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,3
Departments of
* Laboratory Medicine and Pathobiology and
Medicine, Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Toronto, Ontario Canada M5G 2C4
3To whom correspondence should be addressed. E-mail: d.drucker{at}utoronto.ca.
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ABSTRACT |
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 TOP ABSTRACT Stimulation of cellular...Cytoprotective properties of GLP...The GLP-2 receptorGLP-2 and the treatment...LITERATURE CITED |
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KEY WORDS: • glucagon-like peptide-2 • apoptosis • GPCR • intestine
Glucagon-like peptide 2 (GLP-2)3 is produced in and secreted from enteroendocrine L cells following posttranslational processing of proglucagon by prohormone convertase 1/3 (1–3). Intestinal proglucagon-derived peptides (PGDP) liberated with GLP-2 include oxyntomodulin, glicentin, GLP-1 and two intervening peptides, IP-1 and IP-2 (Fig. 1) (4,5). GLP-2 is also produced in the brainstem. Circulating levels of GLP-2 are low in the fasting state and increase following nutrient ingestion (6–8). GLP-2 has a half-life of minutes due principally to rapid inactivation following cleavage by dipeptidyl peptidase IV in vivo (6,9,10), and in part due to renal clearance (11,12).
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Stimulation of cellular proliferation by GLP-2 |
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TOPABSTRACTStimulation of cellular...Cytoprotective properties of GLP...The GLP-2 receptorGLP-2 and the treatment...LITERATURE CITED |
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The lack of specific potent GLP-2 antagonists has hampered delineation of the physiological importance of endogenous GLP-2. GLP-2 (3–33) exhibits both weak antagonist and partial agonist activity (29), complicating its use for elucidation of physiological GLP-2 actions. Upregulated circulating levels of the PGDP including GLP-2, have been detected in untreated diabetic rats, and may be implicated in the generation of increased intestinal mass observed in diabetic rodents (30,31). Levels of circulating GLP-2 increase rapidly following rat small bowel resection (32) and immunoneutralization of GLP-2 using polyclonal antisera partially attenuates the intestinal growth response in diabetic rats (31). GLP-2 also increases intestinal weight and villus height in neonatal pigs (33). The actions of GLP-2 in the brain are less clear; although intracerebroventricular GLP-2 administration modestly inhibits food intake in rats and mice, the physiological importance of GLP-2 as an anorexic peptide is uncertain (34,35).
The increase in bowel weight and mucosal thickness following GLP-2 administration is due principally to the stimulation of crypt cell proliferation, leading to lengthening of the intestinal villi and a modest expansion of the crypt compartment (16,19,36,37). Microscopic analysis of GLP-2–treated small bowel mucosa reveals a considerable increase in the number of microvilli, providing yet another mechanism for expansion of the mucosal absorptive surface area (18). Rodents treated with GLP-2 exhibit increased DNA and protein content in the small bowel and colon (21,38) and an increased crypt cell proliferation rate in the small intestine (36). GLP-2-induced crypt cell proliferation in the large bowel has been observed in parenterally, but not orally fed rats (19). Significantly increased small bowel weight can be maintained with repeated daily subcutaneous administration of GLP-2 for at least 12 wk; cessation of peptide treatment results in normalization of bowel mass within days of peptide withdrawal (36).
The intestinotrophic actions of GLP-2 are largely indirect, consistent with the localization of GLP-2 receptors to murine enteric neurons and human enteroendocrine cells (39,40). Although the downstream mediators of GLP-2 action on growth and apoptosis remain unknown, the GLP-2–dependent stimulation of intestinal glucose uptake and blood flow is blocked by N
-nitro-L-arginine methyl ester, implicating a role for nitric oxide in the transduction of specific GLP-2 signals (41). At pharmacological doses, GLP-2 stimulates cell proliferation measured by increased [3H]-thymidine incorporation in intestinal cell lines not shown to express the cloned GLP-2 receptor in vitro (42,43). Similarly, GLP-2 promotes cell proliferation in baby hamster kidney (BHK) cells stably expressing a transfected rat GLP-2 receptor (44) and in primary cultures of rat astrocytes derived from the cerebral cortex (45).
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Cytoprotective properties of GLP-2 |
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TOPABSTRACTStimulation of cellular...Cytoprotective properties of GLP...The GLP-2 receptorGLP-2 and the treatment...LITERATURE CITED |
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The development of apoptotic mucosal cell death following administration of chemotherapeutic agents can also be reduced by concomitant or prior treatment with h[Gly2]GLP-2. Mice treated with h[Gly2]GLP-2 and either irinotecan or 5'-fluoruracil exhibit increased survival, reduced histological evidence of disease and a highly significant reduction in positional crypt compartment apoptosis (48). The trophic and antiapoptotic actions of GLP-2 have also been demonstrated in rodents and pigs following withdrawal of enteral nutrition. GLP-2 infusion prevents the development of mucosal hypoplasia in the small bowel of normal and tumor-bearing rats (49,50). Similarly, GLP-2 administration to premature pigs maintained on total parenteral nutrition reduced proteolysis and crypt cell apoptosis in the small bowel (51).
