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30-05-2022 | Incretin Mimetics | DDS CITATION CLASSICS

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

Author: Jens Juul Holst

Published in: Digestive Diseases and Sciences | Issue 7/2022

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.

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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

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

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

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

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

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.PubMedCrossRef

10.

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

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.PubMedCrossRef

12.

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

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.PubMedCrossRef

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.

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMed

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.PubMedCrossRef

32.

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

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.PubMedCrossRef

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.PubMed

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedPubMedCentralCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

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.PubMedCrossRef

Title: Discovery of the GI Effects of GLP-1: An Historical Perspective
Author: Jens Juul Holst
Publication date: 30-05-2022
Publisher: Springer US
Keywords: Incretin Mimetics
Incretin Mimetics
Published in: Digestive Diseases and Sciences / Issue 7/2022
Print ISSN: 0163-2116
Electronic ISSN: 1573-2568
DOI: https://doi.org/10.1007/s10620-022-07519-3

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