Gastroenterology

Gastroenterology

Volume 122, Issue 2, February 2002, Pages 531-544
Gastroenterology

Special Reports and Reviews
Biological actions and therapeutic potential of the glucagon-like peptides,☆☆

https://doi.org/10.1053/gast.2002.31068Get rights and content

Abstract

The glucagon-like peptides (GLP-1 and GLP-2) are proglucagon-derived peptides cosecreted from gut endocrine cells in response to nutrient ingestion. GLP-1 acts as an incretin to lower blood glucose via stimulation of insulin secretion from islet β cells. GLP-1 also exerts actions independent of insulin secretion, including inhibition of gastric emptying and acid secretion, reduction in food ingestion and glucagon secretion, and stimulation of β-cell proliferation. Administration of GLP-1 lowers blood glucose and reduces food intake in human subjects with type 2 diabetes. GLP-2 promotes nutrient absorption via expansion of the mucosal epithelium by stimulation of crypt cell proliferation and inhibition of apoptosis in the small intestine. GLP-2 also reduces epithelial permeability, and decreases meal-stimulated gastric acid secretion and gastrointestinal motility. Administration of GLP-2 in the setting of experimental intestinal injury is associated with reduced epithelial damage, decreased bacterial infection, and decreased mortality or gut injury in rodents with chemically induced enteritis, vascular-ischemia reperfusion injury, and dextran sulfate–induced colitis. GLP-2 also attenuates chemotherapy-induced mucositis via inhibition of drug-induced apoptosis in the small and large bowel. GLP-2 improves intestinal adaptation and nutrient absorption in rats after major small bowel resection, and in humans with short bowel syndrome. The actions of GLP-2 are mediated by a distinct GLP-2 receptor expressed on subsets of enteric nerves and enteroendocrine cells in the stomach and small and large intestine. The beneficial actions of GLP-1 and GLP-2 in preclinical and clinical studies of diabetes and intestinal disease, respectively, has fostered interest in the potential therapeutic use of these gut peptides. Nevertheless, the actions of the glucagon-like peptides are limited in duration by enzymatic inactivation via cleavage at the N-terminal penultimate alanine by dipeptidyl peptidase IV (DP IV). Hence, inhibitors of DP IV activity, or DP IV-resistant glucagon-like peptide analogues, may be alternative therapeutic approaches for treatment of human diseases.

GASTROENTEROLOGY 2002;122:531-544

Section snippets

GLP-1 actions in the gastrointestinal tract and pancreas

The actions of GLP-1 are mediated by a single GLP-1 receptor widely expressed in the kidney, heart, central nervous system, gastrointestinal tract, and in the endocrine pancreas.44, 45, 46 The GLP-1 receptor has been localized to human chromosome 6p2147; however, significant linkage to diseases such as diabetes has not yet been detected.48 GLP-1 infusion inhibits sham feeding–induced acid secretion in normal human subjects,49, 50, 51 and these actions on acid secretion are dependent on both

GLP-1, appetite, and the central nervous system

The finding that ICV GLP-1 administration dose-dependently inhibits food intake in rats and mice,70, 82, 83, 84 in association with experimental data demonstrating increased food intake and weight gain following chronic ICV administration of the GLP-1 receptor antagonist exendin (9-39),85 has engendered considerable interest in the anorexic properties of GLP-1 agonists. Subsequent studies demonstrated that peripheral administration of GLP-1 or exendin-4 to rodents also reduced short-term and

GLP-1 agonists and therapy of type 2 diabetes

The actions of GLP-1 including inhibition of gastric emptying, stimulation and inhibition of insulin and glucagon secretion, respectively, expansion of β-cell mass and reduction of food intake and weight gain, represent ideal properties for an agent designed for the treatment of type 2 diabetes.98 Furthermore, GLP-1 actions are highly glucose-dependent, hence excess GLP-1 administration is unlikely to be associated with hypoglycemia in vivo. A principal obstacle to the long-term use of the

