1 Department of Medicine, Ruhr-University, Knappschafts-Krankenhaus, 044892 Bochum, Germany; and 2 Departments of Anatomy and Physiology, Panum Institute, University of Copenhagen, DK-2200 Copenhagen, Denmark
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ABSTRACT |
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Glucagon-like peptide 1 (GLP-1) has been shown
to inhibit gastric emptying of liquid meals in type 2 diabetic
patients. It was the aim of the present study to compare the action of
physiological and pharmacological doses of intravenous GLP-1-(736)
amide and GLP-1-(7
37) on gastric emptying in normal volunteers. Nine
healthy subjects participated (26 ± 3 yr; body mass index 22.9 ± 1.6 kg/m2; hemoglobin
A1C 5.0 ± 0.2%) in five
experiments on separate occasions after an overnight fast. A
nasogastric tube was positioned for the determination of gastric volume
by use of a dye-dilution technique (phenol red). GLP-1-(7
36) amide
(0.4, 0.8, or 1.2 pmol · kg
1 · min
1),
GLP-1-(7
37) (1.2 pmol · kg
1 · min
1),
or placebo was infused intravenously from
30 to 240 min. A liquid
meal (50 g sucrose, 8% amino acids, 440 ml, 327 kcal) was administered
at 0 min. Glucose, insulin, and C-peptide were measured over 240 min.
Gastric emptying was dose dependently slowed by GLP-1-(7
36) amide
(P < 0.0001). Effects of
GLP-1-(7
37) at 1.2 pmol · kg
1 · min
1
were virtually identical. GLP-1 dose dependently stimulated fasting insulin secretion (
30 to 0 min) and slightly reduced glucose concentrations. After the meal (0-240 min), integrated incremental glucose (P < 0.0001) and insulin
responses (P = 0.01) were reduced (dose dependently) rather than enhanced. In conclusion,
1) GLP-1-(7
36) amide or -(7
37)
inhibits gastric emptying also in normal subjects, 2) physiological doses (0.4 pmol · kg
1 · min
1)
still have a significant effect, 3)
despite the known insulinotropic actions of GLP-1-(7
36) amide and
-(7
37), the net effect of administering GLP-1 with a meal is no
change or a reduction in meal-related insulin responses. These findings
suggest a primarily inhibitory function for GLP-1 (ileal brake
mechanisms).
incretin hormones; glucagon-like peptide 1-(736) amide; pancreatic glucagon; enteroinsular axis
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INTRODUCTION |
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THE EXISTENCE OF GLUCAGON-LIKE PEPTIDE 1
[GLP-1; amino acid sequence (137)] was predicted on the
basis of analysis of the proglucagon gene (1). Later, it became clear
that GLP-1-(7
36) amide and, to a lesser degree, GLP-1-(7
37), are
produced in L cells in the lower gastrointestinal tract (6, 25).
Synthetic GLP-1-(7
36) amide and -(7
37) stimulate insulin secretion
in the perfused pancreas (24) and, when infused into humans, in both
normal glucose-tolerant (15, 19) and type 2 diabetic (non-insulin-dependent diabetic) subjects (9, 18, 21), especially at
elevated glucose concentrations [glucose dependence (15, 18, 19,
21)]. As an insulinotropic agent, GLP-1 appears to be the
pharmacologically more potent counterpart to gastric inhibitory
polypeptide [GIP (15, 19)]. GLP-1, therefore, seems to be
the long-sought second incretin hormone, explaining the phenomenon that
oral glucose elicits a greater insulin secretory response than is
explained by the rise in glycemia alone (2).
An incretin role for GLP-1 would imply that physiological increments of
GLP-1 plasma concentrations are accompanied by evidence of stimulated
insulin secretion during the postprandial phase of physiological
hyperglycemia. This has been demonstrated only in animal experiments by
use of a specific GLP-1 receptor antagonist, exendin-(939), which
blocked insulin secretory responses when glucose was administered
orally (29) or intraduodenally (14) in rats. In these experiments,
another potent action of GLP-1, the deceleration of gastric emptying
(30, 31), was not studied and/or had little impact. This
inhibitory action of GLP-1 on gastric emptying has been described in
normal subjects (30) and in type 2 diabetic patients (31). In type 2 diabetic patients with hyperglycemia, exogenous GLP-1 in a
pharmacological dose (1.2 pmol · kg
1 · min
1)
nevertheless stimulated insulin secretion and inhibited glucagon secretion despite a near-complete standstill of gastric emptying (31).
