Recent Advances in Nutritional Sciences
Glucagon-Like Peptide 2: A
Nutrient-Responsive Gut Growth
Factor1,2,3
Douglas G. Burrin,4 Yvette Petersen,* Barbara Stoll
and Per Sangild*
U.S. Department of Agriculture/ARS Children’s Nutrition Research
Center, Department of Pediatrics, Baylor College of Medicine,
Houston, TX 77030 and *Division of Animal Nutrition, Royal
Veterinary and Agricultural University, DK-1870 Copenhagen,
Denmark
ABSTRACT Glucagon-like peptide 2 (GLP-2) is a 33-amino
acid peptide derived from the tissue-specific, post-transla-
tional processing of the proglucagon gene expressed in the
intestinal enteroendocrine L-cell. The primary stimulus for
GLP-2 secretion is nutrient intake, and involves direct lu-
minal stimulation of the L-cell as well as indirect enteroen-
docrine and neural mechanisms. The biological activity of
GLP-2 in circulation is regulated by the proteolytic cleavage
of the N-terminus by dipeptidylpeptidase IV. Several stud-
ies have shown that GLP-2 has specific trophic effects on
the small and large intestine, which are mediated by stim-
ulation of cell proliferation and inhibition of apoptosis and
proteolysis. GLP-2 also has been shown to suppress gas-
tric motility and acid secretion, increase hexose transport
activity and suppress food intake, specifically when infused
centrally. The actions of GLP-2 are mediated by a G-pro-
tein–linked, membrane receptor (GLP-2R) that is localized
largely to the gastrointestinal tract, but also is found in the
brain. The secretion of GLP-2 and expression of the
GLP-2R are present in the late gestation fetus. However,
the developing intestine does not become responsive to
the trophic effect of GLP-2 until after birth. Based on its
efficacy in preventing atrophy and stimulating growth in the
neonatal gut, GLP-2 may be a promising therapeutic adju-
vant for treatment of infants with compromised gut func-
tion. J. Nutr. 131: 709 –712, 2001.
KEY WORDS: ● cell proliferation ● apoptosis ● gut hormone
● enteral nutrition ● neonate
1
Supported by The Danish Agricultural and Veterinary Research Council
(Program 9702803), National Institutes of Health grant RO1-HD33920 (D.G.B.)
and by federal funds from the U.S. Department of Agriculture, Agricultural Re-
search Service under Cooperative Agreement Number 58 – 6250-6 – 001.
2 5
The contents of this publication do not necessarily reflect the views or policies
of the U.S. Department of Agriculture, nor does mention of trade names, commercial
products, or organizations imply endorsement by the U.S. Government.
3
Manuscript received 13 December 2000.
4
To whom correspondence should be addressed.
E-mail: dburrin@bcm.tmc.edu.
0022-3166/01 $3.00 © 2001 American Society for Nutritional Sciences.
709
In the last five years, glucagon-like peptide 2 (GLP-2)5
has emerged as one of the most intriguing and potent
modulators of intestinal growth and function. GLP-2 is a
member of a family of glucagon-like peptides, which have a
variety of important biological functions not only within
the gastrointestinal (GI) tract, where they are produced,
but also in the body as a whole in terms of carbohydrate
metabolism and appetite regulation. Although the biologi-
cal function of pancreatic glucagon is well established, the
precise structural identity and function of gut glucagon, or
“enteroglucagon,” has until recently remained obscure. An
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early clue that glucagon-like peptides have intestinal tro-
phic actions was the report of small bowel hyperplasia in
patients with glucagonomas (1). Drucker and others (2)
reproduced this phenomenon in nude mice implanted with
glucagonomas, and established that the effect was due to
GLP-2. Several subsequent studies (3–5) have suggested
that GLP-2 is a gut peptide with trophic actions that are
highly specific for the GI tract. Moreover, GLP-2 is cur-
rently being developed for therapeutic clinical use; it re-
cently was approved for treatment of gastrointestinal dis-
ease in adults. The aim of this review is to provide an
overview of the biological functions of GLP-2 and to high-
light the gaps in our understanding of its physiologic rele-
vance and mechanism of action, especially in the develop-
ing neonate.
