Published January 20, 2015
NONRUMINANT NUTRITION SYMPOSIUM: The role of glucagonlike peptide-2 in controlling intestinal function in human
infants: Regulator or bystander?1,2,3
D. L. Sigalet4
Alberta Children’s Hospital, University of Calgary, Calgary, Alberta, Canada T3B 6A8
ABSTRACT: The regulation of nutrient absorptive
capacity is a critical factor in the normal growth and
development of infants of all species. In human infants
this is a common problem after surgical resection; the
process of adaptation or upregulation of nutrient transport capacity is the physiologic process, which allows
patients to transition to enteral feeding. The specific
mechanisms that control this are still relatively poorly
understood but are likely relevant for most mammals
with an ontogeny of intestinal function related to the
weaning process. Many actions of the entero-endocrine
hormone glucagon-like peptide (GLP)-2 indicate that
it may be a key factor in regulating physiologic intestinal development, nutrient absorptive capacity, and the
process of adaptative upregulation of nutrient absorption after resection. This article will review the biology
of GLP-2, which is preserved across a broad range of
species. This will include the production of GLP-2 in
the L cell, the regulation of GLP-2 release, and the
mechanism of action. The GLP-2 receptor is specifically located on enteric neurons and pericryptal myofibroblast; thus, effects on the intestinal mucosa involve
a second messenger. We will review the functioning of
this system in the developing human infant and the
role of GLP-2 in the regulation of adaptation, with the
general implications for nutrient absorption in animals
and humans.
Key words: adaptation, enteric neuron, insulin-like growth factor-1, L cell, myofibroblast, ontogeny
©2012 American Society of Animal Science. All rights reserved.
J. Anim. Sci. 2012. 90:1224–1232
http://dx.doi.org/10.2527/jas.2011-4704
INTRODUCTION
The regulation of the ontogeny of nutrient absorption
is a critical aspect of the developmental physiology of
the intestine across mammalian species. In this article,
we will review the regulation of nutrient absorption in
1
Based on a presentation at the Nonruminant Nutrition Symposium titled “Nutrient and neuroendocrine regulation of gastrointestinal function” at the Joint Annual Meeting, July 10 to 14, 2011,
New Orleans, Louisiana. The symposium was sponsored, in part, by
Pancosma SA (Geneva, Switzerland) and EAAP (European Federation of Animal Science, Rome, Italy) with publication sponsored by
the American Society of Animal Science and the Journal of Animal
Science.
2
Funding for these studies came primarily from the Professorship in Pediatric Surgical Research funded by the Alberta Children’s
Hospital Research Foundation, held by D. L. Sigalet. Infrastructure
support for the Sigalet laboratory has been provided by an operating
grant from the Crohn’s and Colitis Foundation of Canada (CCFC).
3
D. L. Sigalet has acted as a paid consultant regarding the development of a glucagon-like peptide 2 ligand for Nycomed Corporation, Konstanz, Germany.
4
Corresponding author: [email protected]
Received September 14, 2011.
Accepted November 10, 2011.
human infants, with a focus on the role of glucagonlike peptide (GLP)-2 in this process. Although some
aspects of the developmental physiology of the intestine reviewed are specific to the human, the majority
of these processes are generalizable across species, and
so likely are relevant in understanding the regulation
of similar physiological processes in domestic animals.
The key points of regulation of nutrient absorption
in human infants have been studied extensively because
of the relative frequency of nutritional problems in this
population; these are typically caused by either congenital atresia or perinatal infections that mandate urgent, often extensive resections of the intestine (Sigalet,
2001; Spencer et al., 2005; Goulet and Ruemmele, 2006;
Sigalet et al., 2011). Thus, it is a relatively common
clinical challenge to have an infant who is quite premature (at 27 to 28 wk of gestational age, normal gestation
being 40 wk) and who develops necrotizing infection
of the small intestinal wall, requiring extensive resection. Thereafter, the care of these infants is a challenge.
