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Departments of Medical Physiology and Medical Anatomy (C.Ø.), The Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Dr. J. J. Holst, Department of Medical Physiology, The Panum Institute, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: holst{at}mfi.ku.dk
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Abstract |
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Although the GLP-1 extractable from the porcine ileum is predominantly the intact peptide (94.6 ± 1.7%), a large proportion of the GLP-1 that is secreted has already been degraded to the truncated form both in vitro (53.8 ± 0.9% intact) and in vivo (32.9 ± 10.8% intact). In the presence of a specific dipeptidyl peptidase IV (DPP IV) inhibitor (valine-pyrrolidide), the proportion of intact GLP-1 released from the perfused ileum was increased under both basal (99% intact; P < 0.05) and stimulated (86–101% intact; P < 0.05) conditions. Immunohistochemical and histochemical studies revealed specific DPP IV staining in the brush border epithelium as well as in the capillary endothelium. Double staining showed juxtapositioning of DPP IV-positive capillaries and GLP-1-containing L cells. From these results, we suggest that GLP-1 is degraded as it enters the DPP IV containing blood vessels draining the intestinal mucosa.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Although several studies have shown that in man GLP-1 is stored primarily as intact GLP-1-(7–36)amide in both the small (3) and large (7) intestines, more than 50% of endogenous GLP-1 occurs in plasma as a truncated form, GLP-1-(9–36)amide (8). Moreover, it has been shown recently that exogenously administered GLP-1-(7–36)amide is extremely labile in vivo, with more than 80% being cleaved into GLP-1-(9–36)amide after sc or iv administration (9, 10), resulting in a t1/2 for the intact peptide of only 1 min in the circulation (11). This is due to GLP-1 being highly susceptible to degradation by the enzyme dipeptidyl peptidase IV (DPP IV) (8, 12, 13), resulting in formation of the truncated peptide. Although it retains affinity for the GLP-1 receptor, this metabolite lacks efficacy and has been shown to be an antagonist both in vitro (10) and in vivo (14).
As the metabolite represents a large proportion of the circulating immunoreactive GLP-1, the present study was undertaken to examine the nature of the newly secreted peptide and to determine where the conversion to GLP-1-(9–36)amide takes place, using both isolated perfused preparations of porcine ileum and intact anesthetized pigs.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-chloralose (50 mg/kg; Merck & Co., Darmstadt,
Germany). The ileum was isolated and perfused in a single pass system
as previously described (15), using a gassed (5% CO2 in
O2) Krebs-Ringer-bicarbonate perfusion medium containing,
in addition, 0.1% human serum albumin (Behringwerke, Marburg,
Germany), 5% Dextran T-70 (Pharmacia Biotech, Uppsala,
Sweden), 7 mmol/liter glucose, a mixture of amino acids (5 mmol/liter;
Vamin, Pharmacia Biotech), and 15–20% freshly washed
bovine erythrocytes (16). A cyclooxygenase inhibitor (1 mg/ml;
indomethacin, Confortid, Dumex, Copenhagen, Denmark) was added to the
medium to prevent generation of PGs in the perfusion system. The gut
lumen was also perfused with oxygenated medium (without erythrocytes)
at a flow rate of 2 ml/min, using catheters inserted into the cut ends
of the intestinal segments. Endogenous GLP-1 secretion was
stimulated by intraarterial infusion of neuromedin C (10 nmol/liter,
final concentration; Peninsula Laboratories, Europe Ltd.,
St. Helens, Merseyside, UK) and intraluminal perfusion of glucose (20%
solution). Neuromedin C is the C-terminal decapeptide of
gastrin-releasing peptide, which is a potent stimulator of
GLP-1 secretion (17). In some experiments, DPP IV
inhibitors, diprotin A (0.3 mmol/liter, final concentration;
Bachem Feinchemikalien, Bubendorf, Switzerland) or
valine-pyrrolidide (0.2 mmol/liter, final concentration; provided by
Dr. T. E. Hughes, Novartis Institute for Biomedical Research,
Summit, NJ) were added to either the arterial or the luminal perfusate.
The venous effluent was collected for 1-min intervals, centrifuged at 4
C, and stored at -20 C until analysis using the RIAs described below.