Gene Expression. Glucagon-like peptide 2, a product of the
proglucagon gene, and belongs to a superfamily of genes that
code for gastrointestinal regulatory peptides including secretin,
glucose-dependent insulinotrophic peptide (GIP) and vasoac-
tive intestinal peptide. In the intestine, GLP-2 is produced as
a 33-amino acid peptide derived from post-translational pro-
cessing of the proglucagon polypeptide in enteroendocrine “L”
cells, which are located predominantly in the distal small
intestine and colon (5,6). There is relatively high homology
(87–97%) in the GLP-2 peptide sequence among the species
reported, including humans, pigs, cows and rats. Other prod-
ucts of the proglucagon gene in the intestine and brain are
glucagon-like peptide 1, glicentin and oxyntomodulin. In the
A-cells of the pancreatic islets, glucagon is the major post-
translational product of the gene. It is noteworthy that GLP-2
is produced from proglucagon expressed in regions of the brain
(4). The tissue-specific processing of the proglucagon-derived
peptides is explained largely by the differential expression of
specific prohormone convertases in the intestinal L-cells and
pancreatic A-cells. Much more is known about the molecular
regulation of proglucagon expression in pancreatic A-cells
than in the enteroendocrine L-cells (7). However, studies in
rodents have demonstrated the presence of intestinal proglu-
Abbreviations used: BHK, baby hamster kidney; DPP-IV, dipeptidylpepti-
dase IV; GI, gastrointestinal; GIP, glucose-dependent insulinotrophic peptide;
GLP-2, glucagon-like peptide 2; GLP-2R, GLP-2 receptor; GRP, gastrin-releasing
peptide; MAP kinase, mitogen-activated protein kinase; PI-3, phosphatidylinositol
3 kinase; PKA, protein kinase A; RT-PCR, reverse transcriptase-polymerase chain
reaction; SCFA, short-chain fatty acids.
710 BURRIN ET AL.
cagon expression during fetal and early neonatal development
(8). Other studies have identified specific transcription factors
and aspects of the promoter sequence that are important for
the early development and tissue-specific regulation of proglu-
cagon gene expression (9,10).
Secretion. Many of the factors that regulate the secretion of
GLP-2 can be inferred from our understanding of GLP-1
secretion; both peptides appear to be secreted in parallel and
are derived from the same gene, precursor peptide and cell
type. The primary stimulus for GLP-2 secretion is enteral
nutrient intake, especially carbohydrate and lipid (11) (Fig.
1). In adult humans after an oral feeding, there is a biphasic
increase in the circulating GLP-2 concentration; a rapid initial
increase occurs within 15 min, followed by a second increase
after ⬃1 h. Our studies in neonatal animals have also shown
that the circulating GLP-2 concentration increases approxi-
mately fourfold within 1 h after an oral feeding and is posi-
tively correlated with the level of enteral intake (12,13). It is
remarkable that although intestinal secretions of GLP-1 and
GLP-2 are stimulated by a meal, the pancreatic secretion of
glucagon is effectively suppressed, a fact that highlights the
tissue-specific regulation of proglucagon processing and secre-
tion. Although direct exposure of the L-cell to luminal nutri-
ents stimulates GLP-2 secretion, the rapid increase in the
circulating concentration after feeding, coupled with the
largely distal localization of these cells, suggests the involve-
ment of other indirect mechanisms. Indeed, evidence suggests
that nutrient-mediated secretion of GLP-2 involves both en-
docrine stimulation, mediated by GIP released from enteroen-
docrine K-cells, and neural reflexes involving gastrin-releasing
peptide (GRP) (14). Moreover, there is evidence that short-
chain fatty acids (SCFA) stimulate ileal proglucagon expres-
sion and GLP-2 secretion, and thus provide a partial explana-
tion for the intestinal trophic effect of SCFA infusion and
dietary fiber consumption (15,16). The stimulation of SCFA
production arising from fermentation of malabsorbed dietary
carbohydrate may be a triggering mechanism for GLP-2 secre-
tion, and hence may act as an important trophic signal in
intestinal adaptation after massive small bowel resection. Con-
sistent with this concept are study findings indicating that the
resection of the distal small bowel and colon significantly
diminishes GLP-2 secretion due to loss of GLP-2–producing
tissue and leads to intestinal failure (17). GLP-2 secretion may
FIGURE 1 Overview of factors involved in the regulation of GLP-2
secretion. Abbreviations: GLP-2, glucagon-like peptide 2; GIP, glu-
cose-dependent insulinotrophic peptide; GRP, gastrin-releasing pep-
tide; SCFA, short-chain fatty acids.