Although the general growth of these patients can be
maintained using intravenous feedings [so-called parenteral nutrient (PN)], the remnant intestine, which is
often much shorter in length than the typical normal
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Glucagon-like peptide-2 in intestinal function
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Figure 1. Schematic of intestinal adaptation. The process of adaptation or upregulation of intestinal nutrient transport capacity is a gradual
process occurring over 1 to 2 yr in the human. Color version available in the online PDF.
physiological situation, can be seen to upregulate nutrient absorptive capacity. We will review this process,
known as adaptation (Figure 1). We will then review
the biology of GLP-2 and its effects on the intestinal
mucosa. These 2 processes will then be integrated, combining our understanding of the mechanism of action of
GLP-2 and the effects that have been shown to occur
in human infants. The basic mechanistic studies have
been derived primarily from animal and in vitro studies; however, the effects in the human infant are now
understood to an extent sufficient to discern the role of
GLP-2 as an important regulator of adaptation in the
developing human.
In clinical practice, the transition of the premature
infant from supportive intravenous nutrition (i.e., PN)
to the much more natural enteral nutrition is often the
primary treatment problem and typically keeps infants
in hospital, in an intensive care setting, for months
(Goulet et al., 1991; Andorsky et al., 2001). During
this time, the feeding regimen consists of a series of
small advancements of the volume of enteral feeds, with
appropriate adjustments of the volume of PN, so that
growth is maintained, without inducing complications.
During this period, the immature intestinal mucosa is
prone to the development of invasive, necrotizing infections of the mucosa, often from common intestinal flora
(Neu and Walker, 2011). These infections are known
as necrotizing enterocolitis, and if advanced, will require resection of the involved segment. Other causes of
major loss of intestinal length are congenital intestinal
atresias, typically caused by an embolic event in the
microvasculature, and gastroschisis (Goulet and Ruemmele, 2006; Sigalet et al., 2011). The latter is a relatively common problem involving a localized defect of the
abdominal wall adjacent to the umbilicus such that the
small bowel and a portion of the colon herniated into
the amniotic fluid. This abnormal intrauterine milieu
may damage the herniated segment, or it may undergo
volvulus. The net result of these varied etiologies is a
profound reduction in the intestinal surface area available for nutrient absorption. Over time, the intestine
responds or adapts, dramatically increasing function as
measured per unit length of bowel. This increase in
absorptive capacity is due to a nonspecific increase in
the surface area of the overall intestinal mucosa that is
available for nutrient absorption. In turn, this intestinal
adaptation is due to an increase in the rate of crypt cell
proliferation, so that more cells are produced, which
migrate up from the crypts to increase the length and,
often, the width of the villus (Williamson, 1978a,b;
Vanderhoof, 1996; Sigalet et al., 2009; Figure 2). A further potential mechanism is a reduction in the rate of
apoptosis as the absorptive cells migrate through the
crypts (O’Brien et al., 2001; Martin et al., 2004; Sheng
et al., 2007). As an example of the compensation in
function that occurs with adaptation, in rats undergoing a resection of 90% of the length of small bowel
(i.e., leaving only 10 cm of distal ileum), the remnant
intestine adapts so that within 1 wk, resected animals,
pair-fed with normal controls, will gain BW at an identical rate. This demonstrates that the severely reduced
surface area, and thus function, after resection has been
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Figure 2. Mechanism of intestinal adaptation. Adaptation is a result of an increase in intestinal mucosal surface area, primarily driven by
an increase in the rate of crypt cell proliferation. In some situations, there may be a reduction in apoptosis as cells ascend the crypt-villus axis.
Color version available in the online PDF.
completely compensated for by the adaptive increase in
mucosal surface area (Martin et al., 2005).