In normal subjects, the prevention of the duodenal delivery of
nutrients would interfere with the rise in glycemia that amplifies the
synergistic insulinotropic actions of GLP-1 (15, 19).
Therefore, we wanted to study the effects of an exogenous
administration of GLP-1-(736) amide in healthy volunteers fed a liquid mixed meal under conditions that allowed the measurement of
gastric emptying by use of a dye-dilution technique (phenol red). The
dosage of GLP-1 was chosen to span the physiological and
pharmacological range as defined by previous studies (15, 19, 31).
Furthermore, the actions of GLP-1-(7
36) amide were compared with
those of GLP-1-(7
37) (25, 26). It was our aim to elucidate
1) whether the inhibition of gastric
emptying by GLP-1 is dose dependent and whether it occurs also with
physiological increments in GLP-1 plasma concentrations,
2) whether GLP-1-(7
36) amide and
-(7
37) might differ with respect to their gastric actions, and
3) whether, under these conditions,
the net effect of exogenous GLP-1 is an augmentation of or a reduction
in meal-related insulin secretory responses, i.e., if the effects on
gastric emptying would potentially outweigh the insulinotropic effects.
Furthermore, these questions have to be answered to define the GLP-1
plasma concentration range compatible with normal nutrition in type 2 diabetic patients, in whom inhibition of gastric emptying
(31) may question a potential "therapeutic" use of GLP-1 or of
its derivatives that has been suggested on the basis of its preserved insulinotropic (18, 21) and glucagon-lowering (21) actions in this
patient group. Preliminary results have been published in abstract form
(20).
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SUBJECTS, MATERIALS, AND METHODS |
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Study protocol. The study protocol was approved by the ethics committee of the medical faculty of Ruhr-University, Bochum, on October 21, 1993 (registration number 437) before the study. Written informed consent was obtained from all participants.
Subjects. Nine healthy volunteers were studied. They were 26 ± 3 yr old, were 187 ± 7 cm tall, weighed 79 ± 5 kg (body mass index was 22.9 ± 1.6 kg/m2), and their hemoglobin A1C was 5.0 ± 0.2% (normal range, 4.0-6.2%). All had a normal oral glucose tolerance according to World Health Organization criteria (fasting glucose 4.5 ± 0.4, 120-min value 4.4 ± 0.8 mmol/l). None had a family history of diabetes mellitus or a personal history of gastrointestinal disorders. Blood cell counts, serum transaminases, creatinine values, and triglyceride, total cholesterol, and high-density cholesterol concentrations were in the normal range.
Study design.
All participants were studied, in random order, on five occasions.
1) A liquid mixed meal (50 g sucrose
plus amino acids, 400 ml Aminosteril N-Hepa 8%; Fresenius, Bad
Homburg, Germany) was instilled intragastrically at
time 0. Placebo (0.9% NaCl with 1%
human serum albumin, Human Albumin 20% Behring, salzarm, Behringwerke, Marburg, Germany) was infused intravenously from 30 to 240 min. 2) A liquid meal was instilled
intragastrically at time 0. GLP-1-(7
36) amide, 0.4 pmol · kg
1 · min
1,
was infused intravenously from
30 to 240 min.
3) A liquid meal was instilled
intragastrically at time 0. GLP-1-(7
36) amide, 0.8 pmol · kg
1 · min
1,
was infused intravenously from
30 to 240 min.
4) A liquid meal was instilled
intragastrically at time 0. GLP-1-(7
36) amide, 1.2 pmol · kg
1 · min
1,
was infused intravenously from
30 to 240 min.
5) A liquid meal was instilled
intragastrically at time 0. GLP-1-(7
37),
1.2 pmol · kg
1 · min
1,
was infused intravenously from
30 to 240 min. All
volunteers were studied at intervals of 7-10 days. A single
experiment was performed on one volunteer per day.
Peptides.
