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Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada M5S 1A8
Address all correspondence and requests for reprints to: Dr. P. L. Brubaker, Room 3366, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada M5S 1A8. E-mail: p.brubaker{at}utoronto.ca
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Introduction |
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The release of GLP-1 and the other PGDPs from ileal L cells is under complex regulation. Agents that can directly stimulate the secretion of GLP-1 have been analyzed in various models of the intestinal L cell, including a primary cell culture of fetal rat intestinal cells (8, 9), a murine intestinal endocrine cell line (10), and a perfused model of the rat ileum (11, 12). The major secretagogues identified using these models include glucose-dependent insulinotropic peptide (GIP), gastrin-releasing peptide (GRP), calcitonin gene-related peptide, and agonists of acetylcholine. Fatty acids, when applied directly to fetal rat intestinal cell cultures, also stimulate GLP-1 secretion (9).
In the in vivo setting, GLP-1 is rapidly released from ileal L cells upon the ingestion of a mixed meal (13, 14) or by the infusion of fat directly into the duodenum (15, 16). Indeed, plasma levels of GLP-1 peak within 5–15 min of nutrient administration despite the fact that nutrients do not reach the ileum within this time frame (17). Furthermore, in patients with ileostomies to divert nutrient flow from the ileum, GLP-1 levels after ingestion of a mixed meal are similar to those observed in individuals with an intact gastrointestinal tract (13). These observations are not consistent with the idea that nutrients act directly on ileal L cells to stimulate the release of GLP-1, at least during the early phase of secretion. Therefore, it has been postulated that the secretion of GLP-1 is under the regulation of a proximal-distal loop, relaying information about nutrient and, in particular, fat ingestion from the proximal duodenum to the distal site of GLP-1-containing L cells (15, 16). Consistent with this concept, we have demonstrated that the duodenal peptide GIP, which is secreted in response to fat ingestion (14, 16), is an endocrine mediator of this proximal-distal loop in rats (16). However, recent data have demonstrated that the secretion of GLP-1 induced by duodenal fat can be completely inhibited by infusion of an antagonist for the neuropeptide GRP (18). These findings suggest that physiological doses of GIP act through the nervous system (either vagal or myenteric) to indirectly stimulate GLP-1 secretion, rather than acting directly at the level of the L cell.
The present investigation further examined the possible existence of a neural component of the proximal-distal loop regulating secretion of GLP-1 in the rat. Specifically, the intrinsic and extrinsic nervous systems were analyzed with respect to their ability to affect duodenal fat-induced GLP-1 secretion. In addition, the humoral mechanism by which nutrients in the proximal duodenum signal the distal L cell was reevaluated by examining the potential interaction of GIP with the vagus nerve.
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Materials and Methods |
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Model of the proximal distal loop
To separate indirect from direct effects of nutrients on the
ileal L cell, the proximal-distal loop governing GLP-1
secretion was modeled by infusing nutrients into a 10-cm segment of
proximal duodenum (15, 16, 18). The duodenum was cannulated above the
common bile duct and isolated from the remaining gut by loose ligation
10 cm distal to the site of the duodenal catheter. This ligation
ensures that nutrients do not progress to the distal portions of the
small intestine to directly stimulate GLP-1 secretion from
the ileal L cells, but permits retention of all neurovascular
connections. Blood was collected at -10 and 0 min to ascertain basal
levels of secretion, and manipulation of the gastrointestinal tract was
performed in the interval between these two time points. At 0 min, 3–4
ml fat in the form of corn oil (56% polyunsaturated fatty acids, 32%
monounsaturated fatty acids, and 12% saturated fatty acids; Sunfresh
Ltd., Toronto, Canada) were infused into the proximal duodenal segment,
and blood samples were collected every 5–10 minutes thereafter up to
60 min.
Vagotomy
To ascertain the role of vagal innervation in the regulation of
GLP-1 secretion, a series of vagotomies was performed
before the start of experimental sampling in the interval between the
first and second basal blood samplings. The procedures included 1) left
cervical vagotomy, 2) bilateral subdiaphragmatic vagotomy, and 3)
selective hepatic branch vagotomy. The bilateral subdiaphragmatic
vagotomy was performed by transection of the esophagus, including the
accompanying vagal trunks.