Importantly, the increase in nutrient absorptive capacity is not due to an increase in nutrient transporter
numbers or density. It is also of importance that this
adaptive process occurs only in response to feeding
(Vanderhoof, 1995; O’Brien et al., 2001; Martin et al.,
2004; Sheng et al., 2007; Sigalet et al., 2011). In the
context of care of clinical patients, this process can be
quite slow and may not be complete until 12 or even
24 mo postresection (Goulet et al., 1991; Wales et al.,
2005; Diamond et al., 2007).
What then is the mechanism that regulates this
adaptive process? There must be a sensor, to detect the
lack of nutrient absorption, and an effector system, to
drive the increase in crypt cell proliferation process. As
we will discuss, it is clear that an important component
of this regulatory system is GLP-2 (Figure 3).
To summarize this process, GLP-2 is produced by
the intestinal L cells, which are increasingly prevalent
in the distal small intestine (i.e., terminal ileum) and
colon. The L cells are stimulated by undigested nutrients, especially long-chain FFA, to release GLP-2.
Glucagon-like peptide-2 acts in both an endocrine and
likely a paracrine fashion at a single specific receptor
localized on enteroendocrine cells, enteric neurons, and
pericryptal myofibroblasts. The early effect of GLP-
2 stimulation of its receptor is to decrease proximal
intestinal motility and, over time, increase crypt cell
proliferation rate; thus, GLP-2 stimulates the essential
components of the adaptive process outlined previously.
In this context, GLP-2 is an enteroendocrine hormone.
However, it has an unusual biology; it is produced from
the proglucagon gene, which undergoes tissue-specific
posttranslational processing. In the pancreas, the transcripts are processed to form glucagon and the major
pancreatic glucagon factor. In the intestinal L cells,
these are processed to form GLP-1, GLP-2, glicentin,
and oxytinomodulin (Orskov et al., 1986; Martin et al.,
2006).
Glucagon-like peptide-1 and GLP-2 are stored as
vesicles within the L cell and are released in response
to signals from the gut. These signals may be either
neuronal or luminal; neuronal signals may explain the
early increase in GLP-1 and GLP-2 concentrations after ingestion of enteral nutrients. However, the most
profound increases in concentrations are associated
with direct stimulation of the L cell by luminal nutrients (Xiao et al., 1999; Brubaker and Anini, 2003).
The L cells are a type of enteroendocrine cell found
throughout the small intestine and colon, with increasing numbers in the most distal colon. They are derived
from the crypt progenitor cells as 1 of the 4 epithelial
cell lineages, but they can be thought as a subtype of
Glucagon-like peptide-2 in intestinal function
1227
from the sequencing of the proglucagon gene done years
previously, but the function was not known (Orskov et
al., 1986). In the context of the present discussion for
a diverse range of scientists working with multiple species, it is relevant to note that the GLP-1 and GLP-2
sequences are highly conserved across vertebrates, and
are expressed in all mammals.
After this initial discovery, the group from the University of Toronto performed a series of studies examining the biology of GLP-2, including interactions with
other trophic hormones, the segments of intestine which
were responsive, and the metabolism of the hormones
(Drucker et al., 1997; DaCambra et al., 2000; Tavares et al., 2000). Interestingly, both GLP-1 and GLP-2
have very short half-lives. At the n-terminus, the first
and second AA are cleaved from the main protein by
the actions of dipeptidyl peptase. This enzyme is found
ubiquitously in the endothelium of blood vessels, the
kidney, and several other tissues. The breakdown of
GLP-1 is extremely rapid with a half-life of less than
2 min, whereas GLP-2 has a slightly longer half-life; in
humans, it is approximately 7 min (Hartmann et al.,
2000; Amin et al., 2008).