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The GLP-2 receptor |
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TOPABSTRACTStimulation of cellular...Cytoprotective properties of GLP...The GLP-2 receptorGLP-2 and the treatment...LITERATURE CITED |
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Signaling through the GLP-2 receptor directly inhibits cell death in transfected heterologous cell lines treated with chemical inducers of apoptosis. GLP-2 inhibits cycloheximide-induced apoptosis in a cAMP-dependent, PKA-, mitogen-activated protein kinase-, and phosphatidylinositol 3-kinase (PI3K)-independent manner in BHK cells stably transfected with the rat GLP-2 receptor (BHK-rGLP-2R) (54). GLP-2 reduces caspase-3 and -8 activation and poly(ADP-ribose) polymerase cleavage following incubation of BHK:rGLP-2R cells with cycloheximide, irinotecan or LY294002, a specific PI3-kinase inhibitor (48,54,55). GLP-2 also inhibits cycloheximide and LY294002-induced mitochondrial cytochrome c release and the caspase-dependent cleavage of ß-catenin and Akt induced by inhibition of PI3K (54,55). Similarly, GLP-2 reduces activation of glycogen synthase kinase-3 (GSK-3) and the mitochondrial association of the proapoptotic molecules Bad and Bax in BHK-rGLP-2R cells treated with LY294002 (55). Interestingly, in contrast to the PKA-independent reduction of cycloheximide-induced apoptosis, GLP-2 inhibits LY294002-induced apoptosis in a PKA-dependent manner (55), illustrating that the cytoprotective effects of GLP-2R signaling are mediated through multiple pathways depending on the apoptotic stimulus.
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GLP-2 and the treatment of intestinal disease |
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TOPABSTRACTStimulation of cellular...Cytoprotective properties of GLP...The GLP-2 receptorGLP-2 and the treatment...LITERATURE CITED |
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In contrast to the evidence for beneficial effects of GLP-2 in experimental models of gut injury, very limited information is available about the potential therapeutic actions of GLP-2 in human subjects. Eight patients with intestinal failure secondary to short bowel syndrome were treated twice daily with subcutaneous injections of wild-type GLP-2 (for 35 d). GLP-2 treatment improved nutrient absorption, increased body weight, delayed gastric emptying and increased bone mass (61,62). Hence, the available data suggests that the proabsorptive beneficial effects of GLP-2 noted in preclinical studies may also be detected in short term studies in human subjects. Whether GLP-2 will also prove to be effective in reducing intestinal injury or enhancing gut repair in patients remains unknown pending further clinical evaluation of GLP-2 in humans.
Although much has been learned about GLP-2 action over the past 7 y, the mechanisms responsible for the pleiotropic effects of GLP-2 in the gastrointestinal tract are poorly defined. The precise chemical identity and subtype of the enteric neurons and endocrine cells that express the GLP-2 receptor remains obscure. Similarly, it seems likely that multiple distinct second mediators transduce the diverse actions of GLP-2 in the stomach, and both small and large bowel, yet little is known about the molecules and second messengers activated or repressed following GLP-2R activation. Finally, the physiological importance of various GLP-2 actions, ideally defined through the use of specific GLP-2 receptor antagonists and/or murine models with inactivating mutations in the GLP-2/GLP-2R axis, remains to be elucidated. The emerging physiological importance and therapeutic potential of GLP-2 suggests that the answers to many of these questions will be pursued vigorously by multiple investigators with complementary experimental approaches.
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FOOTNOTES |
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2 The work from the Drucker lab cited in this review was supported in part by operating grants from the Canadian Institutes of Health Research (CIHR), the National Cancer Institute of Canada, and the Ontario Research and Development Challenge Fund. JLE is supported by a studentship award from the National Science and Engineering Council of Canada, and DJD is a CIHR Senior Scientist. GLP-2 is the subject of a licensing agreement between the University of Toronto, the Toronto General Hospital, DJD, and NPS Pharmaceuticals Inc.
4 Abbreviations used: BHK, baby hamster kidney; BHK-rGLP-2R, BHK cells stably transfected with the rat GLP-2 receptor; cAMP, cyclic adenosine monophosphate; CRE, cAMP-response element; GLP-2, glucagon-like peptide-2; GSK-3, glycogen synthase kinase-3; h[Gly2]GLP-2, degradation-resistant GLP-2 analogue; PGDP, proglucagon-derived peptides; PKA, protein kinase-A; PI3K, phosphatidylinositol 3-kinase.
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LITERATURE CITED |
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TOPABSTRACTStimulation of cellular...Cytoprotective properties of GLP...The GLP-2 receptorGLP-2 and the treatment...LITERATURE CITED |
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