Vagal stimulation
The vagal stimulation protocol was based on parameters used in a
similar study of vagally induced bombesin-like immunoreactivity release
(19). Briefly, the celiac branch of the subdiaphragmatic vagus nerve
was transected 30 min before the commencement of the experimental
procedure. During this interval the distal portion of the celiac branch
was placed over a bipolar stimulating electrode connected to a Grass
stimulator (Grass Instruments, Quincey, MA). This preparation was then
immersed in paraffin oil throughout the experiment. The electrical
stimulation was begun at 0 min and lasted for 15 min at a voltage of 10
V and a frequency of 20 Hz [preliminary studies with lower frequencies
did not significantly affect gut glucagon-like immunoreactivity (gGLI)
secretion]. Blood was collected at 5, 10, and 15 min during the
stimulation period and then every 10 min throughout the remainder of
the experimental time course.
GIP infusions
Human GIP (Bachem California, Inc., Torrance, CA)
was administered as a bolus via the jugular vein followed by a
maintenance infusion through the femoral vein for 40 min and then a
20-min recovery period. Blood samples were collected every 10 min. GIP
was infused at either a high (supraphysiological; 715 ng/kg bolus plus
1070 ng/kg·h infusion) or a low (physiological; 143 ng/kg bolus plus
214 ng/kg·h infusion) dose. The physiological dose of GIP was based
on that used in a previous study, which was found to mimic levels of
GIP produced by the ingestion of a fat meal (16). The
supraphysiological dose of GIP was 5 times greater than the
physiological dose.
Assays
In correlation experiments, RIA for GLI
(glicentin/oxyntomodulin/glucagon) was carried out using 0.1 ml plasma
with antiserum K4023 (Biospacific, Emeryville, CA), whereas RIA for
immunoreactive glucagon (glucagon) used 0.2 ml plasma with antiserum
04A (Dr. R. H. Unger, Dallas, TX). The plasma levels of gGLI were
obtained by subtraction of immunoreactive glucagon from GLI (15, 16, 18). Immunoreactive GLP-1(x-36NH2) was
detected by RIA using an antiserum directed against the
carboxyl-terminus of GLP-17–36NH2
(Affinity Research Products, Nottingham, UK).
Before RIA for GLP-1(x-36NH2), 1 ml plasma was
diluted with 2 ml 1% trifluoroacetic acid (pH 2.5 with diethylamine)
and purified by passage through a C18 Sep-Pak cartridge
(Waters Corp., Milford, MA). Peptides were eluted with 3
ml 80% isopropanol/0.1% trifluoroacetic acid, and the eluate was
dried in vacuo to make a single sample for RIA (20). This
procedure resulted in a recovery rate of 53.9 ± 6% when spiked
plasma samples were analyzed. Immunoreactive GIP levels were determined
using 0.1 ml plasma in a human GIP RIA kit (Peninsula Laboratories, Inc., Belmont, CA).
Data analysis
Peptide secretion is expressed as the change from basal values.
All data are expressed as the mean ± SEM. Statistical
significance between experimental groups was assessed by ANOVA using
n-1 post-hoc custom hypothesis tests with Statistical
Analysis System Software (SAS Institute, Inc., Cary, NC).
Comparisons of plasma levels of hormones between basal levels and
subsequent time points within an experimental group were made using
repeated measures ANOVA. Significance was determined at the
P < 0.05 level in these comparisons. Where single
determinations were made, paired Student’s t test was
performed. Some data were log10 transformed before
analysis.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). gGLI
levels were highly correlated with those of GLP-1 (r
= 0.85; P < 0.05; n = 3). As the gGLI assay
requires only 300 µl plasma, compared with 1 ml for the
GLP-1 RIA, gGLI was used as a measure of
GLP-1 secretion in all subsequent studies.
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and were not affected by left cervical vagotomy.
