Special Reports and ReviewsBiological actions and therapeutic potential of the glucagon-like peptides☆,☆☆
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).
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
References (172)
- et al.
Glucagon gene expression in vertebrate brain
J Biol Chem
(1988) - et al.
Bioactive enteroglucagon (oxyntomodulin): present knowledge on its chemical structure and its biological activities
Peptides
(1981) Molecular evolution of proglucagon
Regul Pept
(2001)- et al.
Preproglucagon gene expression in pancreas and intestine diversifies at the level of post-translational processing
J Biol Chem
(1986) - et al.
Tissue-specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard
J Biol Chem
(1997) - et al.
Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide
J Biol Chem
(1995) - et al.
Processing of mouse proglucagon by recombinant prohormone convertase 1 and immunopurified prohormone convertase 2 in vitro
J Biol Chem
(1995) - et al.
Glucagon-like peptide-1 7-36: A physiological incretin in man
Lancet
(1987) - et al.
Short-chain fatty acid-supplemented total parenteral nutrition alters intestinal structure, glucose transporter 2 (GLUT2) mRNA and protein, and proglucagon mRNA abundance in normal rats
Am J Clin Nutr
(1998) - et al.
Secretion of the intestinotropic hormone glucagon-like peptide 2 is differentially regulated by nutrients in humans
Gastroenterology
(1999)
Amidated and non-amidated glucagon-like peptide-1 (GLP-1): non-pancreatic effects (cephalic phase acid secretion) and stability in plasma in humans
Regul Pept
Comparative effects of GLP-1 (7-36)amide, oxyntomodulin and glucagon on rabbit gastric parietal cell function
Eur J Pharmacol
Sympathetic pathways mediate GLP-1 actions in the gastrointestinal tract of the rat
Regul Pept
Relation between gastric emptying of glucose and plasma concentrations of glucagon-like peptide-1
Peptides
Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut
FEBS Lett
Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats
Brain Res
Central infusion of glucagon-like peptide-1-(7-36) amide (GLP-1) receptor antagonist attenuates lithium chloride-induced c-Fos induction in rat brainstem
Brain Res
Dipeptidyl-peptidase IV (CD26)–role in the inactivation of regulatory peptides
Regul Pept
Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem
Proc Natl Acad Sci U S A
Hamster preproglucagon contains the sequence of glucagon and two related peptides
Nature
Mammalian pancreatic preproglucagon contains three glucagon-related peptides
Proc Natl Acad Sci U S A
Pre-proglucagon messenger ribonucleic acid: Nucleotide and encoded amino acid sequences of the rat pancreatic complementary deoxyribonucleic acid
Endocrinology
Proglucagon gene expression is regulated by a cyclic AMP-dependent pathway in rat intestine
Proc Natl Acad Sci U S A
Identical mRNA for preproglucagon in pancreas and gut
Eur J Biochem
Developmental and tissue-specific regulation of proglucagon gene expression
Endocrinology
Trout and chicken proglucagon: alternative splicing generates mRNA transcripts encoding glucagon-like peptide 2
Mol Endocrinol
Proglucagon is processed to glucagon by prohormone convertase PC2 in aTC1-6 cells
Proc Natl Acad Sci U S A
Defective prohormone processing and altered pancreatic islet morphology in mice lacking active SPC2
Proc Natl Acad Sci U S A
Role of prohormone convertases in the tissue-specific processing of proglucagon
Mol Endocrinol
Proglucagon processing in an islet cell line: effects of PC1 overexpression and PC2 depletion
Endocrinology
Evidence for redundancy in propeptide/prohormone convertase activities in processing proglucagon: an antisense study
Mol Endocrinol
Molecular forms of human enteroglucagon in tissue and plasma: Plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract
J Clin Endocrinol Metab
Radio-immunoassays for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2)
Scand J Clin Lab Invest
Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients
Endocrinology
Somatostatin restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused porcine ileum
Am J Physiol Endocrinol Metab
Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion
Endocrinology
Effects of fasting, refeeding and intraluminal triglyceride on proglucagon expression in jejunum and ileum
Diabetes
Dietary fiber modulates intestinal proglucagon messenger ribonucleic acid and postprandial secretion of glucagon-like peptide-1 and insulin in rats
Endocrinology
Short-chain fatty acids increase proglucagon and ornithine decarboxylase messenger RNAs after intestinal resection in rats
J Parenter Enteral Nutr
Systemic short-chain fatty acids rapidly alter gastrointestinal structure, function, and expression of early response genes
Dig Dis Sci
Biological effects and metabolic rates of glucagonlike peptide-1 7-36 amide and glucagonlike peptide-1 7-37 in healthy subjects are indistinguishable
Diabetes
Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum
Eur J Biochem
Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV
Endocrinology
Both subcutaneously and intravenously administered glucagon-like peptide 1 are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects
Diabetes
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
Circulating and tissue forms of the intestinal growth factor, glucagon-like peptide 2
Endocrinology
Regulation of the biological activity of glucagon-like peptide 2 by dipeptidyl peptidase IV
Nat Biotechnol
In vivo and in vitro degradation of glucagon-like peptide-2 in humans
J Clin Endocrinol Metab
Renal catabolism of human glucagon-like peptides 1 and 2
Can J Physiol Pharmacol
Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig
Am J Physiol
Cited by (452)
Intestinal adaptation and rehabilitation
2023, Seminars in Pediatric SurgeryAge-related morphological and functional changes in the small intestine of senescence-accelerated mouse
2022, Experimental GerontologyComparison of independent and combined effects of the neurotensin receptor agonist, JMV-449, and incretin mimetics on pancreatic islet function, glucose homeostasis and appetite control
2021, Biochimica et Biophysica Acta - General SubjectsGLP-1 based therapies and disease course of inflammatory bowel disease
2021, eClinicalMedicineCitation Excerpt :Regarding GLP-1, it has been suggested that GLP-1 reduces intestinal and systemic inflammation through interaction with GLP-1 receptors expressed in intraepithelial lymphocytes and in other organs and cells [11]. In addition, GLP-2 has in animals been found to possess intestinal reparative and protective properties [29]. Further investigations are needed to establish whether the lower risk of adverse clinical events that we observed amongst patients treated with GLP-1 receptor agonists and/or DPP-4 inhibitors compared with treatment with other antidiabetic therapies is due to a reduced intestinal and systemic inflammation.
Fructo-oligosaccharides alleviate inflammation-associated apoptosis of GLP-1 secreting L cells via inhibition of iNOS and cleaved caspase-3 expression
2020, Journal of Pharmacological SciencesRole of Stress on Driving the Intestinal Paracellular Permeability
2023, Current Issues in Molecular Biology
- ☆
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.