The nature of the endogenous GLP-1 released was also
characterized after concentration on Sep-Pak C18 cartridges
(Waters Corp., Millipore, Milford, MA) by reverse phase
HPLC, using a Nucleosil 120 5-µm C8 column
(Machery-Nagel, Duren, Germany) eluted with gradients of acetonitrile
in 0.1% trifluoroacetic acid, as described previously (8). Fractions
were collected at 15-sec intervals and assayed for GLP-1
with the side-viewing antiserum 2135, the C-terminally directed
antiserum 89390, and/or the N-terminally directed antiserum 93242
described below. The entire procedure (Sep-Pak, HPLC, and RIA)
has an overall recovery of 41% and a detection limit of approximately
95 fmol for both intact GLP-1 and truncated metabolites
(8). To test that nonspecific degradation of the stored GLP-1 was not occurring during the course of the perfusion experiment, in some experiments a piece of ileum was frozen on dry ice immediately after isolation, and a second piece was taken at the end of the experiment from the tissue that had been perfused. The tissue pieces were subsequently extracted with acid-ethanol (18) and subjected to reverse phase HPLC and RIA analysis, as described above. To test whether there was GLP-1-degrading activity in the perfusion medium itself, synthetic GLP-1-(7–36)amide was incubated (30 min at 37 C) in vitro (8) with medium collected from the arterial line (i.e. before it passed through the tissue) and from the venous line, and subjected to HPLC and RIA analysis as before.
In vivo catheterized pig
Danish LYY strain pigs (30–32 kg; n = 4) were used.
Food was withdrawn 24 h before surgery, but animals were allowed
free access to drinking water. After premedication with ketamine and
induction with pentobarbital as before, animals were anesthetized with
-chloralose (66 mg/kg) and ventilated with intermittent positive
pressure. Nonobstructing catheters were placed in a carotid artery and
the ileal vein. In addition, an ear vein was cannulated for peptide
infusion. After surgical preparation, animals were heparinized and left
undisturbed for 30 min. Anesthesia was maintained with additional
chloralose as necessary.
Neuromedin C (Peninsula Laboratories, Europe Ltd.) was infused as a bolus (120 nmol) via the ear vein catheter to stimulate endogenous GLP-1 release. Simultaneous blood samples (4.5 ml) were collected at -15, -7.5, 0, 2.5, 5, 7.5, 10, 15, and 20 min from the carotid artery and the ileal vein into chilled tubes containing EDTA (7.4 mmol/liter, final concentration), aprotinin (500 kallikrein inhibitory equivalents/ml blood; Novo Nordisk, Bagsvaerd, Denmark), and diprotin A (0.1 mmol/liter, final concentration) and kept on ice until centrifugation at 4 C. The volume of blood taken did not exceed 3% of the total blood volume, which has previously been shown not to affect heart rate or blood pressure (11). Plasma was separated and stored at -20 C until analysis.
Immunohistochemistry and histochemistry
For immunohistochemistry of paraffin-embedded human ileum, an
antibody raised in chicken against purified DPP IV from human kidney
was used (a gift from Dr. T. E. Hughes, Novartis Institute for
Biomedical Research). This antibody does not recognize porcine DPP IV.
The antibody was used in a dilution of 1:500. For light microscopy,
sections were stained using a secondary antichicken antibody coupled to
alkaline phosphatase (Promega Corp., Madison, WI; 1:1000),
followed by Fast Red visualization (Fast Red Substrate System,
DAKO A/S, Glostrup, Denmark). To investigate the
specificity of the DPP IV antiserum, the antiserum, diluted as
described above, was preabsorbed with 50 µg/ml human DPP IV (a gift
from Dr. S Branner, Novo Nordisk A/S, Bagsvaerd, Denmark),
and immunohistochemistry was performed as described above. For double
staining, the same primary antibody was used (1:500), but a
biotin-labeled antichicken antibody raised in goat was employed
(Vector Laboratories, Inc., Burlingame, CA; 1:100),
followed by Texas Red-conjugated streptavidin (Amersham Pharmacia Biotech, Aylesbury, UK). Simultaneous staining with a primary
rabbit antibody raised against GLP-1 (antibody 2135;
1:1000) (19), followed by a secondary antirabbit antibody coupled to
fluorescein isothiocyanate (DAKO A/S) was performed.