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). In contrast, infusion of 3–4 ml fat
in the form of corn oil induced a rapid rise in gGLI secretion
(P < 0.05 at 5 min), which was maintained throughout
the remainder of the experimental time course (P <
0.001 vs. saline infusion; n = 5). The role of the
enteric nervous system in mediating this proximal signal to the ileal L
cells was investigated by transection of the gastrointestinal tract at
a site immediately distal to the isolated segment of duodenum before
the infusion of corn oil. This procedure did not reduce the gGLI
secretion induced by duodenal fat, as the infusion of corn oil elicited
a significant rise in gGLI levels compared with that in saline controls
(P < 0.05; n = 6; Fig. 2). The peak change in
gGLI from basal was 132 ± 37 pg/ml (P < 0.05;
n = 6), and this was not significantly different from that
achieved by the infusion of corn oil into the ligated duodenal segment.
However, a significant difference was observed in the timing of the
corn oil-induced response of gGLI secretion in the two protocols, such
that the fat-induced rise in gGLI levels was significantly delayed by
transection of the gut compared with the animals undergoing gut
ligation (P < 0.05 for corn oil/ligation
vs. corn oil/transection at 5 min). Indeed, the peak change
in gGLI secretion occurred at 19 ± 4 min in the transected
enteric nervous system group compared with 6 ± 1 min in the
ligated group (P < 0.05).
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). In
contrast to the response found in rats with an intact vagus, corn oil
infusion into the proximal duodenum of vagotomized rats completely
failed to stimulate gGLI secretion (P < 0.001
vs. intact vagus; n = 5). Changes from basal levels of
plasma glucose and glucagon are shown in Table 2.
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). The celiac
branch of the vagus nerve was transected, and the distal end was
stimulated for a 15-min period. Electrical stimulation using 10 V and a
frequency of 20 Hz resulted in a significant rise in gGLI levels, which
reached a peak of 71 ± 14 pg/ml above basal at the 10 min point
(P < 0.05; n = 5). gGLI levels returned to basal
during the final phase of the stimulation period, but, surprisingly,
increased again to significance during the recovery period. No
significant effect of celiac branch stimulation on plasma glucose and
glucagon levels was detected compared with those in the control group
(Table 1
).
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). Infusion of GIP at a
supraphysiological dose resulted in rapidly elevated GIP levels that
were not significantly different between the control and hepatic branch
vagotomized animals. Peak immunoreactive GIP levels reached 1030
± 121 pg/ml above basal (P < 0.05, n = 7) in the
control group at 13 ± 2 min and returned toward basal during the
subsequent infusion and recovery periods. These elevations in GIP
levels resulted in significant increases in gGLI in control as well as
vagotomized animals. The peak of gGLI above basal induced by the
supraphysiological GIP infusion in the control group was 123 ± 32
pg/ml (P < 0.05; n = 7), and this was not
significantly different from the gGLI response achieved by
supraphysiological GIP infusion in the hepatic branch vagotomized
animals (96 ± 25 pg/ml; P < 0.05; n = 6).
Interestingly, GIP-induced gGLI secretion rapidly returned to baseline
within 20 min of reaching peak levels despite elevated concentrations
of GIP in both control and vagotomized groups.
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). Furthermore, the GIP levels achieved
by the infusion were significantly decreased compared with those after
the supraphysiological dose of GIP (P < 0.001). In
control animals, the physiological dose of GIP led to a small, but
significant, elevation in gGLI secretion, reaching a peak of 40 ±
7 pg/ml above basal levels (P < 0.01; n = 4) and
rapidly returning to basal levels by the 20 min point. In contrast,
hepatic branch vagotomy completely abolished the rise in gGLI secretion
induced by the physiological infusion of GIP (P < 0.05
vs. controls). Changes in plasma glucose and glucagon
produced by the infusions of GIP are demonstrated in Table 3.
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Discussion |
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To investigate the secretion of GLP-1 in vivo, a method to evaluate GLP-1 levels over a prolonged period of time is necessary. The major limitation inherent to the RIA of GLP-1 is the large plasma volume that is necessary to accurately measure GLP-1 levels in rats. The results of the present study demonstrate that changes in the plasma levels of GLP-1 in rats in vivo are highly correlated with those of gGLI, a finding that is not surprising, as glicentin/oxyntomodulin and GLP-1 are cleaved from proglucagon in a one to one relationship (1). Furthermore, plasma levels of GLP-2, which is also cleaved from proglucagon in a one to one relationship with glicentin/oxyntomodulin, has recently been shown to be highly correlated with gGLI levels in the rat (21). Similar findings have been made for gGLI, GLP-1, and GLP-2 using in vitro models of the intestinal L cell (9, 22) (Brubaker, P. L., unpublished data). The results obtained for any one of these peptides may therefore be extrapolated to include all of the other intestinal PGDPs, at least in the rat.