also be regulated developmentally, based on evidence that
GLP-2 is present at low levels in fetal plasma and the fact that
the concentration increases progressively during early neona-
tal development (8,18). It is interesting to note that the rate
of intestinal growth and its trophic response to enteral nutri-
tion also increase during early postnatal development, raising
the possibility that GLP-2 secretion may be involved. The
marked increases in the proportion of dietary carbohydrate and
fiber associated with weaning may upregulate GLP-2 secretion
and partially mediate the increased gut growth and cell pro-
liferation observed during this developmental transition.
Biological Activity and Metabolism. An important regu-
latory aspect of GLP-2 activity and metabolism is its rapid rate
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of degradation and renal clearance once secreted from the
intestinal L-cell (19). GLP-2 is secreted as a 33-amino acid
peptide, but is rapidly degraded at an N-terminus site to GLP-2
[3–33] in circulation, in large part, by dipeptidylpeptidase IV
(DPP-IV). This results in a relatively short half-life (7 min) for
full-length GLP-2 [1–33] compared with the truncated GLP-2
[3–33] form (27 min) (5). The truncated GLP-2 [3–33] is
believed to be largely biologically inactive (20). To prolong its
half-life and enhance the biological activity of GLP-2, the
exquisite sensitivity to DPP-IV has been exploited experimen-
tally using a synthetic GLP-2 peptide analog h[Gly2]-GLP-2,
with an N-terminus substitution of glycine for alanine (3,4)
and specific inhibitors of DPP-IV activity, such as valine-
pyrrolidide (20), both of which increase the potency of GLP-2.
The potency of GLP-2 is also greater in mice than in rats due
to the species differences in DPP-IV activity. It is important to
note that the DPP IV enzyme activity is relatively abundant in
the intestinal mucosa and thus may have an important influ-
ence on the biological activity of GLP-2 even before it reaches
the systemic circulation (5). Furthermore, the intestinal ac-
tivity of DPP IV is higher in neonatal than adult animals, and
higher in the distal than proximal gut; however, it is not
known whether this alters the biological effect of GLP-2 in
neonates.
Physiologic and Metabolic Effects. The peptide sequence
of GLP-2 was deduced initially after the proglucagon gene
sequence was reported by Bell and others (21). However, the
biological function of GLP-2 was virtually unknown until the
seminal studies by Drucker and others (2) revealed the marked
intestinal trophic effects of GLP-2. Their initial report and a
series of subsequent studies showed that chronic treatment
with GLP-2 has potent and specific trophic effects on the GI
tract that are characterized grossly by increased tissue mass and
mucosal thickness and morphologically by increased villous
length and crypt depth. In vivo studies in humans and pigs
have demonstrated that GLP-2 infusion acutely inhibits gas-
tric secretion and motility, an effect that is common among
the other peptides secreted from the intestinal L-cell, namely
GLP-1 and PYY (5). As such, GLP-2 may be implicated
together with these peptides in the “ileal brake” phenomenon
(6).
There are conflicting reports concerning the effects of
GLP-2 treatment on intestinal digestive enzyme and nutrient
transport. In some cases, GLP-2 has been found to increase the
activities and expression of hydrolases, such as sucrase-isomal-
tase, maltase-glucoamylase, lactase and aminopeptidase N
(18,22,23). However, some studies in rodents and neonatal
pigs indicate that GLP-2 enhances intestinal hexose transport
by modulating the activity and localization of GLUT2 and
SGLT1 (24,25,26), whereas others found expression of these
transporters to be decreased by GLP-2 (22). Furthermore,
 GLP-2 ACTION IN THE GUT
studies show that GLP-2 increases amino acid transport
(25,27). Yet, in vivo kinetics studies suggest only modest
increases in nutrient absorption in GLP-2–treated mice (22).
