The Journal of Clinical Endocrinology & Metabolism Vol. 86, No. 4 1759-1764
Copyright © 2001 by The Endocrine Society
Glucagon-Like Peptide 21
Daniel J. Drucker2
Department of Medicine, Banting and Best Diabetes Centre, Toronto
General Hospital, University of Toronto, Toronto, Ontario, Canada M5G
2C4
Address correspondence and requests for reprints to: Dr. D. J. Drucker, Toronto General Hospital, 101 College Street CCRW3-845, Toronto, Ontario, Canada M5G 2C4. E-mail: d.drucker{at}utoronto.ca
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Abstract
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Glucagon-like peptide 2 (GLP-2) is a 33 amino acid peptide-encoded
carboxyterminal to the sequence of GLP-1 in the
proglucagon gene. Both GLP-1 and GLP-2 are secreted from
gut endocrine cells and promote nutrient absorption through distinct
mechanisms of action. GLP-2 regulates gastric motility, gastric acid
secretion, intestinal hexose transport, and increases the barrier
function of the gut epithelium. GLP-2 significantly enhances the
surface area of the mucosal epithelium via stimulation of crypt cell
proliferation and inhibition of apoptosis in the enterocyte and crypt
compartments. The cytoprotective and reparative effects of GLP-2 are
evident in rodent models of experimental intestinal injury. GLP-2
reduces mortality and decreases mucosal injury, cytokine expression,
and bacterial septicemia in the setting of small and large bowel
inflammation. GLP-2 also enhances nutrient absorption and gut
adaptation in rodents or humans with short bowel syndrome. The actions
of GLP-2 are transduced by the GLP-2 receptor, a G protein-coupled
receptor expressed in gut endocrine cells of the stomach, small bowel,
and colon. Activation of GLP-2 receptor signaling in heterologous cells
promotes resistance to apoptotic injury in vitro. The
cytoprotective, reparative, and energy-retentive properties of GLP-2
suggests that GLP-2 may potentially be useful for the treatment of
human disorders characterized by injury and/or dysfunction of the
intestinal mucosal epithelium.
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Introduction
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THE GLUCAGON-LIKE PEPTIDES (GLPs) are
produced in open type gut endocrine cells of the small and large
intestine and play diverse roles in the regulation of energy
homeostasis. Food ingestion sets in motion coordinated peptidergic
responses that regulate nutrient transit through the gut, and nutrient
absorption. Gut peptides also contribute to optimization of mucosal
epithelial function for nutrient digestion and absorption. Following
nutrient absorption into the blood stream, enteroendocrine-derived
peptides such as GLP-1 facilitate nutrient disposal by
regulating islet hormones and, indirectly, energy absorption via
effects on liver, muscle, and adipose tissue. The aim of this review is
to highlight recent advances in our understanding of the role played by
GLP-2 in the regulation of intestinal epithelial biology and nutrient
absorption.
The sequence of proglucagon contains a number of distinct peptides with
pleiotropic actions, including glicentin, glucagon, oxyntomodulin, and
two GLPs as well as two intervening or spacer peptides (Fig. 1
). Whereas glucagon, GLP-1,
and GLP-2 exert well-defined actions through known receptors, the
biological actions of the remaining proglucagon-derived peptides remain
less well characterized. Furthermore, no receptors have yet been
isolated for glicentin, oxyntomodulin, or the intervening peptides
(1, 2, 3, 4).
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Figure 1. Structure of mammalian proglucagon, the
proglucagon-derived peptides, and the biological actions of GLP-2. The
numbers above and below the proglucagon
molecule correspond to the positions and length of specific PGDPs.
MPGF, Major proglucagon fragment; IP, intervening peptide.