Figure 3. Glucagon-like peptide (GLP)-2 axis. Glucagon-like peptide-2 is released by the L cell of the distal ileum and colon and acts
acutely to slow proximal motility and chronically increases mucosal
surface area, increasing nutrient transport capacity. Color version
available in the online PDF.
taste cell. They have a unique morphology with the
main cell body located on the mucosal basal membrane
but with an apical extension, which extends to the lumen where the cell can act to “taste” enteral contents
(Figure 4). The L cell responds to a variety of nutrients,
but the most potent stimulus is likely long-chain FFA,
18 carbons and longer (Brubaker and Anini, 2003).
As an aside, it is interesting to note that GLP-1,
the other major protein released by the system, acts to
increase the action and release of insulin. Thus, both
GLP-1 and GLP-2 act to help the organism respond
to nutrient availability; GLP-1 aids in the short-term
anabolic response by increasing the release of insulin,
and possibly increasing insulin sensitivity. Conversely,
GLP-2 acts over the medium term to slow proximal
motility and reduce the rate of gastric emptying (Meier
et al., 2006). Over the long term, GLP-2 drives crypt
cell proliferation and an increase in nutrient absorptive
capacity and, thus, improves the efficiency in nutrient
absorptive handling. The fundamental observations
regarding this were made by Drucker and coworkers
(Drucker et al., 1997; Drucker, 2005; Dubé et al., 2006).
They were investigating tumor cell lines which had been
noted to produce peptides that were of the glucagon
family. One such tumor produced a peptide that had
profound trophic effects on the gastrointestinal tract
in a mouse model; when characterized, the peptide was
GLP-2. This solved the puzzle of the physiological actions of GLP-2; the peptide product had been predicted
MECHANISM OF ACTION
With the initial description of the effects of GLP-2,
it was assumed that the receptor was located on the
intestinal mucosa. An extensive series of investigations
showed that this was not so and the receptor was very
discretely localized within a subset of enteroendocrine
cells, enteric neurons, and the myofibroblast. It was
also shown by Bjerknes and Chang (2001) that the trophic actions of GLP-2, in some model systems, required
the activation of enteric neurons. However, the full relationship of GLP-2 activation of the enteric neurons as
a potentially obligatory step in the pathway to mucosal
proliferation is still uncertain. In our own work, we have
shown that in the context of the anti-inflammatory actions, GLP-2 stimulates vasoactive intestinal peptide
(VIP) expressing neurons within the intestinal submucosa (Sigalet et al., 2007). Blockade of VIP activation
also blocks the anti-inflammatory effects of GLP-2, but
it is not clear whether this will also affect the trophic
actions in vivo. Further work is needed to characterize
these pathways more fully.
Interestingly, work done by Dubé et al. (2006) has
shown that IGF-1 expression is required for GLP-2 to
have its major trophic effects on the small intestine. In
those studies using an IGF-1−/− mouse, the stimulatory
effects of GLP-2 were abrogated (Dubé et al., 2006). In
further work, they have also shown that the IGF-1 response appears to be mediated by GLP-2 stimulation of
the peri-cryptal myofibroblast (Leen et al., 2011). The
myofibroblasts are a localized cell group, physically cradling the crypt zone, and so are uniquely positioned to
provide significant regulatory input into both the proliferation and differentiation of the crypt cells as they
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Sigalet
Figure 4. Release of glucagon-like peptide (GLP)-2 by L cells. The L cell projects to the intestinal lumen, and “tastes” luminal contents.
Undigested nutrients, especially (esp) fat, stimulate release of L cell contents, typically GLP-1 and GLP-2, which likely function both in a local
paracrine and a classical endocrine fashion. PYY = peptide YY. Color version available in the online PDF.
migrate up the crypt-villus axis to become the nutrient
absorptive cells of the villus.