Histochemical staining for DPP IV was performed on frozen sections of
human and porcine ileum according to the method of Schlagenhauff
et al. (20), employing H-Ala-Pro4MßNA HCl
(Bachem, Torrance, CA) and Fast Blue B (Merck & Co.).
Hormonal analysis
Plasma samples and HPLC fractions were assayed for
GLP-1 using specific RIAs. Antiserum 2135 (19) is
side-viewing and recognizes all molecules containing the central
sequence of GLP-1 regardless of C- or N-terminal
truncations or extensions. It cross-reacts fully with
GLP-1-(7–36)amide and 79% with
GLP-1-(9–36)amide, and endows the assay with a detection
limit of 5 pmol/liter. N-Terminal immunoreactivity was measured using
antiserum 93242 (21), which has a cross-reactivity of about 10% with
GLP-1-(1–36)amide and less than 0.1% with
GLP-1-(8–36)amide and GLP-1-(9–36)amide.
With this antibody, the detection limit is 5 pmol/liter. HPLC supports
the use of RIAs with this specificity for determination of intact
GLP-1 (8). C-Terminal immunoreactivity was determined
using antiserum 89390 (22), which has an absolute requirement for the
intact amidated C-terminus of GLP-1-(7–36)amide and
cross-reacts less than 0.01% with C-terminally truncated fragments and
83% with GLP-1-(9–36)amide. This assay has a detection
limit of 1 pmol/liter. For all assays, the intraassay coefficient of
variation was less than 6%. Plasma samples were extracted with 70%
ethanol (vol/vol, final concentration) before assay, giving a recovery
of 75% (23), whereas perfusate samples were analyzed directly using
perfusate as solvent for the standards.
Statistical analysis
The proportion of intact GLP-1 was calculated as
the ratio of immunoreactivity measured by the N-terminally directed RIA
to the total measured by the C-terminally directed assay and/or that
measured by the side-viewing assay. The area under the curve (AUC) for
the peptide secreted in vivo was calculated using the
trapezoidal method, after subtraction of the basal values.
Data are expressed as the mean ± SEM and were analyzed by ANOVA and two-tailed t tests for paired data as appropriate. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. HPLC analysis of extracts of
freshly isolated ileum and tissue taken at the end of the perfusion
experiment revealed the presence of a major immunoreactive peak
corresponding to intact GLP-1-(7–36)amide (92.9 ±
1.7% and 87.8 ± 2.1% before and after perfusion, respectively;
n = 3; determined using antiserum 89390) and a minor peak
corresponding to the N-terminally truncated metabolite,
GLP-1-(9–36)amide (7.1 ± 1.7% and 12.2 ±
2.1% before and after perfusion, respectively).
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In vitro secretion of GLP-1
In the absence of DPP IV inhibitors, basal secretion (n = 13)
of intact GLP-1 (determined using antiserum 93242)
amounted to 57.4 ± 5.4% of the total immunoreactivity determined
with antiserum 89390 (Fig. 2).
GLP-1 secretion was stimulated by intraarterial neuromedin
C and intraluminal glucose (n = 13; Fig. 2), but the proportion of
intact peptide was unchanged (55.1 ± 5.5% intact during
neuromedin C and 61.9 ± 6.2% intact during glucose; not
significantly different from basal values). As shown in Fig. 3, HPLC analysis (n = 3) of
endogenous GLP-1 secreted from the isolated perfused ileum
during neuromedin C stimulation revealed two major immunoreactive
peaks, showing that only 53.8 ± 0.9% of the newly secreted
peptide is released as intact GLP-1. The N-terminally
truncated metabolite accounts for the remainder (46.2 ± 0.9%).
