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1 Division of Surgery, Danderyd Hospital, Karolinska Institutet, SE-182 88; Departments of 2 Gastroenterology and Hepatology, 3 Radiology, and 4 Nuclear Medicine, Karolinska Hospital, 171 76 Stockholm, Sweden; and 5 Department of Medical Physiology, University of Copenhagen, Copenhagen, DK-1017 Denmark
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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The aim of
the present study was to assess the effect of glucagon-like peptide-1
(GLP-1) on solid gastric emptying and the subsequent release of
pancreatic and intestinal hormones. In eight men [age 33.6 ± 2.5 yr, body mass index 24.1 ± 0.9 (means ± SE)], scintigraphic solid gastric emptying during infusion of GLP-1 (0.75 pmol · kg
1 · min1)
or saline was studied for 180 min. Concomitantly, plasma concentrations of C- and N-terminal GLP-1, glucose, insulin, C-peptide, glucagon, and
peptide YY (PYY) were assessed. Infusion of GLP-1 resulted in a
profound inhibition of both the lag phase (GLP-1: 91.5, range 73.3-103.6 min vs. saline: 19.5, range 10.2-43.4 min) and
emptying rate (GLP-1: 0.34, range 0.06-0.56 %/min vs. saline:
0.84, range 0.54-1.33 %/min; P < 0.01 for both) of solid gastric emptying. Concentrations of both
intact and total GLP-1 were elevated to supraphysiological levels.
Plasma glucose and glucagon concentrations were below baseline during
infusion of GLP-1 in contrast to saline infusion, where concentrations
were elevated above baseline (both P < 0.001). The insulin and C-peptide responses were lower during infusion with GLP-1 than with saline
(P < 0.004 and
P < 0.001, respectively). Plasma PYY
concentrations decreased below baseline during GLP-1 infusion in
contrast to saline, where concentrations were elevated above baseline
(P = 0.04). Infusion of GLP-1 inhibits solid gastric emptying with secondary effects on the release of insulin, C-peptide, and glucagon, resulting in lower plasma glucose concentrations. In addition, the release of PYY into the circulation is
inhibited by GLP-1 infusion, suggesting a negative feedback of GLP-1 on
the function of the L-cell.
glucagon-like peptide-1; peptide YY; radionuclide; ileal break; gut peptides
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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GLUCAGON-LIKE
PEPTIDE-1-(7
36)
AMIDE (GLP-1) is a peptide of 30 amino acids produced in and
secreted from L-cells of the intestinal mucosa into the circulation
after intake of a mixed meal (3, 14). GLP-1 has been shown have a wide
range of physiological effects. By exerting a receptor-mediated
insulinotropic action on the pancreatic 
-cell in the postprandial
state, GLP-1 acts as an incretin. GLP-1 also inhibits gastric acid
secretion, and it has been shown that peptide YY (PYY), which is
colocalized with GLP-1 in the L-cells of the gut, has an additive
inhibitory effect on acid secretion (36). In addition, GLP-1 has been
shown to inhibit food intake on intracerebroventricular injection in animal models (33) and after intravenous infusion in normal-weight (9)
and obese humans (24).
Several of the proposed effects of GLP-1 in human physiology seem to depend on the peptide's ability to inhibit gastric emptying. In a recent study it was shown that the net effect of GLP-1 administered in conjunction with a meal was inhibition of gastric emptying and, as a further consequence, blunted meal-related insulin responses (22). Similarly, gastric emptying was delayed in a study demonstrating decreased feelings of hunger after administration of GLP-1 (23). Thus one way by which GLP-1 decreases appetite might be by increased gastric satiety signals, which may be a result of the decreased rate of gastric emptying. Although there is no "gold standard" for assessing gastric emptying, scintigraphic studies are often considered "best" for the assessment of solid gastric emptying (20, 28). Previous studies on the gastric inhibitory effect of GLP-1 have used different methods to assess liquid gastric emptying, such as paracetamol absorption, dye dilution and other liquid markers (11, 22, 29, 37, 38), and solid gastric emptying by 13C-labeled octanoic acid breath test (30).
The aim of the present study was to assess the effect of GLP-1 on the different phases of solid gastric emptying. Because GLP-1 and PYY are colocalized in the L-cells, a second aim was to study if exogenous administration of GLP-1 influences the secretion of PYY into the circulation.