From this background it would seem logical to propose that GLP-2 is a major regulatory factor in controlling the adaptive response of the intestine as it responds
to a loss of proximal effective mucosa. This was a major
focus of our own work; to establish the relationship
between GLP-2 and the adaptive process, we first examined the response of the GLP-2 response in animals
undergoing natural adaptation after a resection (Martin et al., 2005). In these studies, by regulating nutrient
input so that the nutrient load was constant after resection, the postprandial GLP-2 response could be profiled
and compared with control animals undergoing a sham
resection. In animals studied at 3 d after 90% resection
of the total small intestinal length, a phase when the resected animals were clearly malabsorbing nutrients, the
GLP-2 production was significantly and persistently
increased in resected animals (Figure 5). In this figure,
we can see that the GLP-2 concentrations are increased
at baseline, before stimulation from the acute nutrient loading. This increased baseline concentration was
likely due to overnight feeding, with ongoing stimulation of GLP-2 release from nocturnal nutrients in the
distal intestine. After enteral nutrient stimulation, us-
ing a constant load of mixed nutrients (10 kcal/kg), the
GLP-2 concentrations were stimulated and remained
so for a prolonged period postprandially. If the areas
under the curve of the resected and controlled animals
are compared, there was a 210-fold increase in exposure
to GLP-2 in the resected animals. This increased GLP2 response is maintained even to 30 d postresection,
when the nutrient absorptive capacity of the intestine
has normalized; the peak postprandial concentrations
of GLP-2 were double that of normal animals (Martin
et al., 2005).
In subsequent studies, a similar 90%-small-intestinalresection model was used, but the animals were maintained with complete PN (Martin et al., 2004). In this
way, the major natural stimulus for adaptation was
eliminated. The adaptative response of the small intestinal mucosa was compared between enterally fed
animals and animals supported with an iso-nitrogenous
iso-caloric formulation of PN, with and without GLP2 at 10 µg∙kg−1∙h−1. There was a consistent increase
in the crypt cell proliferation in the GLP-2 plus PN
animals; morphologically, the mucosa had an overall
increase in villus height and crypt depth that was almost equivalent to that achieved by the group supported with enteral nutrition after resection. It is in-
Glucagon-like peptide-2 in intestinal function
1229
Figure 5. Glucagon-like peptide (GLP)-2 response after resection. Peak GLP-2 concentrations after a constant meal stimulation in resected
(i.e., 90% resection of small intestinal length) and control (transaction and reanastomosis) animals, studied at 3 d postoperation. Glucagon-like
peptide-2 concentrations are serum concentrations of active GLP-2 (1–33) analyzed by RIA. Note that the basal concentrations are greater in
resected animals and increase significantly after enteral stimulation. Studies done using 90% resection of proximal bowel in juvenile rats. Gavaged
with standard meal. Note the greatly increased postprandial “exposure”: 210 × area under curve. Adapted from Martin et al. (2005). Color version available in the online PDF.
teresting to note that the animals that received GLP-2
also had a very significant increase in the length of
the remnant bowel, and this was significantly greater
than the animals that were fed enterally. Overall, the
combined effect of the increase in length, diameter, and
height of villi increased the mucosal area for absorption
significantly in the GLP-2-treated animals. From these
data and work by others, we feel that GLP-2 is likely
an important regulator of adaptation after resection;
however, it must be noted that the adaptive response
seen with exogenous GLP-2 did not completely recapitulate the spontaneous adaptation stimulated with
enteral feeds. There is likely a role for additive effects
of factors, such as local IGF-1, epidermal growth factor,
and keratinocyte growth factor, among others (O’Brien
et al., 2001; Martin et al., 2006).
RELEVANCE IN WEANING
IN HIGHER MAMMALS
Despite this evidence of the activity of the GLP-2
axis in animal models (primarily rodents), the relevance to physiological and pathophysiological processes
in higher mammals is not clear. It is likely that these
systems exist and function similarly across species; it
appears that the actions of GLP-2 are similar in ruminants and nonruminants (Petersen et al., 2001; Burrin
et al., 2007; Taylor-Edwards et al., 2011). The actions
in human infants should, therefore, be predictive of
the effects in the equivalent development stage of other higher-order mammals (Sangild, 2006). A focus of
our own research has been to determine the actions of
GLP-2 in the developing human infant; to do this, we
examined the GLP-2 response after enteral feeding in
premature infants in neonatal intensive care (Amin et
al., 2008). The typical course of the premature infant is
a gradual increase in enteral feeds over weeks, guided
primarily by clinical response as the infants mature
from their preterm to a more normal newborn status.