Synthetic GLP-1-(736) amide and GLP-1-(7
37) were
purchased from Saxon Biochemicals (Hannover, Germany). The lot number
of GLP-1-(7
36) amide (pharmaceutical grade) was PGAS 242, FGLP7369301 A, and net peptide content was 88%. The lot number for GLP-1-(7
37) was PGAS 243, Lot ZJ 222, and net peptide content was 91%. The peptides were dissolved in 0.9% NaCl/1% human serum albumin, filtered through 0.2-µm nitrocellulose filters (Millipore, Bedford, MA), and
stored frozen at
30°C as previously described.
High-performance liquid chromatography profiles (provided by the
manufacturer) showed that the preparation was >99% pure (single peak
coeluting with appropriate standards). Samples were analyzed for
bacterial growth (standard culture techniques) and for pyrogens
(Limulus amebocyte lysate endo-LAL, Chromogenix, Mölndal,
Sweden). No bacterial contamination was detected. Endotoxin
concentrations in the GLP-1 stock solutions (50 µg peptide/ml) always
were <0.03 endotoxin units/ml.
Experimental procedures. The tests were performed in the morning after an overnight fast. Two forearm veins were punctured with an 18-gauge Teflon cannula (Moskito 123, Vygon, Aachen, Germany), and the cannulas were kept patent with 0.9% NaCl for blood sampling and for GLP-1 and/or placebo administration.
After basal blood specimens were drawn, atGastric emptying. Before the study, a 120-cm nasogastric tube (CH12, Freka-Ernährungssonde, Fresenius) was placed and tape-fixed with the tip ~55 cm from the nostrils. Gastric juice was aspirated, and an acidic pH was ascertained with pH-sensitive Lackmus paper. The gastric lumen was washed with 100 ml of water (37°C). The position of the tube was adjusted to allow a near-complete aspiration of instilled fluid. The subjects lay on their backs in a semi-recumbent position, with the upper half of the body 45° upright. At 0 min, 440 ml (total volume) of the liquid test meal was instilled into their stomachs. It was composed of 50 g of sucrose dissolved in 400 ml of Aminosteril Hepa 8% (Fresenius). The amino acid content of the meal (in mmol) was 131.7 isoleucine, 39.9 leucine, 18.8 lysine, 2.9 methionine, 1.7 cysteine, 31.0 glycine, 2.1 phenylalanin, 14.8 threonine, 1.4 tryptophan, 34.4 valine, 20.4 arginine, 7.2 histidine, 20.8 alanine, 19.9 proline, and 8.5 serine. Acetic acid (29.4 mmol) was also contained in this commercial amino acid mixture.
This composition of the meal was chosen because the solution had to be clear for the photometric measurement of phenol red (see description of the measurement of gastric emptying to follow) and should have been similar in caloric and nutrient content to a normal mixed meal. Amino acids were added to stimulate the release of cholecystokinin (17), a physiological regulator of gastric emptying in humans. The meal contained 32 g of mixed amino acids (131 kcal = 40%) and 50 g of sucrose (196 kcal = 60%) (20), and total energy content was 327 kcal (energy density: 0.82 kcal/ml). Gastric emptying was measured by a double-sampling dye-dilution technique using phenol red (Merck, Darmstadt, Germany) according to George (7), with modifications introduced to reduce measurement error by Hurwitz (12). In principle, at all time points chosen to measure gastric volume, a known amount of the nonabsorbable phenol red dye was added to the translucent liquid test meal in a volume of 5 to 15 ml. After thorough mixing with gastric contents for ~2 min, a gastric sample was drawn, and the resulting step-up in phenol red concentrations was determined photometrically. The volume of gastric contents was determined as the volume of distribution of phenol red. Increasing amounts of phenol red were used as the experiments proceeded to get well-measurable increments in optical density also in the presence of previously instilled phenol red. According to the expected rate of gastric emptying (30, 31), gastric contents were determined at intervals (see Fig. 2) over 240 min.Blood specimens.
Blood was drawn into chilled tubes containing EDTA and aprotinin
(Trasylol; 20,000 kallikrein-inhibitor units/ml, 200 µl/10 ml blood;
Bayer, Leverkusen) and kept on ice. A sample (~100 µl) was stored
in NaF (Microvette CB 300; Sarstedt, Nümbrecht, Germany) for the
measurement of glucose. After centrifugation at 4°C, plasma for
hormone analyses was kept frozen at 30°C.
Laboratory determinations.