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Although the sequence of GLP-2 was not detected in anglerfish islet
proglucagon complementary DNAs (cDNAs; Ref. 5), the GLP-2
sequence (Fig. 2) was detected in all
isolated mammalian proglucagon cDNAs and genes (6, 7, 8, 9, 10) as
a 33 amino acid peptide located carboxyterminal to GLP-1
and intervening peptide 2 (Figs. 1
and 2). Subsequent studies
demonstrated that fish, chickens, and lizards generate GLP-2 in the gut
as a result of tissue-specific alternative RNA splicing of proglucagon
RNA transcripts (11, 12). In mammals, tissue-specific
posttranslational processing liberates GLP-2 from proglucagon in the
intestine and brain but not in pancreas, as a result of cell-specific
expression of prohormone convertases in gut endocrine cells
(13). Isolation and sequencing of GLP-2 from the porcine
and human intestine confirmed that GLP-2 is a 33 amino acid peptide
(Fig 2), corresponding to proglucagon 126–158, ending in a
carboxyterminal Asp residue (14, 15).
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Figure 2. Peptide sequences of human glucagon,
GLP-1, and GLP-2. Amino acids common to all three peptides
are shown in bold. Amino acids common to glucagon and
GLP-1, GLP-1, and GLP-2, and glucagon and
GLP-2 are shown in green, blue, and
red, respectively.
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Initial studies of GLP-2 biological activity demonstrated increased
adenylate cyclase activity in rat hypothalamic and pituitary membrane
preparations following incubation with 50 pM GLP-2
(16). Subsequent analyses of GLP-2 activity in the gut
either failed to demonstrate activity of GLP-2 or demonstrated
GLP-2-mediated inhibition of serum-stimulated intestinal cell growth
in vitro (17). Nevertheless, despite these
negative findings, considerable experimental evidence correlated
increased expression and secretion of intestinal proglucagon-derived
peptides (PGDPs) with bowel injury and mucosal growth of the small
intestine (18, 19, 20, 21, 22). Furthermore, two patients with
glucagonomas exhibited marked small bowel villus hyperplasia that was
reversed following surgical removal of the tumor (23, 24).
Following observations that mice with sc glucagonomas developed massive
small bowel hyperplasia, peptide injection studies identified GLP-2 as
the PGDP with significant intestinotrophic activity
(25).
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GLP-2 synthesis, secretion, and degradation
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A single proglucagon messenger RNA (mRNA) transcript, identical in
sequence to proglucagon mRNAs in pancreas and brain (Fig. 1), is
expressed in the mammalian small and large intestine
(26, 27, 28). GLP-1 and GLP-2 are cosecreted from
the gut (29) with the type and amount of nutrient
ingestion representing a primary determinant of both intestinal
proglucagon gene expression (30, 31, 32, 33) and GLP-2 secretion
in rodent, pig, and human studies (34, 35, 36, 37). Fiber-enriched
diets and fatty acids are potent stimulators of GLP-2 secretion in
rodents and human subjects (36, 38).
Intestinal injury or resection is associated with increased levels of
proglucagon mRNA transcripts in the intestinal remnant as a result of
an increase in proglucagon RNA content in the remaining enteroendocrine
cells (39, 40, 41, 42). The kidney seems to be an important
determinant of GLP-2 clearance as levels of immunoreactive GLP-2 are
increased in human patients with renal failure (43).
Similarly, experimental nephrectomy results in delayed clearance and
increased circulating levels of GLP-2 in rats (44, 45).
The estimated elimination t1/2 of exogenously
administered GLP-2 in human studies seems to be 
7.2 min
(46), considerably longer than the
t1/2 of GLP-1 in similar
studies.
Analysis of rat and human plasma using a combination of
high-performance liquid chromatography and site-specific GLP-2 antisera
reveals the presence of two principal circulating molecular forms,
GLP-21–33 and GLP-23–33
(15, 35, 46, 47). GLP-1, gastric inhibitory
peptide, and GLP-2 all contain an alanine residue in position 2,
rendering them ideal substrates for degradation by dipeptidyl peptidase
IV (DP IV), a ubiquitous protease expressed in the gut and vascular
endothelium (48, 49). Incubation of GLP-2 with DP IV
in vitro results in cleavage to the bioinactive
GLP-23–33 peptide, and inhibitors of DP IV
prevent GLP-2 degradation both in vitro and in
vivo (35, 46, 47). The importance of DP IV for the
biological activity of GLP-2 is exemplified by studies in rats
demonstrating considerably greater intestinotrophic activity of an
exogenously administered GLP-2 analog resistant to DP IV-mediated
inactivation (47). Similarly coadministration of a DP IV
inhibitor potentiates the trophic activity of exogenous native GLP-2 in
rats (50).