To investigate the hypothesis that a neural component of the proximal-distal loop operates in conjunction with the previously described endocrine-based loop (15, 16), the vagus nerve was examined for global effects on basal GLP-1 secretion. This nerve represents the major parasympathetic innervation of the proximal portion of the gastrointestinal tract and is known to influence the secretion of other gut-derived hormones, including GRP (23) and secretin (24). Left cervical vagotomy significantly depressed the basal secretion of gGLI to approximately 56% of basal levels in control rats. This finding demonstrates a tonic stimulatory role for the left cervical vagus nerve in regulating secretion of GLP-1 from the L cell.
Nutrients such as fat can exert effects on GLP-1 secretion
directly by stimulating the L cells at their luminal surface (9) or can
have indirect effects on the L cell by exerting their influence through
an intermediate messenger such as GIP. This duodenal hormone has
previously been shown to stimulate secretion of GLP-1 in
response to fat ingestion (16). The direct and indirect effects of fat
can be separated in vivo by ensuring that the progress of
nutrients is impeded before they can reach the site of the majority of
the GLP-1-containing L cells within the ileum. This was
accomplished in our model by applying a ligature loosely around the
gastrointestinal wall at a position approximately 10 cm downstream from
the duodenal site of infusion. Saline infusion into the proximal
isolated segment did not induce secretion of GLP-1 from
the L cells, indicating that the effects of fat on GLP-1
secretion are specific to this nutrient and are not due to distension
of the duodenal wall or the mere presence of a fluid in the lumen of
the duodenum. Consistent with the results of previous studies (15, 16),
infusion of fat into the duodenum induced a rapid and prolonged rise in
gGLI secretion despite the fact that this fat did not reach the ileum
at any time during the experimental time course. Furthermore, the
secretion of GLP-1 induced by duodenal fat cannot be
explained by the presence of a few hypersensitive L cells in this
region, because the response to fat is completely abolished when all
sections of the intestine distal to the duodenum are removed (18).
However, the rapid response of the L cell to duodenal fat (
5 min) as
well as the finding that this response is dependent on the neuropeptide
GRP (18) led to the current hypothesis that in addition to GIP, a
component of the nervous system may also be involved in mediating the
proximal nutrient signal to the distal L cell.
To explore the possibility that fibers within the submucosal or myenteric nervous plexus may play a role in the rapid L cell response to fat ingestion, possible contributions of the enteric nervous system were abolished by transection of the gastrointestinal tract before the infusion of corn oil. This procedure did not prevent gGLI secretion compared with the control group, thereby indicating that the enteric nervous system is not responsible for relaying information about nutrient ingestion to the ileal L cells. However, an element contained within the walls of the gastrointestinal tract may be necessary for maintaining the appropriate timing of the response, as transection of the gut wall caused a marked delay in the peak of gGLI secretion. One possible explanation for this finding is that local afferents of vagal fibers may have been transected in this procedure. Local afferents are extensions of vagal afferents that divide from the main afferent nerve and supply a target organ directly without synapsing with higher centers (25). These have been shown to contain calcitonin gene-related peptide, which is a potent stimulator of gGLI secretion in vitro (8). In the present scenario, such afferents could possibly branch from vagal afferents that innervate the duodenal region and travel to the ileum within the walls of the gastrointestinal tract to exert effects on gGLI secretion in a reflex manner. As the main vagal nerves are not affected by the gut wall transection, this might explain why the gGLI response was only delayed rather than being totally abolished in these studies.