Glucose was measured using a glucose oxidase method with a Glucose
Analyzer 2 (Beckman Instruments, Munich, Germany). Insulin was measured
using an insulin microparticle enzyme immunoassay, IMx Insulin (Abbott
Laboratories, Wiesbaden, Germany). Intra-assay coefficients of
variation were 4%. C-peptide was measured using C-peptide
antibody-coated microtitre wells (C-peptide MTPL EIA) from DRG
Instruments (Marburg, Germany). Intra-assay coefficients of variation
were
6%. Human insulin and C-peptide were used as standards.
Statistical analysis.
Results are reported as means ± SE. Integrations were carried out
according to the trapezoidal rule, with separate calculations for
increments above and decrements below baseline. Meal-related responses
were calculated over true baseline values (as determined at
45/
30 min of Figs. 2 and 3), because GLP-1 administration changed values determined at 0 min.
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RESULTS |
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Plasma GLP-1 concentrations.
The liquid mixed meal raised plasma GLP-1-(736) amide concentrations
from basal
5 pmol/l to 11.6 ± 1.6 pmol/l at 30 min, with a return
to baseline values at ~150 min. Steady-state plasma concentrations
during the exogenous administration of GLP-1-(7
36) amide were
25, 36, and 51 pmol/l for doses of 0.4, 0.8, and 1.2 pmol · kg
1 · min
1
reached 15-60 min after start of the infusion (Table
1). In any case, clearly elevated
concentrations were already achieved at the time point of liquid test
meal administration (Fig. 1, top). Plasma levels during the
infusion of GLP-1-(7
37) were comparable to those obtained with the
same dose of GLP-1-(7
36) amide. Directly measured steady-state
concentrations as determined using the nonspecific antiserum 2135 were 87 ± 10 pmol/l [GLP-1-(7
37)]
and 93 ± 6 pmol/l [GLP-1-(7
37)].
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Gastric emptying.
With placebo, gastric volume declined over 120 min to a residual value
of 54 ± 18 ml, with half-emptying occurring at 45-60 min. Under
the influence of exogenous GLP-1-(736) amide, gastric emptying was
dose dependently decelerated (Fig. 2). Even
the lowest dose studied, 0.4 pmol · kg
1 · min
1,
significantly slowed gastric emptying. Effects of GLP-1-(7
37) were
similar to those of GLP-1-(7
36) amide. With the highest dose, gastric
contents remained at
250 ml 240 min after the meal was instilled.
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Plasma glucose.
The liquid test meal caused an increment in plasma glucose with placebo
(Fig. 3,
top). With GLP-1-(736) amide or
-(7
37), glucose concentrations started to decline when the exogenous
(intravenous) administration was initiated. Also, meal-related
increments in glycemia were reduced or abolished, respectively,
depending on the dose of GLP-1 administered (Fig. 3).
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Insulin secretory responses.
Insulin and C-peptide increased during the infusion of GLP-1-(736)
amide (starting at -30 min) or, in the placebo experiment, after the
liquid meal was instilled (0 min) (Fig. 3). Meal-related increments in
insulin and C-peptide (from 29 ± 2 to 325 ± 78 pmol/l at 45 min and
from 0.42 ± 0.04 to 1.45 ± 0.16 nmol/l at 60 min, respectively,
with placebo), however, were reduced rather than enhanced by the
simultaneous administration of GLP-1. GLP-1-(7
37) was as
effective as GLP-1-(7
36) amide. This reduction in meal-related integrated increments (Table 2) was
significant in the case of insulin responses
(P = 0.01) but not for C-peptide
measurements (P = 0.19). However,
C-peptide responses clearly did not increase because of the
administration of GLP-1. Both insulin and C-peptide tended to remain
elevated by the end of the experiments with the highest doses of
GLP-1-(7
36) amide and -(7
37) but returned to basal levels
with 0.4 and 0.8 pmol · kg
1 · min
1
GLP-1-(7
36) amide (Fig. 3). Integrated insulin secretory responses (Fig. 4) also showed a preprandial
stimulation but a trend to a postprandial reduction due to GLP-1
(P = 0.10).
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Pancreatic glucagon.
In the placebo study, there was a clear meal-related response of
glucagon (Fig. 1, bottom). Exogenous
GLP-1 dose dependently reduced glucagon before the liquid test meal was
instilled (30 to 0 min) and blunted meal-related increments.