In this study, as feeds of infants were progressed, their
postprandial concentrations of GLP-2 were systematically determined. In these studies, we found that the
initial feedings resulted in a very high level of GLP-2
production (Amin et al., 2008). Interestingly, the concentrations of baseline GLP-2 were also increased, and
the more premature the infant, the more exaggerated
the GLP-2 response. This indicates that the production of GLP-2 at baseline in these infants was greater
than seen in normal newborns and indicates that GLP2 may be important on the ontogeny of the gut. This
recapitulates findings seen in the developing rat model
(Lovshin et al., 2000). In the juvenile rat, the greatest
expression of GLP-2 and the GLP-2 receptor was in the
late weaning phase. In human infants, it appears that
the greatest potential GLP-2 production occurs in the
last weeks of in utero development, so that if the child
is born prematurely, increased concentrations of GLP-2
are produced. In utero, the concentrations appear to
be relatively low (Bodé et al., 2007). However, because
it is impossible to sample human infants in utero, the
true concentrations of the normal developing infant in
utero are not known. In the developing pig in utero, it
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Sigalet
Figure 6. Glucagon-like peptide (GLP)-2 concentrations in human infants after resection. Peak GLP-2 concentrations after meal stimulation
(>10 kcal/kg) in infants with intestinal resections. The upper curve shows the response of infants who were able to be weaned from parenteral
nutritional (PN) support; peak concentrations were typically 140 pmol/L in the period preceding discontinuation of PN. The lower curve shows
the response of infants who had continued requirement for PN: peak concentrations were typically 40 pmol/L. Glucagon-like peptide-2 (1–33) was
measured by RIA. Note the prolonged time course, to 700 d. Color version available in the online PDF.
appears that GLP-2 concentrations are truly reduced
and then are quickly upregulated at birth, whereas the
tissue expression of the receptor decreases after birth
(Petersen et al., 2003). Thus, the patterns of expression in the pig were similar to those seen in the studies with human, and both were different from the pattern described in rodents (Burrin et al., 2005; Sangild,
2006). Further work is warranted to understand how
the expression of GLP-2 may control normal intestinal
growth in utero, and the subsequent postnatal maturation in higher mammals.
In further studies, we examined the GLP-2 response
in infants who had undergone a major resection of the
intestine. In an initial pilot study, infants that had anatomic short bowel (i.e., less than 25% of intestinal
length predicted for gestational age) tended to have
low or very low concentrations of GLP-2, especially if
the ileum was resected (Sigalet et al., 2004). If patients
were unable to produce a postprandial concentration
of GLP-2 greater than 15 pmol/L (normal = 65 to 80
pmol/L), then none of these patients were able to induce intestinal adaptation, and all died from complications of the prolonged PN (Sigalet et al., 2004). In
more recent studies, we have corroborated these results
and shown that in 33 infants who underwent intestinal
resection, the infants who underwent adaptation in 6
mo or less after intestinal resection, a typical response
was a time of increased postprandial GLP-2 production
(average 116 ± 38 pmol/L of GLP-2 production vs. 60
± 18 pmol/L in normal patients, n = 32). In the subset
of infants that were not able to come off PN, the peak
levels never went above 40 pmol/L (Sigalet et al., 2008,
2011; Figure 6).
