion of lipids delayed gastric emptying, reduced food intake, and induced satiety Welch et al. (1985), in addition to its functions as an incretin hormone. GLP-1 was subsequently identified as a physiological inhibitor of appetite and food intake, and based on these actions, the GLP-1 receptor agonists are today considered among the most powerful and effective antiobesity and antidiabetic agents available, with the added benefits of reducing the risk of the cardiovascular and renal complications associated with these conditions.

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References

  1. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78–107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993;38:665–673.

    Article  CAS  PubMed  Google Scholar 

  2. Muller TD, Finan B, Bloom SR, D’Alessio D, Drucker DJ, Flatt PR et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72–130.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Welch I, Saunders K, Read NW. Effect of ileal and intravenous infusions of fat emulsions on feeding and satiety in human volunteers. Gastroenterology. 1985;89:1293–1297.

    Article  CAS  PubMed  Google Scholar 

  4. Rehfeld JF, Heding LG, Holst JJ. Increased gut glucagon release as pathogenetic factor in reactive hypoglycaemia? Lancet. 1973;1:116–118.

    Article  CAS  PubMed  Google Scholar 

  5. Holst JJ. Gut glucagon, enteroglucagon, gut glucagonlike immunoreactivity, glicentin–current status. Gastroenterology. 1983;84:1602–1613.

    Article  CAS  PubMed  Google Scholar 

  6. Holst JJ. Evidence that glicentin contains the entire sequence of glucagon. Biochem J. 1980;187:337–343.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Thim L, Moody AJ. The primary structure of porcine glicentin (proglucagon). Regul Pept. 1981;2:139–150.

    Article  CAS  PubMed  Google Scholar 

  8. Holst JJ. Evidence that enteroglucagon (II) is identical with the C- terminal sequence (residues 33–69) of glicentin. Biochem J. 1982;207:381–388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bataille D, Tatemoto K, Gespach C, Jornvall H, Rosselin G, Mutt V. Isolation of glucagon-37 (bioactive enteroglucagon/oxyntomodulin) from porcine jejuno-ileum. Characterization of the peptide. FEBS Lett. 1982;146:79–86.

    Article  CAS  PubMed  Google Scholar 

  10. Sheikh SP, Baldissera FG, Karlsen FO, Holst JJ. Glicentin is present in the pig pancreas. FEBS Lett. 1985;179:1–6.

    Article  CAS  PubMed  Google Scholar 

  11. Moody AJ, Holst JJ, Thim L, Jensen SL. Relationship of glicentin to proglucagon and glucagon in the porcine pancreas. Nature. 1981;289:514–516.

    Article  CAS  PubMed  Google Scholar 

  12. Bell GI, Santerre RF, Mullenbach GT. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature. 1983;302:716–718.

    Article  CAS  PubMed  Google Scholar 

  13. Orskov C, Holst JJ, Knuhtsen S, Baldissera FG, Poulsen SS, Nielsen OV. Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas. Endocrinology. 1986;119:1467–1475.

    Article  CAS  PubMed  Google Scholar 

  14. Holst JJ, Orskov C, Schwartz TW, Buhl T, Proglucagon Baldissera F. a potent insulinotropic hormone from the lower small intestine. Diabetologia 1986;29:78–107.

    Google Scholar 

  15. Holst JJ, Orskov C, Nielsen OV, Schwartz TW. Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut. FEBS Lett. 1987;211:169–174.

    Article  CAS  PubMed  Google Scholar 

  16. Buhl T, Thim L, Kofod H, Orskov C, Harling H, Holst JJ. Naturally occurring products of proglucagon 111–160 in the porcine and human small intestine. J Biol Chem. 1988;263:8621–8624.

    Article  CAS  PubMed  Google Scholar 

  17. Drucker DJ, Erlich P, Asa SL, Brubaker PL. Induction of intestinal epithelial proliferation by glucagon-like peptide 2. Proc Natl Acad Sci U S A. 1996;93:7911–7916.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7–36: a physiological incretin in man. Lancet. 1987;2:1300–1304.

    Article  CAS  PubMed  Google Scholar 

  19. Orskov C, Holst JJ, Nielsen OV. Effect of truncated glucagon-like peptide-1 [proglucagon-(78–107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach. Endocrinology. 1988;123:2009–2013.

    Article  CAS  PubMed  Google Scholar 

  20. Loud FB, Chirstiansen J, Holst JJ, Petersen B, Kirkegaard P. Effect of endogenous pancreatic glucagon on gastric acid secretion in patients with duodenal ulcer before and after parietal cell vagotomy. Gut. 1981;22:359–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Oxyntomodulin from distal gut role in regulation of gastric and pancreatic functions. Dig Dis Sci 1989;34:1411–1419.

    Article  CAS  PubMed  Google Scholar 

  22. Schjoldager BT, Mortensen PE, Christiansen J, Orskov C, Holst JJ. GLP-1 (glucagon-like peptide 1) and truncated GLP-1, fragments of human proglucagon, inhibit gastric acid secretion in humans. Dig Dis Sci. 1989;34:703–708.

    Article  CAS  PubMed  Google Scholar 

  23. Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997;273:E981–E988.

    CAS  PubMed  Google Scholar 

  24. Nauck MA, Kemmeries G, Holst JJ, Meier JJ. Rapid tachyphylaxis of the glucagon-like peptide 1-induced deceleration of gastric emptying in humans. Diabetes. 2011;60:1561–1565.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Layer P, Holst JJ, Grandt D, Goebell H. Ileal release of glucagon-like peptide-1 (GLP-1) association with inhibition of gastric acid secretion in humans. Dig Dis Sci 1995;40:1074–1082.