Glucagon-like peptide-2

GLP-2 is a 33 amino acid peptide cosecreted with GLP-1 from enteroendocrine L cells in the small and large intestine. The biological role of GLP-2 remained obscure until 1996, when GLP-2 was shown to be a potent stimulator of mucosal epithelial proliferation in the murine small intestine.113 Studies linking proglucagon-derived peptides to intestinal growth and adaptation were fostered by the description of a patient with a glucagonoma who presented with small intestinal mucosal hyperplasia and

Glucagon-like peptide-2: Synthesis and secretion

The sequence of GLP-2 is highly conserved in vertebrates with rat and mouse GLP-2 sequences differing from human GLP-2 by a single amino acid.8 GLP-2, like GLP-1, contains an alanine at position 2 (Figure 2), rendering it a substrate for DP IV cleavage. Analysis of the circulating forms of GLP-2 in rats and humans demonstrates the presence of GLP-21-33 and the N-terminally inactivated peptide GLP-23-33.37, 39, 40, 132, 133 Consistent with the importance of DP IV for degradation of bioactive

GLP-2 action in the gastrointestinal tract

The principal histological finding in the rodent gut after repeated GLP-2 administration is mucosal growth in the small bowel due to stimulation of cell proliferation in the crypt compartment and inhibition of enterocyte apoptosis,113, 131, 140, 141, 142 principally evident histologically as elongation of the villous epithelium (Figure 3).

. Histological photomicrograph of a H&E-stained cross-section of the murine jejunum following treatment with either saline or the human GLP-2 analogue

GLP-2 and intestinal injury

The mucosal atrophy observed in the intestine of parenterally fed rodents may be attributable in part to reduced circulating levels of GLP-2 in the absence of periodic nutrient stimulation of GLP-2 secretion. Intravenous infusion of GLP-2 together with parenteral nutrition prevented mucosal hypoplasia in the small bowel, but not in the large bowel of fasted rats.131, 151 The trophic effects of exogenous GLP-2 on the rat small bowel mucosa were also preserved in parenterally fed tumor-bearing

Identifying mechanisms mediating GLP-2 action

GLP-2 exerts its actions through a recently identified G protein-coupled receptor isolated from hypothalamic and intestinal cDNA libraries. The GLP-2 receptor (GLP-2R) is comprised of 550 amino acids and was localized to human chromosome 17p13.3.162 The GLP-2R is expressed in a tissue-specific manner in the stomach, small and large intestine, central nervous system, and lung.162, 163, 164 GLP-2R expression in the human gut epithelium has been localized to subsets of enteroendocrine cells in the

GLP-2 and treatment of human intestinal disease

Although GLP-2 exerts beneficial effects in experimental models of intestinal injury, experience with GLP-2 in the setting of human disease is limited. Treatment of 8 patients with short bowel syndrome and energy malabsorption with twice daily subcutaneous injections of native human GLP-2 for 35 days resulted in modest but statistically significant improvements in nutrient absorption as assessed by metabolic balance studies carried out before and after completion of GLP-2 therapy.169 GLP-2

Glucagon-like peptides: Future research directions

The original finding that GLP-1 functions as an incretin to increase insulin secretion has been followed by the delineation of multiple nonincretin actions of GLP-1 on gastric emptying, small bowel motility, glucagon secretion, and islet β-cell proliferation. The possibility that GLP-1 administration may also be associated with islet regeneration in human subjects with type 2 diabetes has engendered considerable interest in the development of GLP-1 analogues suitable for long-term diabetes

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    Supported in part by grants from the Canadian Institutes of Health Research (CIHR) and the Ontario Research and Development Challenge Foundation (ORDCF). Dr. Drucker is a Senior Scientist of the CIHR and a consultant to Merck Research Laboratories, Amylin Pharmaceuticals Inc, Conjuchem Inc, and NPS Pharmaceuticals Inc. GLP-2 is the subject of a licensing agreement between NPS Pharmaceuticals, the University of Toronto, The University Health Network, and Dr. Drucker.

    ☆☆

    Address correspondence to: Daniel J. Drucker, M.D., Banting and Best Diabetes Centre, Toronto General Hospital, 101 College Street CCRW3-845, Toronto, Ontario, Canada M5G 2C4. e-mail: [email protected]; fax: (416) 978-4108.

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