Symptoms. In some volunteers, abdominal discomfort was reported during the high-dose GLP-1 infusions, typically at time points when phenol red was mixed with gastric contents.
Gastric chloride secretion. Chloride output increased after the intragastric instillation of the liquid meal (Fig. 5). A rapid increment was followed by a more sustained stimulation. With GLP-1, the early chloride output was reduced. This, however, was significant only for the lowest dose (P = 0.02). Later in the time course, chloride output was enhanced by GLP-1. At these time points, more gastric content was present when GLP-1 was administered (Fig. 2).
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DISCUSSION |
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The physiological incretin role for GLP-1 was deduced from experiments
showing glucose-dependent stimulation of insulin secretion in perfused
pancreas models (24) and in humans (15, 19), to whom glucose was
administered together with GLP-1 in doses leading to
close-to-physiological plasma concentrations. More recently, insulin
responses to oral (29) or intraduodenal (14) glucose in rats were shown
to be reduced by a specific GLP-1 receptor antagonist, exendin-(939).
Experiments in humans to explore effects of exogenous GLP-1
administered together with a meal have been reported only in type 2 diabetic patients (31) or have not specifically examined the
consequences of decelerated gastric emptying on postprandial glucose,
insulin, and glucagon responses (3, 8, 9, 18).
The present results demonstrate that GLP-1-(736) amide and -(7
37)
have a similar, profoundly inhibitory effect on gastric emptying of a
liquid mixed test meal in healthy, normoglycemic volunteers (Fig. 2)
and that the effect of GLP-1 on gastric emptying is dose dependent and
highly significant also, with physiological concentrations
~25 pmol/l (Figs. 1 and 2). In the present study GLP-1-(7
36) amide
concentrations after intragastric instillation of a liquid test meal
were only ~12 pmol/l, but in previous experiments involving normal
mixed meals, but using the same assay methodology [antiserum
89390 (25, 26)], postprandial GLP-1-(7
36) amide concentrations
were stimulated to 21 ± 4 pmol/l with the same test meal in type 2 diabetic patients (31). This shows that the plasma level of GLP-1
achieved by the lowest infusion rate of GLP-1-(7
36) amide (0.4 pmol · kg
1 · min
1),
in line with previous studies (15, 19), is similar to approximately postprandial increments in GLP-1-(7
36) amide plasma
concentrations. Therefore, like cholecystokinin (17), GLP-1-(7
36)
amide seems to effectively decelerate gastric emptying even at
physiological plasma concentrations.
Because the dye-dilution technique used in the present experiments measures only gastric volume and not duodenal delivery, differences in intragastric volume curves could be the result of differences in gastric juice secretion during the experiments. GLP-1 has been shown to reduce pentagastrin-stimulated gastric acid secretion (22, 28). A priori, increasing doses of GLP-1 would be expected to decrease intragastric volume rather than the opposite. Therefore, the differences in the gastric volume (Fig. 2) can mainly be ascribed to effects on gastric emptying, which, if anything, are likely to be somewhat underestimated. On the basis of chloride secretion rates (Fig. 5), there were only marginal changes in gastric acid secretion due to GLP-1 administration. Therefore, the differences in gastric volume observed (Fig. 2) can mainly be ascribed to effects on gastric emptying itself.
In contrast to experiments with subcutaneous administrations of GLP-1, which lead to a short-lived elevation of GLP-1 plasma levels (8), the deceleration of gastric emptying with intravenous GLP-1 lasts as long as plasma GLP-1 concentrations are elevated, both in type 2 diabetic patients (31) and in healthy subjects (this study).
In line with previous studies (15, 19), there was a significant and dose-related effect of exogenous GLP-1 on insulin (Figs. 3 and 4) and glucagon (Fig. 1, bottom) concentrations in fasting normal subjects, leading to a reduction in fasting glycemia. Again, this produced no clinical hypoglycemia, even at pharmacological doses. Surprisingly, however, postprandial insulin and glucagon responses were unchanged or diminished by the administration of GLP-1, and not enhanced, as would be expected for an incretin hormone (2). This is most likely explained by the inhibition of gastric emptying (Fig. 2), which slows the transit of nutrients into the duodenum and jejunum, where the absorption of glucose, fructose, and amino acids takes place, as is clearly illustrated by plasma glucose concentrations that remained below basal levels in all experiments involving exogenous GLP-1 (15, 19). Because the mechanism of GLP-1's insulinotropic effect is to potentiate substrate-induced secretion, it is understandable that the insulin response decreased despite increased GLP-1 concentrations.