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SUBJECTS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects. Eight healthy men [age 33.6 ± 2.5 yr, body mass index 24.1 ± 0.9 (means ± SE)] were recruited for this study. The Ethics and Radiation Protection Committees of the Karolinska Hospital approved the study, and informed consent was obtained from each subject.
Study protocol. The study was
performed in a randomized crossover fashion on two occasions, 1 wk
apart. The subjects were studied after an overnight fast at 8:00 in the
morning, and an indwelling catheter was placed in each antecubital
vein. Simultaneously with the intake of a
99mTc-labeled omelet, either GLP-1
(0.75 pmol · kg1 · min1;
Bachem AG, Bubendorf, Switzerland) dissolved in 0.9% saline containing
1% albumin (Albumin Kabi, 200 mg/ml), subjected to sterile filtration,
and stored at 
20°C until use or saline was started in one of
the intravenous catheters and continued for 180 min.
Scintigraphic gastric emptying. The scintigraphic gastric emptying test of a solid meal has been described in detail elsewhere (10), and the present technique differs only in that water and not fruit punch was served with the meal. In short, subjects fasted overnight were studied after ingesting a 310-kcal omelet with 12-15 MBq 99mTc-labeled macroaggregated albumin (Pulmonate; Amersham International, Little Chalfont, UK). Anterior and posterior 1-min acquisitions were performed with the subject in sitting position. Acquisitions were obtained every 5 min during the first 50 min and thereafter every 10 min during 70 min and finally at 180 min.
The following parameters were calculated: 1) lag phase, defined as the time period from termination of meal until 90% of radioactivity remained in the stomach; 2) gastric emptying rate, defined as percentage of radioactivity per minute during the linear slope after termination of the lag phase; and 3) half-emptying time (T50), defined as the time for 50% emptying of gastric radioactivity after termination of the meal.
During infusion with saline, there was a biphasic release of GLP-1. C-terminal GLP-1 data for each individual were assessed by two independent observers, and the time of the first and second elevation of plasma GLP-1 concentrations was identified. The anatomical location for the leading edge of the meal was then assessed in the scintigraphic frame corresponding to the exact time of the elevation of plasma C-terminal GLP-1 in each individual.
Blood samples and RIAs. The blood
samples were collected in prechilled heparinized tubes for the analysis
of glucose, insulin, C-peptide, C- and N-terminal GLP-1, PYY, and
glucagon 20 and 10 min before intake of the
99mTc-labeled omelet and then at
the same time intervals as the scintigraphic acquisitions. The samples
were centrifuged at 4°C for 10 min at 2,000 g. Plasma was collected and stored at
20°C for analysis in one series.
Glucose was analyzed by an enzyme assay (mutarotase and glucose dehydrogenase; Boeringer-Mannheim, Mannheim, Germany) with a Hitachi 917 automatic analyzer.
Insulin was analyzed with an enzyme immunoassay (DAKO Insulin Kit K6219, Copenhagen, Denmark). The assay cross-reacts to 0.3% with proinsulin but not with C-peptide. The detection limit of the assay was 21 pmol/l, and the coefficient of variation was 8%.
C-peptide concentrations in plasma were determined by a RIA (Euro-Diagnostica, Malmö, Sweden). The assay cross-reacts to 41% with proinsulin but not with insulin. The detection limit was 50 nmol/l, and the coefficient of variation was 5%.
GLP-1-like immunoreactivity (GLP-LI) in plasma was studied with RIAs
specific for each terminus of the molecule. N-terminal immunoreactivity
was measured with a newly described antiserum (12) raised in rabbits
against synthetic proglucagon-(7887) with a C-terminal cysteine
coupled to keyhole limpet hemocyanin by means of the cystein thiol
method. The selected antiserum (code 93242) was used in a final
dilution of 1:15,000, endowing the assay with a detection limit of 5 pmol/l. The antiserum has a cross-reactivity of ~10% with
GLP-1-(136) amide and 0.1% with GLP-1-(836) amide and
GLP-1-(936) amide. HPLC supports the use of RIA with this specificity
to measure concentrations of intact GLP-1 (4). C-terminal
immunoreactivity was measured using antiserum 89390 (26), which has an
absolute requirement for the intact amidated C-terminus of GLP-1-
(736) amide and cross-reacts to <0.01% with truncated fragments
and to 83% with GLP-1-(936)amide. For both assays the coefficient of
variation was <6%. GLP-1-(736) amide was used as standard, and
125I-labeled GLP-1-(736) amide
was used as tracer. Before analysis, plasma was extracted with 70%
ethanol (vol/vol, final concentration) before assay, giving recoveries
of 75%. Separation was achieved using plasma-coated charcoal.