There was no effect of intraluminal diprotin A, but a trend toward an
increased proportion of intact peptide was seen when diprotin A was
administered intraarterially; this was significant only under basal
conditions (n = 6; Fig. 4). The
stable DPP IV inhibitor, valine-pyrrolidide (both intraarterially and
intraluminally administered), increased the proportion of intact
GLP-1 under both basal and stimulated conditions (n =
7; Fig. 4). Figure 5 illustrates this for
the effect of intraluminal valine-pyrrolidide on glucose-stimulated
GLP-1 release. During glucose stimulation in the presence
of the inhibitor, GLP-1 concentrations determined with
antiserum 93242 converge with those determined with antiserum 89390. To
verify that this was due to the inhibitor preventing the N-terminal
degradation of GLP-1, the venous effluent from an
experiment was analyzed by HPLC. When valine-pyrrolidide was included,
only one major immunoreactive peak (amounting to 88.5% of the total
immunoreactivity) was identified. This corresponded to intact
GLP-1-(7–36)amide and was detected equally with both
N-terminal (1.87 pmol; antiserum 93242) and side-viewing (1.93 pmol;
antiserum 2135) assays. A second minor peak (11.5% of the total
immunoreactivity), corresponding to the truncated metabolite
GLP-1-(9–36)amide, was detected only with the
side-viewing assay (0.25 pmol with antiserum 2135 vs. <0.01
pmol with antiserum 93242).
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). The
AUC for total peptide (both intact and N-terminally degraded
metabolite, determined with antiserum 89390) was 102.2 ± 16.4
pmol/liter·20 min in the carotid artery, as opposed to 221.6 ±
31.6 pmol/liter·20 min in the ileal vein, with the corresponding
values for the intact peptide (determined with antiserum 93242) being
35.3 ± 11.3 pmol/liter·20 min (artery) and 80.9 ± 24.8
pmol/liter·20 min (vein). The total amount of peptide secreted
(calculated as the increase in AUC in the vein compared with that in
the artery) is 119.3 ± 25.4 pmol/liter·20 min (determined with
antiserum 89390) compared with 45.6 ± 23.0 pmol/liter·20 min
for the intact peptide, determined with antiserum 93242. Thus, the
intact peptide accounts for only 32.9 ± 10.8% of the total
amount of GLP-1 secreted.
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. In the human ileum,
specific DPP IV staining was found in the brush border of the
absorptive epithelium and in the capillaries in the lamina propria
(Fig. 7, A and B) as well as in capillaries in all other layers of the
intestinal wall. By histochemical staining of fixed, frozen human (Fig. 7C) and porcine (Fig. 7D) samples of ileum, an intense staining of the
brush border was seen in both species.
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).
Preabsorption of the DPP IV antiserum with 50 µg/ml human DPP IV
completely abolished the DPP IV immunostaining (Fig. 8).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is known that GLP-1 is stored in intestinal L cells as the intact peptide (3, 7), but recent studies have shown convincingly that the peptide is subjected to extensive N-terminal degradation by DPP IV in vivo (8, 11, 13). It has been assumed that this inactivation by DPP IV occurs once the peptide reaches the systemic circulation, and indeed, tissue-specific degradation of GLP-1 does occur (11). This is particularly significant in sites such as the liver and kidney, where DPP IV occurs as a membrane-bound ectoenzyme (24), but some degradation also occurs within the blood itself (8, 13, 25), where DPP IV is found in a soluble form (26). We now show that over half of the newly secreted GLP-1 is already N-terminally degraded even before it enters the systemic circulation. This degradation is probably attributable to the local action of DPP IV present in the endothelium of the capillary bed in close proximity to the GLP-1-secreting L cells. DPP IV inhibitors prevent degradation of exogenously administered GLP-1 in pigs in vivo (27) and are associated with an improvement of glucose tolerance in rodents, suggesting that endogenous incretins are also protected from degradation (28, 29). In the present study, the stable DPP IV inhibitor, valine-pyrrolidide (30), was able to prevent N-terminal degradation of newly secreted GLP-1 almost entirely, whereas diprotin A was less effective. This may be due to the fact that diprotin A, being a substrate for the enzyme (31), is itself degraded, particularly after intraluminal administration when it comes into contact with the high density of DPP IV found in the brush border of the absorptive epithelium, resulting in diminished inhibitor concentrations reaching the site of GLP-1 degradation. It is unlikely that the brush border DPP IV isoform is involved in GLP-1 degradation, as it is an ectoenzyme situated on the luminal side of the brush-border membrane, whereas the GLP-1-containing granules are located deeper within the cell, toward the basolateral membrane. In an electron microscopic study, DPP IV immunoreactivity was demonstrated to be actually associated with the secretory granules of the L cell (32), suggesting that some conversion of intact GLP-1 may occur even before the peptide is secreted from the cell; however, this is likely to be relatively insignificant, given that the stored form is predominantly intact. The related proglucagon-processing product, GLP-2, seems to be degraded by DPP IV in rats (33), and it is of interest that the resulting metabolite GLP-2-(3–33) has been found in extracts of rat ileum, where it accounts for 16% of the total GLP-2 immunoreactivity (34). Why the stored form of GLP-2 should undergo further processing when this apparently does not happen for GLP-1 is unclear, but it may represent a species difference between the rat and pig. Even compared with the mouse, the effects of DPP IV seem to be more pronounced in the rat (33), with direct measurements indicating that the rat has greater plasma DPP IV activity (13) compared with man (12).