In addition to the reported effects of GLP-2 on intestinal
absorptive function, the increased mucosal growth and villous
surface area that occur with GLP-2 treatment may have an
important role in gut barrier function. Indeed, GLP-2 has been
shown to reduce the permeability of the intestine to macro-
molecules, decrease bacteria translocation and suppress the
local expression of proinflammatory cytokines (4,28,29).
GLP-2 may have limited effects on systemic or whole-body
metabolism, given evidence that its actions are confined
largely to the GI tract. Indeed, there is no reported evidence
that systemic GLP-2 administration affects food intake,
growth rate or metabolism. Yet, it is interesting that central
administration of GLP-2 into the lateral cerebral ventricle
suppresses food intake in rats and thus, like GLP-1, it may be
implicated in appetite regulation (30). We have recently
found that GLP-2 stimulates intestinal protein anabolism in
neonatal piglets receiving total parenteral nutrition (TPN) by
suppressing proteolysis, whereas protein synthesis was unaf-
fected (31). However, whether GLP-2 affects any aspect of
whole-body protein, carbohydrate or lipid metabolism remains
to be determined. Thus, from a physiologic perspective, the
general picture that has emerged suggests that GLP-2 acts to
slow the ingestion and transit of food through the GI tract,
while increasing the absorption of nutrients from the small
intestine.
Cellular Actions of GLP-2 Receptor. The cellular actions
of GLP-2 are mediated initially by binding to the GLP-2
receptor (GLP-2R). The recent cloning of cDNAs encoding
the human and rat GLP-2R indicate that it is a G-protein–
linked, seven- transmembrane-domain receptor with homol-
ogy to glucagon, GLP-1 and GIP receptors (4). The human
GLP-2R is encoded by a single gene localized to chromosome
17p13.3. The initial cloning of the GLP-2R was performed
using hypothalamic cDNA libraries; however, efforts to quan-
tify expression based on a ribonuclease protection assay de-
tected mRNA transcripts primarily in the GI tract. A recent
report has confirmed the tissue-specific distribution of the
GLP-2R mRNA, using Northern analysis and reverse tran-
scriptase-polymerase chain reaction (RT-PCR), demonstrat-
ing expression in the gut, brain and the lung (32). This report
has shed light on the more critical issue of localization within
the GI tract using immunohistochemistry, and provides evi-
dence of GLP-2R immunopositivity localized to a limited
number of enteroendocrine cells within the stomach and the
large intestine. That finding is supported by the fact that
RT-PCR analysis failed to detect GLP-2R transcripts among
several intestinal epithelial cells lines studied. In contrast,
another recent report demonstrated that GLP-2 treatment
stimulated proliferation of colonic epithelial (Caco-2) cells,
albeit at concentrations that were ⬃100-fold greater than the
circulating concentration in plasma (33). Yet another group
found that injection of 125I-GLP-2 into rats resulted in specific
binding of labeled GLP-2 localized diffusely along the villous
epithelium (34). Thus, the definitive cellular and regional
localization of the GLP-2R within the GI tract remains to be
established. However, if indeed the GLP-2R is localized to
enteroendocrine cells, this implies that there is a secondary
signal or signals that mediate the biological action on sur-
rounding epithelial cells via a paracrine mechanism). An
additional interpretation of these recent reports is that GLP-2
clearly acts by an endocrine mechanism because it is secreted
711
from cells that are predominantly localized in the distal regions
of the GI tract, yet its effects occur throughout the GI tract.