    Article  CAS  PubMed  Google Scholar 

  26. Groger G, Unger A, Holst JJ, Goebell H, Layer P. Ileal carbohydrates inhibit cholinergically stimulated exocrine pancreatic secretion in humans. Int J Pancreatol. 1997;22:23–29.

    Article  CAS  PubMed  Google Scholar 

  27. Holst JJ, Rasmussen TN, Harling H, Schmidt P. Effect of intestinal inhibitory peptides on vagally induced secretion from isolated perfused porcine pancreas. Pancreas. 1993;8:80–87.

    Article  CAS  PubMed  Google Scholar 

  28. Wettergren A, Wojdemann M, Meisner S, Stadil F, Holst JJ. The inhibitory effect of glucagon-like peptide-1 (GLP-1) 7–36 amide on gastric acid secretion in humans depends on an intact vagal innervation. Gut. 1997;40:597–601.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wettergren A, Petersen H, Orskov C, Christiansen J, Sheikh SP, Holst JJ. Glucagon-like peptide-1 7–36 amide and peptide YY from the L- cell of the ileal mucosa are potent inhibitors of vagally induced gastric acid secretion in man. Scand J Gastroenterol. 1994;29:501–505.

    Article  CAS  PubMed  Google Scholar 

  30. Wettergren A, Wojdemann M, Holst JJ. Glucagon-like peptide-1 inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am J Physiol. 1998;275:G984–G992.

    CAS  PubMed  Google Scholar 

  31. Brierley DI, de Lartigue G. Reappraising the role of the vagus nerve in GLP-1-mediated regulation of eating. Br J Pharmacol 2021;179:584.

    Article  PubMed  Google Scholar 

  32. Holst JJ, Andersen DB, Grunddal KV. Actions of glucagon-like peptide-1 receptor ligands in the gut. Br J Pharmacol 2021;179:727.

    Article  PubMed  Google Scholar 

  33. Geary N. Glucagon and the control of appetite. In: Lefebvre PJ, editor. Glucagon III. Handbook of Experimental Pharmacology 123. Berlin: Springer; 1996. p. 223–38.

  34. Turton MD, O’Shea D, Gunn I, Beak SA, Edwards CM, Meeran K et al. A role for glucagon-like peptide-1 in the central regulation of feeding [see comments]. Nature. 1996;379:69–72.

    Article  CAS  PubMed  Google Scholar 

  35. Tang-Christensen M, Larsen PJ, Goke R, Fink-Jensen A, Jessop DS, Moller M et al. Central administration of GLP-1-(7–36) amide inhibits food and water intake in rats. Am J Physiol. 1996;271:R848–R856.

    CAS  PubMed  Google Scholar 

  36. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like Peptide 1 Promotes Satiety and Suppresses Energy Intake in Humans. J Clin Invest. 1998;101:515–520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384:989.

    Article  CAS  PubMed  Google Scholar 

  38. Carlsson LMS, Sjoholm K, Jacobson P, Andersson-Assarsson JC, Svensson PA, Taube M et al. Life Expectancy after Bariatric Surgery in the Swedish Obese Subjects Study. N Engl J Med. 2020;383:1535–1543.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Sattar N, Lee MMY, Kristensen SL, Branch KRH, Del Prato S, Khurmi NS et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021;9:653–662.

    Article  CAS  PubMed  Google Scholar 

  40. Sjostrom L, Peltonen M, Jacobson P, Ahlin S, Andersson-Assarsson J, Anveden A et al. Association of bariatric surgery with long-term remission of type 2 diabetes and with microvascular and macrovascular complications. JAMA. 2014;311:2297–2304.

    Article  PubMed  Google Scholar 

  41. Jeppesen PB, Hartmann B, Thulesen J, Graff J, Lohmann J, Hansen BS et al. Glucagon-like peptide 2 improves nutrient absorption and nutritional status in short-bowel patients with no colon. Gastroenterology. 2001;120:806–815.

    Article  CAS  PubMed  Google Scholar 

  42. Jeppesen PB, Gabe SM, Seidner DL, Lee HM, Olivier C. Factors Associated With Response to Teduglutide in Patients With Short-Bowel Syndrome and Intestinal Failure. Gastroenterology. 2018;154:874–885.

    Article  CAS  PubMed  Google Scholar 

  43. Kissow H. Glucagon-like peptides 1 and 2: intestinal hormones implicated in the pathophysiology of mucositis. Curr Opin Support Palliat Care. 2015;9:196–202.

    Article  PubMed  Google Scholar 

  44. Yusta B, Baggio LL, Koehler J, Holland D, Cao X, Pinnell LJ et al. GLP-1R Agonists Modulate Enteric Immune Responses Through the Intestinal Intraepithelial Lymphocyte GLP-1R. Diabetes. 2015;64:2537–2549.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

These studies were supported by the Danish Medical Research Council and by the NovoNordisk Foundation.

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  1. Department of Biomedical Sciences and NovoNordisk Foundation Center for Basic Metabolic Research, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark

    Jens Juul Holst

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Correspondence to Jens Juul Holst.

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Holst, J.J. Discovery of the GI Effects of GLP-1: An Historical Perspective. Dig Dis Sci 67, 2716–2720 (2022). https://doi.org/10.1007/s10620-022-07519-3

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