If one accepts the conditions of this study (a liquid mixed meal) as
physiological, the results challenge a physiological incretin role for
GLP-1. Because there are differences in the regulation of gastric
emptying of liquid and solid meal components, which may be
differentially affected by agents that regulate the velocity of
emptying, the present results should be reproduced with a meal also
containing solid components. However, in the study by Gutniak et al.
(9), even with a normal test meal, reduced meal-related insulin and
glucagon responses were described in normal volunteers receiving an
intravenous infusion of 0.75 pmol · kg1 · min
1
GLP-1-(7
36) amide. In their study, gastric emptying was not measured
directly.
Because with nutrients administered into the lower small intestinal lumen inhibitory effects on upper gastrointestinal functions [e.g., gastric emptying, antro-duodenal motility, exocrine pancreatic secretion (16)] have been documented, the main physiological role for GLP-1 may be participation in the "ileal brake" mechanism (16). This would also be more compatible with its main localization, the ileum and colon/rectum (6). The importance of the other incretin hormone, GIP, would then be strengthened by the present results (15, 19). GIP, in contrast to GLP-1, does not inhibit but rather accelerates gastric emptying slightly (5). Furthermore, physiological replacement doses of GIP in healthy human subjects almost reproduce insulin secretory responses during physiological hyperglycemia to levels observed after oral glucose stimulation (19).
There has been concern about the almost total inhibition of gastric
emptying caused by exogenous GLP-1-(736) amide (1.2 pmol · kg
1 · min
1)
in type 2 diabetic patients (31). It could be extrapolated that, during
attempts to reduce glycemia through the insulinotropic and
glucagonostatic actions of GLP-1, nutritional problems or side effects
could be caused by the inhibitory actions of GLP-1 on gastric emptying
if pharmacological concentrations are maintained throughout the day.
The present results show that a reduction in therapeutic plasma levels
to those achieved by an infusion rate of 0.8 pmol · kg
1 · min
1
leads to nearly complete gastric emptying after 240 min (Fig. 2).
Because 1.0 to 1.2 pmol · kg
1 · min
1
GLP-1-(7
36) amide or -(7
37) infused intravenously completely normalized fasting hyperglycemia in type 2 diabetic patients within 3-4 h in recent studies (21, 31), a slight reduction in dosage to
0.8 pmol · kg
1 · min
1
can still be assumed to be effective. It may be suggested that the
partial inhibition of gastric emptying observed with this dose may add
to the therapeutic effectiveness of GLP-1, because slowing nutrient
entry into the circulation by dietary measures or
-glucosidase
inhibition is an established principle in the therapy of type 2 diabetic patients.
In conclusion, the present study demonstrates
1) a dose-dependent inhibitory
effect on gastric emptying of a liquid mixed meal by exogenous GLP-1
in healthy volunteers that was similar in magnitude for
GLP-1-(736) amide and -(7
37).
2) At all GLP-1 plasma
concentrations studied, including a physiological replacement dose,
meal-related insulin secretory responses were diminished rather than
enhanced, emphasizing GLP-1's functions as one of the hormones of the
ileal brake mechanism.
3) It should be carefully studied
whether GLP-1 may be administered as a therapeutic agent in type 2 diabetic patients during meal ingestion. It must be made certain that
the dosage and plasma levels are in the range that leads to only a
partial inhibition of gastric emptying.
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ACKNOWLEDGEMENTS |
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The excellent technical assistance of S. Richter, T. Gottschling, K. Faust, L. Rabenhøj, and L. Albaek, and the secretarial assistance of I. Andreae, are gratefully acknowledged.
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FOOTNOTES |
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This study was supported by the Deutsche Forschungsgemeinschaft, Bonn 2 (Bad Godesberg) Grant 203/2-2, the Danish Medical Research Council, and Eli Lilly and Co.
Address for reprint requests: M. Nauck, Dept. of Medicine, Ruhr-Univ. Bochum, Knappschafts-Krankenhaus, In der Schornau 23-25, 044892 Bochum, Germany.
Received 25 February 1997; accepted in final form 24 July 1997.
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