Consistent with a major role for the vagus nerve in mediating the proximal-distal loop, bilateral subdiaphragmatic vagotomy performed in addition to gut transection completely abolished the fat-induced rise in gGLI secretion. Two scenarios or a combination of the two may provide the reason why bilateral subdiaphragmatic vagotomy totally attenuated the fat-induced rise in gGLI secretion. The first deals with the possibility that transection of the subdiaphragmatic vagus nerve has rendered higher brain centers insensitive to sensory messages from the duodenum. The vagus nerve is known to contain many afferent fibers arising from the proximal gastrointestinal tract and has been previously shown to mediate both nutrient and hormonal signals from the gut in response to nutrient administration (24, 26, 27). In fact, the vagus nerve has been shown to express receptors that are able to differentiate between distinct classes of ingested lipid (28). This is an important finding, considering that both fat and GLP-1 are potent inhibitors of gastric motility (2, 29). Thus, activation of vagal afferents by ingested lipid may induce the secretion of GLP-1, thereby augmenting the enterogastrone effects of fat. Another possibility that may explain the reduced secretion of gGLI in response to bilateral subdiaphragmatic vagotomy is that the efferent mechanisms that act to stimulate GLP-1 secretion were disrupted by the vagotomy. It has been previously suggested that the parasympathetic nervous system is involved in the modulation of L cell secretion (30), and indeed, the L cell is stimulated by muscarinic agonists in vitro (8, 10). Thus, disruption of afferent and/or efferent vagal fibers in the rat results in a loss of the rapid L cell response to ingested nutrients. Consistent with this finding, it has recently been reported that administration of atropine abolishes the GLP-1 response to an oral glucose tolerance test in humans, although the effects of cholinergic blockade to inhibit gastric emptying were not taken into account in this study (30).
To differentiate between the afferent and efferent signals mediating GLP-1 secretion, the celiac branch of the vagus nerve was directly stimulated, resulting in significant stimulation of gGLI secretion at the 10 min point. The delay observed in the secretion of gGLI induced by electrical stimulation was very similar to that observed in the experiments involving fat-induced secretion in gut-transected animals. These findings lend further support to the idea of a role for the enteric nervous system in mediating a component of the proximal-distal loop, as this pathway was not affected by the electrical stimulation. The delay may also occur due to involvement of a peptidergic mediator in the efferent signaling pathway, as the effects of these neuromodulators are known to be preceded by long latent periods (31). Such a possibility is also supported by recent experiments showing that infusion of an antagonist to the GRP receptor completely abolishes proximal fat-induced gGLI secretion despite the fact that GIP levels remained elevated (18). A role for GRP in the signaling process at a level downstream of GIP was therefore indicated. GRP is localized extensively in the myenteric plexus (32) and potently stimulates the secretion of GLP-1 (8, 11, 12). Therefore, GRP is a likely candidate neuropeptide that may be released upon electrical stimulation of the celiac branch of the vagus nerve. It should be noted that the delayed secretion of gGLI in response to electrical stimulation is not dependent upon release of GIP from the duodenum, as vagal stimulation has previously been shown to have no effect on the GIP-containing K cell (33). The mechanism underlying the rebound secretion of gGLI during the recovery period remains to be elucidated. However, GLP-1 secretion is known to be pulsatile, with a frequency of approximately one pulse every 10–15 min. This pattern of secretion has been proposed to be regulated by the parasympathetic nervous system (30). Thus, it is possible that the initial vagal stimulation stimulating the release of gGLI in the present study coordinated the dispersed L cells in the distal small intestine, leading to an integrated rebound pulse of gGLI secretion during the recovery period.
The finding that a GRP receptor antagonist completely inhibits gGLI secretion in the presence of elevated GIP levels suggested that the neural and humoral arms of the proximal-distal loop may be integrated in the regulation of the L cell. This hypothesis was examined by experiments in which GIP was infused at different doses into animals that possessed intact or disrupted vagal innervation at the level of the hepatic afferent. When infused at supraphysiological doses, GIP stimulated gGLI secretion significantly in both control and vagotomized animals; however, a vagal dependence of GIP became evident when GIP was infused at physiological doses. This finding indicates that in the normal rat, the hepatic branch of the subdiaphragmatic vagus nerve mediates the stimulatory effect of GIP on the L cell. Consistent with this finding, both cholecystokinin (27) and secretin (24) have been reported to act on the exocrine pancreas through vagal afferents when administered at physiological doses, exerting direct effects only when infused at supraphysiological concentrations. Vagal sensory endings in the duodenum do not make contact with epithelial cells, but terminate in close association with the lamina propria (34). Thus, GIP-containing cells may function as taste cells by sampling the duodenal contents and, in turn, activating vagal afferents to stimulate GLP-1 secretion.