Increased circulating levels of GLP-2 are associated with the
development of intestinal mucosal hyperplasia in rodents with
experimental diabetes (38, 51). Administration of insulin
to diabetic rats reduces the levels of circulating GLP-2 and reverses
the small bowel mucosal hyperplasia (51). Human subjects
with inflammatory bowel disease exhibit normal to increased levels of
circulating bioactive GLP-21–33
(52), attributable in part to a decrease in levels of
circulating DP IV activity. Patients with Crohn’s disease and marked
involvement of the terminal ileum and patients with short bowel
syndrome and lack of a colon in continuity with the remnant small bowel
exhibit deficient levels of circulating GLP-2 and reduced
meal-stimulated GLP-2 secretion, respectively (52, 53). In
contrast, patients with ileal resection but a preserved colon exhibit
increased fasting and meal-stimulated levels of GLP-2 and enhanced
intestinal adaptation (54), providing a possible
physiological explanation linking the presence of a colon with
facilitated intestinal adaptation.
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Biological activities of GLP-2
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The gastrointestinal tract, from the stomach to the colon, is the
principal target for GLP-2 action. GLP-2 inhibits stimulated gastric
acid secretion in human subjects and reduces antral gastric motility in
the pig (55, 56). Acute GLP-2 infusion rapidly increases
intestinal hexose transport in rats, with significant increases in both
hexose and SGLT-1 transport activity detectable within 60 min after
initiation of iv GLP-2 infusion (57, 58). Administration
of GLP-2 to normal mice produces significant increases in intestinal
barrier function. Reduced epithelial permeability as measured by
decreased ion and macromolecule transport, is detectable in Ussing
chamber studies after a single injection of GLP-2 (59).
Morphologically, intestinal epithelial cells appear narrower and
longer, with increased numbers of longer microvilli detectable on the
luminal surface of the enterocyte following several days of GLP-2
administration (59).
GLP-2 administered exogenously to mice and rats promotes expansion of
the mucosal epithelium in the small and large bowel, with the most
prominent trophic effects seen in the small bowel, specifically in the
jejunum (25, 60). The trophic effects of GLP-2 are
independent of the route of GLP-2 administration and are observed after
iv, sc, or ip GLP-2 administration (57, 60, 61, 62). Although
the optimal dosing and timing of GLP-2 administration for human
clinical studies remains to be determined, GLP-2 is intestinotrophic in
rodents even in daily or every other day administration regimens
(60, 61). Whereas small changes in intestinal length have
been detected after GLP-2 treatment (63), increased
thickness of the intestinal mucosa, predominantly an increase in small
bowel villus height and mucosal surface area, is invariably detected
after several days of GLP-2 treatment (25, 47, 60, 61, 63). Enhanced thickness of the mucosal epithelium may be
explained by GLP-2-stimulated increases in crypt cell proliferation,
coupled with a decrease in the rate of enterocyte apoptosis (25, 61).
The GLP-2-treated bowel is functionally normal as assessed by analysis
of macromolecule expression, and normal levels of mucosal enzymes are
observed in the GLP-2-treated murine intestine (64).
Absorption of carbohydrates, lipids, and proteins is normal to enhanced
in GLP-2-treated mice (64). Similarly, GLP-2-treated rats
exhibit enhanced absorption of glycine and galactose in association
with increased mucosal DNA and protein content (65).
Despite the suggestion that intracrebroventricular GLP-2 administration
inhibits food intake (66), GLP-2 treatment of normal
animals results in normal food intake, weight gain commensurate with
intestinal growth and an enhanced capacity for nutrient absorption
(64).
The finding that enteral nutrients regulate GLP-2 secretion suggests a
role for GLP-2 in mediating the trophic effect of nutrients on
maintaining the normal thickness of the mucosal epithelium. Rats
maintained on parenteral nutrition develop atrophy of the intestinal
epithelium in both the small and large intestine, possibly as a result
of reduced GLP-2 secretion. Intravenous coinfusion of GLP-2 and
parenteral nutrition prevented the development of mucosal atrophy in
the small but not the large bowel, illustrating the differential
regional sensitivity of the gut to the trophic effects of GLP-2
(62, 67). Consistent with these findings, GLP-2
significantly improved the endogenous intestinal adaptive response to
major small bowel resection in rats, with increased nutrient absorption
and reduced intestinal permeability observed in the GLP-2-treated
animals (68, 69).