The results described above strengthen our hypothesis (Stanger et al., 2011) that GLP-2 is an important
overall regulator of nutrient absorptive capacity in human infants. If an infant is unlucky enough to require a
resection of such magnitude that they cannot produce
a postprandial GLP-2 concentration greater than 40
pmol/L, they are likely to be unable to be weaned from
intravenous nutritional support. These findings also indicate that the use of exogenous GLP-2 as a therapy to
promote intestinal adaptation may be effective in this
difficult-to-treat group of patients. There are differences between the human condition and animal models of
short bowel syndrome; the degree of pathology is typically much greater in the human condition, and so the
remnant intestine may not be able to respond to signals
to which the more narrowly defined models retain sensitivity (Sigalet, 2001; Sigalet et al., 2008). However, the
main issue here appears to be one of timing; it seems
that even with significant injury, the intestine will recover sensitivity to all endogenous regulatory pathways
(Sigalet et al., 2009, 2011). It appears that in the pure
resection model, the optimal timing for the use of exogenous GLP-2 is immediately after surgery; this may not
be so for disease states where a phase of recovery from
a more wide-spread mucosal injury is necessary (Kaji
Glucagon-like peptide-2 in intestinal function
et al., 2009). This would also be relevant for the use of
GLP-2 ligands in the treatment of animal diseases such
as scours.
In summary, the rhetorical question of whether GLP2 is a regulator or bystander clearly appears to be answered, with the answer being that GLP-2 is an important player in the control of nutrient absorption in the
human infant. Glucagon-like peptide-2 also likely has a
very active role in the normal physiologic development
of the gut in many species; in infants, the increased
concentrations of the GLP-2 seen in “normal” premature infants indicate that GLP-2 has a stimulatory role
in normal gut development in humans. Superimposed
on this background, it appears that GLP-2 is critically
important in regulating the adaptive response to the
intestine to the pathologic stimulus of resection or major loss. In the human infant, a postprandial GLP-2
concentration of 40 pmol/L appears to be discriminatory; infants that are not able to produce this amount
will likely require very long-term parenteral nutrition.
Further studies in other animal species are required.
Given the paradigm outlined here, it is plausible that
the production of, or response to GLP-2 may be an important regulatory factor in intestinal homeostasis, especially the rate of crypt proliferation, and potentially
the expression of transporter proteins. These factors
are vitally important in the efficiency of nutrient absorption and BW gain, which in turn relate to the economics of production livestock; however, the effects of
variations in the GLP-2 axis on the scope of intestinal
efficiency is simply not known at this time. A further
associated factor is the relationship of GLP-2 stimulation with inflammation; in models of mucosal damage
GLP-2 significantly reduces inflammation, and in so
doing, improves healing. It is important to note that
this is not due to a simple trophic effect; when GLP-2
is given to animals with inflamed intestinal mucosa, the
effect is reduced inflammation in the tissue, coupled
with a reduction in crypt cell proliferation rates. This
is because the endogenous response to mucosal injury
drives a hyper-proliferative response; GLP-2, by reducing the inflammation, diminishes the proliferation (Sigalet et al., 2007). This system may be relevant in the
animal world as part of the response to intestinal inflammation that may occur from acute infections, such
as scours, which are similar to the necrotizing intestinal
infections seen in the human infant.
SUMMARY AND CONCLUSIONS
There are several gaps in our knowledge regarding
this interesting system, both in terms of the stimulus
for GLP-2 release and the intestinal response to GLP-2.
As examples, the relationship of the L cell to the GLP2 response and its development over time is not well understood. Similarly, the relationship between GLP-2 activation of the enteric neurons and subsequent signaling
of the crypt and whether these are done by neurons and
the pericrypt myofibroblast or whether these systems
1231
work in tandem is unknown. These are relevant because
this system appears to be very active in regulating the
proliferative and potentially the differentiation of the
small intestinal mucosa. Answers to these seemingly
fundamental aspects of absorptive physiology will be
relevant for clinicians caring for patients, and a wide
variety of mammalian systems. These will certainly apply to livestock in such matters as the efficiency of conversion of nutrients to BW. Scholars interested in this
field should keep a watchful eye on studies from the
animal production, basic science, and clinical literature.
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