In conclusion, the secretion of GLP-1 and gGLI from the
rat ileal L cell is regulated by a complex proximal-distal loop that
involves both endocrine and neural factors (Fig. 7). Fat is sensed in the duodenum by
luminal K cells, which secrete GIP in response to fat and glucose. GIP
exerts its effects on the ileal L cell in two ways depending on the
concentration achieved. Physiological levels of GIP act through vagal
afferent pathways to stimulate the L cell indirectly. This stimulation
is carried to the L cell by efferent pathways located in the celiac
branch of the vagus nerve and is thought to involve GRP. GIP can also
stimulate the L cell directly at higher levels. Finally, a component of
the enteric nervous system also appears to be responsible for the early
stimulation of GLP-1 secretion within this loop. The
secretion of GLP-1 from the distal L cell is, therefore,
intimately connected with the presence of nutrients in the proximal
duodenum through an interaction of neural and endocrine pathways. As
knowledge is gained concerning the functioning of the neuroendocrine
loop, examination of the function of this axis can be made in disease
states, such as type II diabetes mellitus.
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Footnotes |
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Received December 11, 1998.
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D. W. Nelson, X. Liu, J. J. Holst, H. E. Raybould, and D. M. Ney Vagal afferents are essential for maximal resection-induced intestinal adaptive growth in orally fed rats. Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1256 - R1264. [Abstract] [Full Text] [PDF]
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 O. Chaudhri, C. Small, and S. Bloom Gastrointestinal hormones regulating appetite Phil Trans R Soc B, July 29, 2006; 361(1471): 1187 - 1209. [Abstract] [Full Text] [PDF]
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 B. Stoll, P. T. Price, P. J. Reeds, X. Chang, J. F. Henry, J. B. van Goudoever, J. J. Holst, and D. G. Burrin Feeding an Elemental Diet vs a Milk-Based Formula Does Not Decrease Intestinal Mucosal Growth in Infant Pigs JPEN J Parenter Enteral Nutr, January 1, 2006; 30(1): 32 - 39. [Abstract] [Full Text] [PDF]
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 A. Gameiro, F. Reimann, A. M. Habib, D. O'Malley, L. Williams, A. K. Simpson, and F. M. Gribble The neurotransmitters glycine and GABA stimulate glucagon-like peptide-1 release from the GLUTag cell line J. Physiol., December 15, 2005; 569(3): 761 - 772. [Abstract] [Full Text] [PDF]
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 E. M Sinclair and D. J. Drucker Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential Physiology, October 1, 2005; 20(5): 357 - 365. [Abstract] [Full Text] [PDF]
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X. Qin, H. Shen, M. Liu, Q. Yang, S. Zheng, M. Sabo, D. A. D'Alessio, and P. Tso GLP-1 reduces intestinal lymph flow, triglyceride absorption, and apolipoprotein production in rats Am J Physiol Gastrointest Liver Physiol, May 1, 2005; 288(5): G943 - G949. [Abstract] [Full Text] [PDF]
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G. R. Martin, L. E. Wallace, B. Hartmann, J. J. Holst, L. Demchyshyn, K. Toney, and D. L. Sigalet Nutrient-stimulated GLP-2 release and crypt cell proliferation in experimental short bowel syndrome Am J Physiol Gastrointest Liver Physiol, March 1, 2005; 288(3): G431 - G438. [Abstract] [Full Text] [PDF]
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F Reimann, M Maziarz, G Flock, A. M Habib, D. J Drucker, and F. M Gribble Characterization and functional role of voltage gated cation conductances in the glucagon-like peptide-1 secreting GLUTag cell line J. Physiol., February 15, 2005; 563(1): 161 - 175. [Abstract] [Full Text] [PDF]
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J. Overduin, R. S. Frayo, H. J. Grill, J. M. Kaplan, and D. E. Cummings Role of the Duodenum and Macronutrient Type in Ghrelin Regulation Endocrinology, February 1, 2005; 146(2): 845 - 850. [Abstract] [Full Text] [PDF]