The trophic and reparative effects of GLP-2 on the gut mucosa have also
been observed in the setting of experimental intestinal injury.
Following induction of indomethacin-induced intestinal inflammation,
GLP-2 significantly reduced intestinal disease activity scores and
cytokine expression, decreased bacterial sepsis, and reduced
mortality in mice with enteritis (70). Remarkably, GLP-2
was most effective in ameliorating disease activity when administered
as a pretreatment regimen before onset of indomethacin-induced
enteritis (70). GLP-2 also increased mucosal DNA content
and significantly reduced mortality in rats following vascular
ischemia-reperfusion injury of the small intestine (71).
The protective effects of GLP-2 in the gut have also been observed in
the large bowel as mice with dextran sulfate colitis exhibit reduced
parameters of disease activity, decreased intestinal interleukin
expression, and significantly reduced weight loss after GLP-2
administration (72). Similarly, GLP-2 significantly
reduced gross and microscopic mucosal damage and decreased cytokine
expression in rats with antigen-induced inflammatory bowel disease
(73).
The detection of GLP-2 receptor mRNA transcripts in the fetal and
neonatal rat intestine (74) raises the possibility that
GLP-2 may play a role in the development and maturation of the
gastrointestinal tract. Daily administration of h[Gly2]-GLP-2 to
neonatal rats enhanced stomach and small bowel weight and small bowel
length (74). Furthermore, iv infusion of GLP-2 decreased
proteolysis, reduced apoptosis, increased villus height, and was
trophic to the gastrointestinal tract of immature pigs
(75). Whether GLP-2 plays a role in growth and
differentiation of the developing fetal gut remains unclear.
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Mechanisms underlying GLP-2 action: the GLP-2 receptor
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The actions of GLP-2 in the gut are mediated by a distinct GLP-2
receptor, a recently cloned member of the glucagon/GLP-1 G
protein-coupled receptor superfamily (76). GLP-2R cDNAs
isolated from intestinal and hypothalamic cDNA libraries are identical
in sequence and encode a predicted receptor of 550 amino acids,
exhibiting considerable amino acid identity with the glucagon and
GLP-1 receptors. The GLP-2R gene was localized to human
chromosome 17p13.3, a chromosomal region not yet linked to inheritance
of familial intestinal diseases. Activation of GLP-2R signaling is
coupled to an increase in cAMP with an EC50 of
0.58 nM GLP-2. In contrast, structurally related
peptides such as glucagon, GLP-1, GIP, or exendin-4 do not
activate the GLP-2R even at 10-nM concentrations
(76). The intestinotrophic properties of GLP-2 derivatives
in mice in vivo correlate well with the relative activation
of GLP-2R signaling in transfected fibroblasts by these same peptides
in vitro (76, 77). Analysis of the activity of
alanine-substituted and both N- and C-terminally deleted GLP-2
molecules using the transfected GLP-2R expressed in fibroblasts
identified a number of amino acid substitutions in the GLP-2 molecule
that result in either diminished receptor binding and/or reduced
receptor activation in vitro (77).
The GLP-2R is expressed in a highly tissue-specific manner,
predominantly in the stomach, jejunum, ileum, and colon (76, 78). The results of Northern blotting, RNase protection, and
RT-PCR experiments are consistent with the presence of a single GLP-2R
transcript in the gastrointestinal tract and central nervous system of
rodents and humans (78). The GLP-2R has been localized to
subsets of enteroendocrine cells in the human gut. GLP-2R+ gut
endocrine cells also exhibit immunopositivity for either GIP,
serotonin, peptide YY, chromogranin, or GLP-1
(78). Although GLP-2 presumably exerts direct effects on
enteroendocrine cells expressing the GLP-2R, it seems likely that many
of the effects of GLP-2 on gastrointestinal target cells that do not
express the GLP-2R are indirect, resulting in modulation of gastric
motility, small bowel permeability, and both crypt cell proliferation
and apoptosis. Hence, one model that explains GLP-2 action suggests
that GLP-2 synthesized in and secreted from the small and large
intestine exerts many of its actions in an autocrine, paracrine, or
endocrine manner by stimulating the release of as yet unidentified
mediators from GLP-2R+ gut endocrine cells. It seems likely that these
GLP-2R+ enteroendocrine cells then release one or more factors that
mediate the pleiotropic biological actions of GLP-2 in the gut (Fig. 1).