PYY-LI was analyzed by means of antiserum code no. 8412-2II (a
gift from R. Håkanson, Dept. of Pharmacology, University of Lund,
Lund, Sweden) raised in rabbits against synthetic porcine PYY-(136)
(Peninsula Europe, Merseyside, UK) as previously described (15) but
without conjugation to carrier protein (7). The antiserum cross-reacts
to 100% with human PYY. The detection limit of the assay was 1 pmol/l,
and the coefficient of variation was 5%.
Glucagon-LI was assayed by means of a previously described RIA technique. The glucagon assay is directed against the C-terminus of the glucagon molecule (antibody code no. 4305) and therefore measures glucagon of mainly pancreatic origin (13). The detection limit of the assay was 1 pmol/l, and the coefficient of variation was 5%.
Statistics and calculations. All
values are means ± SE or median (range), as appropriate, and
P < 0.05 was considered
statistically significant. The gastric lag phase, linear emptying rate,
and T50 were
statistically evaluated by means of Wilcoxon's signed rank test for
matched pairs. The gastric emptying curve and plasma concentrations of
C- and N-terminal GLP-1 were analyzed by employing an ANOVA for
repeated, paired measures, with time and treatment as factors. For
glucose, insulin, C-peptide, PYY, and glucagon the changes from
baseline were calculated by using the mean fasting value (20,
10, and 0 min), and then the results were analyzed with an ANOVA
for repeated, paired measures, with time and treatment as factors.
Baseline concentrations during saline and GLP-1 infusions were compared
by means of an ANOVA.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Gastric emptying. Infusion of GLP-1
resulted in a profound inhibition of the lag phase, emptying rate, and
T50 of solid
gastric emptying compared with infusion with saline (Figs.
1 and 2; Table 1; P < 0.001 for time effect, treatment effect, and time × treatment interaction effect, respectively). At the end of the study, 180 min
after intake of the omelet, 64.8 ± 6.4 and 6.1 ± 3.5% of the activity remained in the stomach during infusion of GLP-1 and saline,
respectively.
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Anatomical location of meal and release of
GLP-1. There was a bimodal peak of C-terminal GLP-1
secretion after the meal (Fig. 3). In
individual subjects, the first and second elevation of plasma
C-terminal GLP-1 occurred 15-45 and 50-100 min, respectively, after meal ingestion. The location of the leading edge of the meal was
proximal jejunum at the first elevation of plasma C-terminal GLP-1 and
ileum at the second elevation of plasma GLP-1. Data for individual
subjects are presented in Table 2, and the
scintigraphic pictures for one representative subject are presented in
Fig. 4.
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Plasma GLP-1 concentrations. Infusion
of GLP-1 at 0.75 pmol · kg1 · min1
resulted in significantly elevated plasma concentrations of both C- and
N-terminal GLP-1 (Fig. 5;
P < 0.003 for time effect, treatment effect, and time × treatment interaction effect, respectively, for C- and N-terminal GLP-1 concentrations).
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Plasma glucose, insulin, C-peptide, and
glucagon
concentrations. Baseline plasma
glucose concentrations were 5.2 ± 1.0 and 5.2 ± 1.5 mmol/l
before GLP-1 and saline infusion, respectively. Postprandial glucose
concentrations were significantly lower during GLP-1 infusion than
during saline infusion (P < 0.001 for time effect, P = 0.007 for
treatment effect, and P < 0.001 for
time × treatment interaction effect; Fig.
6).
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Baseline plasma insulin concentrations were 7.2 ± 1.8 and 7.3 ± 1.3 mU/l before GLP-1 and saline infusion, respectively. Postprandial insulin levels were significantly lower during GLP-1 infusion than during saline infusion (P = 0.03 for time effect, P = 0.01 for treatment effect, and P < 0.004 for time × treatment interaction effect; Fig. 6).