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L. Hansen, S. Lampert, H. Mineo, and J. J. Holst Neural regulation of glucagon-like peptide-1 secretion in pigs Am J Physiol Endocrinol Metab, November 1, 2004; 287(5): E939 - E947. [Abstract] [Full Text] [PDF]
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G. R. Martin, L. E. Wallace, and D. L. Sigalet Glucagon-like peptide-2 induces intestinal adaptation in parenterally fed rats with short bowel syndrome Am J Physiol Gastrointest Liver Physiol, June 1, 2004; 286(6): G964 - G972. [Abstract] [Full Text] [PDF]
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A. P. Goldstone, E. L. Thomas, A. E. Brynes, G. Castroman, R. Edwards, M. A. Ghatei, G. Frost, A. J. Holland, A. B. Grossman, M. Korbonits, et al. Elevated Fasting Plasma Ghrelin in Prader-Willi Syndrome Adults Is Not Solely Explained by Their Reduced Visceral Adiposity and Insulin Resistance J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1718 - 1726. [Abstract] [Full Text] [PDF]
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D. L. Williams, H. J. Grill, D. E. Cummings, and J. M. Kaplan Vagotomy Dissociates Short- and Long-Term Controls of Circulating Ghrelin Endocrinology, December 1, 2003; 144(12): 5184 - 5187. [Abstract] [Full Text] [PDF]
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 D. J. Drucker Enhancing Incretin Action for the Treatment of Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2929 - 2940. [Abstract] [Full Text] [PDF]
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N. A. Walsh, B. Yusta, M. P. DaCambra, Y. Anini, D. J. Drucker, and P. L. Brubaker Glucagon-Like Peptide-2 Receptor Activation in the Rat Intestinal Mucosa Endocrinology, October 1, 2003; 144(10): 4385 - 4392. [Abstract] [Full Text] [PDF]
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Y. Anini and P. L. Brubaker Muscarinic Receptors Control Glucagon-Like Peptide 1 Secretion by Human Endocrine L Cells Endocrinology, July 1, 2003; 144(7): 3244 - 3250. [Abstract] [Full Text] [PDF]
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R. H. Lustig, P. S. Hinds, K. Ringwald-Smith, R. K. Christensen, S. C. Kaste, R. E. Schreiber, S. N. Rai, S. Y. Lensing, S. Wu, and X. Xiong Octreotide Therapy of Pediatric Hypothalamic Obesity: A Double-Blind, Placebo-Controlled Trial J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2586 - 2592. [Abstract] [Full Text] [PDF]
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F. M. Gribble, L. Williams, A. K. Simpson, and F. Reimann A Novel Glucose-Sensing Mechanism Contributing to Glucagon-Like Peptide-1 Secretion From the GLUTag Cell Line Diabetes, May 1, 2003; 52(5): 1147 - 1154. [Abstract] [Full Text] [PDF]
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S. Y. Wang, M. M.-Y. Chi, L. Li, K. H. Moley, and B. M. Wice Studies with GIP/Ins cells indicate secretion by gut K cells is KATP channel independent Am J Physiol Endocrinol Metab, May 1, 2003; 284(5): E988 - E1000. [Abstract] [Full Text] [PDF]
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Y. Anini and P. L. Brubaker Role of Leptin in the Regulation of Glucagon-Like Peptide-1 Secretion Diabetes, February 1, 2003; 52(2): 252 - 259. [Abstract] [Full Text] [PDF]
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 Z. Ni, Y. Anini, X. Fang, G. Mills, P. L Brubaker, and T. Jin Transcriptional Activation of the Proglucagon Gene by Lithium and beta -Catenin in Intestinal Endocrine L Cells J. Biol. Chem., January 3, 2003; 278(2): 1380 - 1387. [Abstract] [Full Text] [PDF]
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Y. Anini, T. Hansotia, and P. L. Brubaker Muscarinic Receptors Control Postprandial Release of Glucagon-Like Peptide-1: In Vivo and in Vitro Studies in Rats Endocrinology, June 1, 2002; 143(6): 2420 - 2426. [Abstract] [Full Text] [PDF]
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M. Nian, J. Gu, D. M. Irwin, and D. J. Drucker Human glucagon gene promoter sequences regulating tissue-specific versus nutrient-regulated gene expression Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R173 - R183. [Abstract] [Full Text] [PDF]