The observations that GLP-2 inhibits enterocyte and crypt compartment
apoptosis following intestinal injury (70) prompted
analysis of the mechanisms coupling GLP-2R signaling to reduced cell
death. Remarkably, direct activation of GLP-2R signaling in transfected
baby hamster kidney fibroblasts expressing the GLP-2 receptor
(BHK-GLP-2R cells) confers resistance to cycloheximide-induced
apoptosis (79). GLP-2 reduced activation of caspase-8,
caspase-9, decreased cytochrome c release, and reduced caspase-3
cleavage, in a protein kinase A-independent manner. The
antiapoptotic actions of GLP-2 are not diminished by inhibitors of the
phosphatidyl inositol-3 kinase or mitogen-activated protein
kinase pathways (79). Furthermore, GLP-2 enhanced survival
and decreased intestinal apoptosis in tumor-bearing mice treated with
chemotherapy and reduced apoptosis and caspase activation in BHK-GLP-2R
cells treated with irinotecan in vitro (80).
These findings demonstrating a direct antiapoptotic effect of GLP-2 on
cells expressing a GLP-2 receptor, taken together with the
cytoprotective effects of GLP-2 in vivo on target cells that
do not seem to express the GLP-2 receptor (70, 72, 80)
suggest that GLP-2 inhibits cell death via both direct and indirect
signaling pathways.
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Summary of current knowledge and unanswered questions
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The available data demonstrate that GLP-2 regulates motility,
nutrient absorption, epithelial permeability, cell proliferation, and
apoptosis in the gastrointestinal tract. Whether one or more of these
actions will prove to be essential for normal gut physiology in the
absence of intestinal injury awaits the development of GLP-2
antagonists or rodent models of disrupted GLP-2 action. Similarly, the
actions of GLP-2 have been principally delineated in rodents and the
biological activities of GLP-2 in human subjects currently remain
unclear. Nevertheless, the strong conservation of GLP-2 and GLP-2R
sequences across species suggests that the physiological actions of
GLP-2 in rodents and humans are likely to be comparable. In this
regard, the results of a recent study of GLP-2 administration in human
subjects with short bowel syndrome demonstrated enhanced energy
absorption and increased crypt plus villus height in GLP-2-treated
patients (81). Given the expression of the GLP-2 receptor
in the central nervous system (76, 78), it seems likely
that GLP-2, like GLP-1, also subserves one or more
functions in the brain. Indeed, intracerebroventricular injection of
GLP-2 in the rat reduces food intake (66), raising the
possibility that GLP-2, perhaps like GLP-1, acts as a
central satiety factor. The multiple actions of GLP-2 that include
protection and restoration of the gut epithelium and enhancement of
nutrient absorption will likely stimulate clinical testing of the
therapeutic potential of this peptide in human diseases characterized
by injury and/or dysfunction of the gut epithelium. Whether GLP-2 will
ultimately prove therapeutically useful and safe for the treatment of
human gastrointestinal diseases requires careful assessment in properly
controlled clinical trials.
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Footnotes
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1 Studies from the Drucker laboratory are supported by an operating
grant from the Canadian Institute of Health Research and the Ontario
Research and Development Challenge Fund. 
2 Senior Scientist of
the Canadian Institute of Health Research, a consultant to NPS Allelix
Corp., and a party to a glucagon-like peptide 2-related licensing
agreement between the University of Toronto, the Toronto General
Hospital, and NPS Allelix Corp.
Received October 4, 2000.
Revised December 8, 2000.
Accepted December 27, 2000.
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Top
Abstract
Introduction