Around half of the secreted GLP-1 is already degraded before it reaches the general circulation, questioning its function as a circulating insulinotropic hormone. It has previously been shown that the plasma t1/2 is very short, only 1 min (11). Moreover, more than 40% of the circulating peptide is N-terminally degraded during a single passage across the hepatic bed (11), i.e. before it reaches the pancreas. Together, these findings pose the question of why, if GLP-1 is a circulating insulinotropic hormone, so much of the peptide is inactivated before it can reach its primary target tissue, the pancreatic ß-cell. Furthermore, under normal conditions, does intact, biologically active peptide reach the pancreas in sufficient concentrations to elicit an insulinotropic response? With this in mind, it could be postulated that the primary mechanism of action is a local one. Thus, GLP-1, secreted in response to nutrients entering the distal small intestine, is released from the L cell to stimulate the local afferent nerve fibers and thereby cause insulin to be released from the pancreatic ß-cell. The GLP-1 is then subjected to N-terminal degradation by local DPP IV before it enters the capillary bed, thus limiting the amount of intact peptide that reaches the pancreas via the circulation. Some intact peptide reaches the portal vein, where it has been shown to increase hepatic afferent vagal nerve activity concomitantly with an increase in pancreatic vagal efferent nerve activity, leading to the suggestion of the existence of a vagal hepatopancreatic relex pathway (35). This is further supported by a preliminary report in which GLP-1 in the portal vein was shown to augment the ß-cell response to intraportal glucose, an effect that was inhibited by ganglionic blockade, suggesting that insulin release may be mediated via a nonmuscarinic, neural reflex of hepatic origin (36). When a large meal, particularly one rich in complex carbohydrates and lipids, results in a greater requirement for insulin, GLP-1 secretion is increased further, so that the amount of intact peptide that escapes the local degradation is increased, thereby allowing it to have an additional direct insulinotropic effect by a hormonal mechanism.
In the case of the gastrointestinal effects of GLP-1, the concept that the peptide acts via neural pathways has already received support. In man, exogenous GLP-1 is unable to inhibit gastric acid secretion in vagotomized subjects, indicating that the inhibitory effect of GLP-1 on acid secretion depends upon intact vagal innervation (37). In another study, which used the release of pancreatic polypeptide as a humoral marker of cholinergic tone, it was suggested that GLP-1 inhibits efferent vagal activity and may thereby contribute to delayed gastric emptying via a central pathway (38). A detailed study comparing the effects of GLP-1 in intact anesthetized pigs with those obtained in an isolated perfused antrum and pancreas preparation with intact vagal innervation concluded that the inhibitory effects of GLP-1 on upper gastrointestinal function involved interaction with centers in the brain or with afferent neural pathways to the brain (39). The latter conclusion is supported by findings in rats, in which gastric emptying and gastric acid secretion were inhibited by GLP-1 by mechanisms including a capsaicin-sensitive pathway, indicating that the effect of GLP-1 is mediated via activation of vagal afferent nerve fibers (40).
GLP-1 is also found in the large intestine, where, like ileal GLP-1, it is stored in the intact form (7). Although the present study did not examine the nature of the GLP-1 derived from the colon, given the fate of ileal GLP-1, it is likely that colonic GLP-1 is similarly N-terminally degraded by DPP IV in the local capillary endothelium. The role of GLP-1 from the colon is unclear, with some studies concluding that it does not contribute significantly to circulating levels (41, 42), whereas another study indicates that under some circumstances, colonic GLP-1 can make a sizable contribution (43). However, in analogy with GLP-1 released from the small intestine, it could be speculated that GLP-1 from the large intestine may primarily exert its effects via activation of local nerve fibers. Clearly, the large intestine secretion of GLP-1 and its significance demand further study.