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P. Gilon and J.-C. Henquin Mechanisms and Physiological Significance of the Cholinergic Control of Pancreatic {beta}-Cell Function Endocr. Rev., October 1, 2001; 22(5): 565 - 604. [Abstract] [Full Text] [PDF]
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R. A. Reimer, C. Darimont, S. Gremlich, V. Nicolas-Metral, U. T. Ruegg, and K. Mace A Human Cellular Model for Studying the Regulation of Glucagon-Like Peptide-1 Secretion Endocrinology, October 1, 2001; 142(10): 4522 - 4528. [Abstract] [Full Text] [PDF]
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S. Blat and C. H. Malbert The vagus is inhibitory of insulin secretion under fasting conditions Am J Physiol Endocrinol Metab, October 1, 2001; 281(4): E782 - E788. [Abstract] [Full Text] [PDF]
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F. Y. Enc, N. Imeryuz, L. Akin, T. Turoglu, F. Dede, G. Haklar, N. Tekesin, N. Bekiroglu, B. C. Yegen, J. F. Rehfeld, et al. Inhibition of gastric emptying by acarbose is correlated with GLP-1 response and accompanied by CCK release Am J Physiol Gastrointest Liver Physiol, September 1, 2001; 281(3): G752 - G763. [Abstract] [Full Text] [PDF]
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M.-B. Toft-Nielsen, M. B. Damholt, S. Madsbad, L. M. Hilsted, T. E. Hughes, B. K. Michelsen, and J. J. Holst Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3717 - 3723. [Abstract] [Full Text] [PDF]
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 Y.-H. Choi and G. H. Anderson An Interaction between Hypothalamic Glucagon-Like Peptide-1 and Macronutrient Composition Determines Food Intake in Rats J. Nutr., June 1, 2001; 131(6): 1819 - 1825. [Abstract] [Full Text]
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A. S. Rocca, J. LaGreca, J. Kalitsky, and P. L. Brubaker Monounsaturated Fatty Acid Diets Improve Glycemic Tolerance through Increased Secretion of Glucagon-Like Peptide-1 Endocrinology, March 1, 2001; 142(3): 1148 - 1155. [Abstract] [Full Text] [PDF]
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D. G. Burrin, Y. Petersen, B. Stoll, and P. Sangild Glucagon-Like Peptide 2: A Nutrient-Responsive Gut Growth Factor J. Nutr., March 1, 2001; 131(3): 709 - 712. [Abstract] [Full Text]
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J. B. van Goudoever, B. Stoll, B. Hartmann, J. J. Holst, P. J. Reeds, and D. G. Burrin Secretion of Trophic Gut Peptides Is Not Different in Bolus- and Continuously Fed Piglets J. Nutr., March 1, 2001; 131(3): 729 - 732. [Abstract] [Full Text]
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D. J. Drucker Minireview: The Glucagon-Like Peptides Endocrinology, February 1, 2001; 142(2): 521 - 527. [Abstract] [Full Text] [PDF]
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 P B Jeppesen, B Hartmann, J Thulesen, B S Hansen, J J Holst, S S Poulsen, and P B Mortensen Elevated plasma glucagon-like peptide 1 and 2 concentrations in ileum resected short bowel patients with a preserved colon Gut, September 1, 2000; 47(3): 370 - 376. [Abstract] [Full Text] [PDF]
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 D. G Burrin, B. Stoll, R. Jiang, X. Chang, B. Hartmann, J. J. Holst, G. H Greeley Jr, and P. J Reeds Minimal enteral nutrient requirements for intestinal growth in neonatal piglets: how much is enough? Am. J. Clinical Nutrition, June 1, 2000; 71(6): 1603 - 1610. [Abstract] [Full Text] [PDF]
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T. J. Kieffer and J. Francis Habener The Glucagon-Like Peptides Endocr. Rev., December 1, 1999; 20(6): 876 - 913. [Abstract] [Full Text]
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A. M. J. Buchan Nutrient Tasting and Signaling Mechanisms in the Gut. III. Endocrine cell recognition of luminal nutrients Am J Physiol Gastrointest Liver Physiol, December 1, 1999; 277(6): G1103 - G1107. [Abstract] [Full Text] [PDF]
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