Given the limited and, to some extent, conflicting recent
findings concerning the localization of the GLP-2R, it is
perhaps not surprising that our knowledge of its intracellu-
lar signaling mechanisms is also in its infancy. On the basis
of the known sequence information and initial biochemical
characterization, the GLP-2R is a G-protein–linked mem-
brane receptor, which activates a cyclic AMP, protein ki-
nase A (PKA)-dependent pathway when transfected into
baby hamster kidney (BHK) fibroblasts (35). However, the
coupling of GLP-2R activation with downstream cellular
events that mediate increased proliferation and cell survival
has not been established. The studies with transfected BHK
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fibroblasts suggest that GLP-2 actions are not mediated by
PKA, phosphatidylinostiol 3 kinase (PI-3 kinase) or mito-
gen-activated protein (MAP) kinase pathways. However,
the GLP-2– dependent stimulation of thymidine uptake in
Caco-2 cells was suppressed in a dose-dependent manner by
inhibitors of both the PI 3-kinase and MAP-kinase path-
ways (33). Thus, it is uncertain whether these signaling
pathways that are apparently activated by GLP-2 in Caco-2
cells, but not in transfected BHK fibroblasts, are indeed
present in normal intestinal epithelial cells. This again
raises the critical question of the existence of a secondary
signal that may act via a heterologous, paracrine cellular
mechanism between enteroendocrine and other intestinal
epithelial cells.
An aspect of GLP-2 function in which we have been
especially interested is the ontogeny of GLP-2R expression
and the onset of GLP-2 responsiveness during early mam-
malian development. A recent report in rodents (8) and our
studies in pigs (unpublished results) indicate that the
GLP-2R is expressed during fetal and neonatal develop-
ment. These findings are consistent with evidence of tro-
phic and functional effects of GLP-2 in suckling rat pups
and in TPN-fed piglets delivered preterm and at term.
Interestingly, however, in fetuses given GLP-2 infusions in
utero for 6 d, there was no stimulation of intestinal growth
or enhanced development of digestive hydrolase expression,
despite the presence of the GLP-2R transcript in the GI
tract (18). In our neonatal piglets studies (31), we found
that although GLP-2 potently blocked the mucosal villous
atrophy normally induced by TPN, this was mediated by
suppression of apoptosis and proteolysis. In contrast, the
intestinal trophic effect of enteral nutrition was mediated
by a suppression of apoptosis and a stimulation of cell
proliferation and protein synthesis. Thus, although it is
clear that restoring the circulating GLP-2 concentration to
supraphysiologic levels can maintain near-normal intestinal
growth in the absence of any enteral nutrient stimulus, the
trophic effect was mechanistically different than that of
enteral nutrition. This finding raises a critical, yet unre-
solved, question regarding the physiologic importance of
GLP-2, given that most of the studies reported have admin-
istered supraphysiologic doses of GLP-2. The development
of experimental approaches to block endogenous GLP-2
action via immunoneutralization, peptide antagonist and
targeted disruption of the GLP-2R gene should provide
answers to this question. However, it appears that during
fetal life, GLP-2 is not essential for intestinal development,
based on recent evidence from newborn Pax6 mutant mice
with deficient intestinal endocrine cell development and
proglucagon expression (10).
Therapeutic Potential. Since the original report of the
712 BURRIN ET AL.
intestinotrophic actions of GLP-2 by Drucker and col-
leagues (2), a number of studies have demonstrated the
therapeutic efficacy of GLP-2 and the protease-resistant
h[Gly2]-GLP-2 analog in several models of intestinal dys-
function, injury and insufficiency, including TPN (31,36),
massive small bowel resection (37), colitis and nonsteroidal
anti-inflammatory drug–induced enteritis (4), inflammatory
bowel syndrome (29), ischemic bowel (38) and chemother-
apeutic injury (39). The suppression of intestinal cytokine
expression (3,29) and proteolytic activity (31) may be key
cellular mechanisms whereby GLP-2 ameliorates gut injury
and inflammation. The fact that GLP-2 effectively stimu-
lates intestinal growth, while slowing proximal bowel mo-
tility and secretion, makes it a promising therapeutic option
for patients with short-bowel syndrome. In fact, the pro-
tease-resistant GLP-2 analog, h[Gly2]-GLP-2, also referred
to as ALX-0600, was recently granted orphan drug status by
the Food and Drug Administration and is in Phase II
clinical trial for treatment of short-bowel syndrome in
adults. Moreover, in a recent study in short-bowel patients,
GLP-2 treatment increased nutrient absorption and weight
gain (40). Thus, provided that GLP-2 treatment is safe,
other clinical applications may be anticipated, including
the treatment of infants with compromised intestinal
function.
ACKNOWLEDGMENTS
The authors would like to thank Jane Schoppe for assistance in
preparation of the manuscript and Leslie Loddeke for editorial assis-
tance.
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