As so much of the GLP-1 leaving the intestine and entering the systemic circulation has already been degraded to N-terminally truncated forms, careful thought should be given to the specificity of assays used to determine GLP-1 levels. If the study is designed to determine the biological response to GLP-1, then clearly an N-terminally directed GLP-1 assay should be used. This will primarily measure levels of intact, biologically active GLP-1. However, if the study is designed to assess the response of the L cell to a given stimulus, then an N-terminally directed assay, because it does not recognize the N-terminally truncated peptides, will underestimate the true magnitude of the response. In this case, C-terminally directed assays are preferable for determination of the aggregate GLP-1 response.
In summary, this study has demonstrated that a large part of the newly secreted GLP-1 from the intestinal L cell is already N-terminally truncated by the time it leaves the local capillary bed. This results in the formation of a peptide that lacks efficacy at the GLP-1 receptor, suggesting that the main mechanism of action of GLP-1 may be a local one involving activation of nerve fibers lying in close proximity to the L cells.
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Acknowledgments |
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Footnotes |
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Received March 15, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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kun, Villanueva-Peñacarrillo ML, Ulusoy NB 1997
Glucagon-like peptide-1 inhibits gastric emptying via vagal
afferent-mediated central mechanisms. Am J Physiol
273:G920–G927
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V. Ionut, I. F. Liberty, K. Hucking, M. Lottati, D. Stefanovski, D. Zheng, and R. N. Bergman Exogenously imposed postprandial-like rises in systemic glucose and GLP-1 do not produce an incretin effect, suggesting an indirect mechanism of GLP-1 action Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E779 - E785. [Abstract] [Full Text] [PDF]
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 J. Ryskjaer, C. F Deacon, R. D Carr, T. Krarup, S. Madsbad, J. Holst, and T. Vilsboll Plasma dipeptidyl peptidase-IV activity in patients with type-2 diabetes mellitus correlates positively with HbAlc levels, but is not acutely affected by food intake Eur. J. Endocrinol., September 1, 2006; 155(3): 485 - 493. [Abstract] [Full Text] [PDF]
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D. J. Drucker Enhancing the action of incretin hormones: a new whey forward? Endocrinology, July 1, 2006; 147(7): 3171 - 3172. [Full Text] [PDF]
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P. T. Gunnarsson, M. S. Winzell, C. F. Deacon, M. O. Larsen, K. Jelic, R. D. Carr, and B. Ahren Glucose-Induced Incretin Hormone Release and Inactivation Are Differently Modulated by Oral Fat and Protein in Mice Endocrinology, July 1, 2006; 147(7): 3173 - 3180. [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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C. F. Deacon Therapeutic Strategies Based on Glucagon-Like Peptide 1 Diabetes, September 1, 2004; 53(9): 2181 - 2189. [Abstract] [Full Text] [PDF]
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J. J. Meier, M. A. Nauck, D. Kranz, J. J. Holst, C. F. Deacon, D. Gaeckler, W. E. Schmidt, and B. Gallwitz Secretion, Degradation, and Elimination of Glucagon-Like Peptide 1 and Gastric Inhibitory Polypeptide in Patients with Chronic Renal Insufficiency and Healthy Control Subjects Diabetes, March 1, 2004; 53(3): 654 - 662. [Abstract] [Full Text] [PDF]
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 M. G. Beconi, A. Mao, D. Q. Liu, C. Kochansky, T. Pereira, C. Raab, P. Pearson, and S.-H. Lee Chiu METABOLISM AND PHARMACOKINETICS OF A DIPEPTIDYL PEPTIDASE IV INHIBITOR IN RATS, DOGS, AND MONKEYS WITH SELECTIVE CARBAMOYL GLUCURONIDATION OF THE PRIMARY AMINE IN DOGS Drug Metab. Dispos., October 1, 2003; 31(10): 1269 - 1277. [Abstract] [Full Text] [PDF]
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T. P. Vahl, B. W. Paty, B. D. Fuller, R. L. Prigeon, and D. A. D'Alessio Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on Intravenous Glucose Tolerance and Glucose-Induced Insulin Secretion in Healthy Humans J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1772 - 1779. [Abstract] [Full Text] [PDF]
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J. A. Pospisilik, J. Martin, T. Doty, J. A. Ehses, N. Pamir, F. C. Lynn, S. Piteau, H.-U. Demuth, C. H.S. McIntosh, and R. A. Pederson Dipeptidyl Peptidase IV Inhibitor Treatment Stimulates {beta}-Cell Survival and Islet Neogenesis in Streptozotocin-Induced Diabetic Rats Diabetes, March 1, 2003; 52(3): 741 - 750. [Abstract] [Full Text] [PDF]
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 Y. Li, T. Hansotia, B. Yusta, F. Ris, P. A. Halban, and D. J. Drucker Glucagon-like Peptide-1 Receptor Signaling Modulates beta Cell Apoptosis J. Biol. Chem., January 3, 2003; 278(1): 471 - 478. [Abstract] [Full Text] [PDF]
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T. Vilsboll, H. Agerso, T. Krarup, and J. J. Holst Similar Elimination Rates of Glucagon-Like Peptide-1 in Obese Type 2 Diabetic Patients and Healthy Subjects J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 220 - 224. [Abstract] [Full Text] [PDF]
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J. A. Pospisilik, S. G. Stafford, H.-U. Demuth, C. H.S. McIntosh, and R. A. Pederson Long-Term Treatment With Dipeptidyl Peptidase IV Inhibitor Improves Hepatic and Peripheral Insulin Sensitivity in the VDF Zucker Rat: A Euglycemic-Hyperinsulinemic Clamp Study Diabetes, September 1, 2002; 51(9): 2677 - 2683. [Abstract] [Full Text] [PDF]
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J.A. Pospisilik, S.G. Stafford, H-U. Demuth, R. Brownsey, W. Parkhouse, D.T. Finegood, C.H.S. McIntosh, and R.A. Pederson Long-Term Treatment With the Dipeptidyl Peptidase IV Inhibitor P32/98 Causes Sustained Improvements in Glucose Tolerance, Insulin Sensitivity, Hyperinsulinemia, and {beta}-Cell Glucose Responsiveness in VDF (fa/fa) Zucker Rats Diabetes, April 1, 2002; 51(4): 943 - 950. [Abstract] [Full Text] [PDF]
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M. E. Doyle, N. H. Greig, H. W. Holloway, J. A. Betkey, M. Bernier, and J. M. Egan Insertion of an N-Terminal 6-Aminohexanoic Acid after the 7 Amino Acid Position of Glucagon-Like Peptide-1 Produces a Long-Acting Hypoglycemic Agent Endocrinology, October 1, 2001; 142(10): 4462 - 4468. [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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R. Burcelin, A. Da Costa, D. Drucker, and B. Thorens Glucose Competence of the Hepatoportal Vein Sensor Requires the Presence of an Activated Glucagon-Like Peptide-1 Receptor Diabetes, August 1, 2001; 50(8): 1720 - 1728. [Abstract] [Full Text] [PDF]
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T. Vilsbøll, T. Krarup, C. F. Deacon, S. Madsbad, and J. J. Holst Reduced Postprandial Concentrations of Intact Biologically Active Glucagon-Like Peptide 1 in Type 2 Diabetic Patients Diabetes, March 1, 2001; 50(3): 609 - 613. [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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K. Persson, R. L. Gingerich, S. Nayak, K. Wada, E. Wada, and B. Ahren Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice Am J Physiol Endocrinol Metab, November 1, 2000; 279(5): E956 - E962. [Abstract] [Full Text] [PDF]
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B. Balkan and X. Li Portal GLP-1 administration in rats augments the insulin response to glucose via neuronal mechanisms Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2000; 279(4): R1449 - R1454. [Abstract] [Full Text] [PDF]
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B. Hartmann, M. B. Harr, P. B. Jeppesen, M. Wojdemann, C. F. Deacon, P. B. Mortensen, and J. J. Holst In Vivo and in Vitro Degradation of Glucagon-Like Peptide-2 in Humans J. Clin. Endocrinol. Metab., August 1, 2000; 85(8): 2884 - 2888. [Abstract] [Full Text]
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C. F. Deacon, A. Plamboeck, S. Moller, and J. J. Holst GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E873 - E879. [Abstract] [Full Text] [PDF]
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), which measures total GLP-1.
Significant differences (P < 0.05) between the two
assays were obtained under both basal and stimulated conditions. Data
are the mean ± SEM (n = 13).