Baseline plasma C-peptide concentrations were 0.74 ± 0.14 and 0.76 ± 0.13 nmol/l before GLP-1 and saline infusion, respectively. Postprandial C-peptide concentrations were lower during GLP-1 infusion than during saline infusion (P < 0.001 for time effect, P = 0.004 for treatment effect, and P < 0.001 for time × treatment interaction effect; Fig. 6).
Baseline plasma glucagon concentrations were 27.7 ± 1.0 and 26.0 ± 1.5 pmol/l before GLP-1 and saline infusion, respectively. Postprandial glucagon concentrations were lower during GLP-1 infusion than during saline infusion and were reduced to under baseline values during GLP-1 infusion (P = 0.03 for time effect, P = 0.006 for treatment effect, and P < 0.001 for time × treatment interaction effect; Fig. 6).
Plasma PYY. Baseline PYY
concentrations were not significantly different before GLP-1 and saline
infusion (7.3 ± 1.9 and 4.8 ± 1.9 pmol/l, respectively).
Treatment with GLP-1 resulted in decreased plasma PYY concentrations to
levels below baseline and different from concentrations obtained during
saline infusion (P = 0.18 for time effect, P = 0.04 for
treatment effect, and P = 0.35 for
time × treatment interaction effect; Fig.
7).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
SUBJECTS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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This study demonstrates that GLP-1 has a powerful inhibitory effect on solid gastric emptying in man. Previous studies show that GLP-1 administered intravenously, subcutaneously, and as buccal tablets inhibits gastric emptying of a liquid meal (11, 22, 29, 37, 38) and that subcutaneous GLP-1 administered as one dose 20 min after a meal inhibits the lag phase of solid gastric emptying (30). Our present study extends these observations to the emptying of a standard solid meal during continuous intravenous administration of GLP-1 and demonstrates that both phases of solid gastric emptying are inhibited by GLP-1 during intravenous administration. Both the gastric lag phase and the linear emptying rate were retarded, resulting in a markedly prolonged T50 with GLP-1 compared with saline infusion. This slowing of gastric emptying seems to be in effect during the whole infusion period up to 3 h, as indicated by the constant reduction of emptying rate.
GLP-1 exhibits incretin properties (17, 18, 21, 34) and has been shown
to stimulate insulin secretion and inhibit glucagon secretion (8, 25).
In the present study, infusion of GLP-1 at supraphysiological
concentrations resulted in an early reduction of postprandial plasma
glucose along with decreased plasma glucagon concentrations. In
addition, there is a marked inhibition of gastric emptying. Thus the
observed reduced postprandial plasma insulin and C-peptide
concentrations during GLP-1 infusion are most likely the result of
falling plasma glucose concentrations and a decreased stimulation of
insulin release caused by an inhibited delivery of nutrients into the
duodenum and jejunum with reduced preabsorptive bioavailability.
Further studies with a GLP-1 antagonist, such as exendin (939)amide,
are needed to fully elucidate the effect of GLP-1 on glucose disposal
and metabolic control in the postprandial state.
This study demonstrates that there is a continuous recruitment of GLP-1-releasing cells after a meal, with a first elevation of plasma GLP-1 corresponding to the point when the leading edge of the meal reaches the proximal jejunum. The GLP-1 secreting L-cells are most abundantly found in the lower gut (ileum to rectum) (6), which is consistent with our finding of a second elevation of plasma GLP-1 as the meal reaches the ileum. Administration of nutrients into the lower gut has been shown to inhibit upper gastrointestinal functions, the so-called ileal brake mechanism (31). Thus the main physiological role for GLP-1 may be to contribute to the ileal brake on gastrointestinal motility, which in turn results in decreased plasma glucose concentrations as a result of a slower and more sustained delivery of nutrients into the upper gut from the stomach. This effect seems to be mediated via vagal afferent-mediated central mechanisms as shown in the rat (16).
At least a subpopulation of the GLP-1-secreting L-cells also contains and releases PYY (2). PYY and GLP-1 have been shown to exert similar effects on upper gastrointestinal function in several species, including man (1, 35), and have an additive inhibitory effect on gastric acid secretion (3). Like GLP-1, PYY secretion may be stimulated by the presence of nutrients in the gut lumen. The lower plasma concentrations observed in the present study may thus be secondary to the decreased exposure of the gut to nutrients during the GLP-1 infusion. However, the fact that plasma PYY concentrations actually decreased below basal concentrations during GLP-1 infusion suggests that GLP-1 may have a direct inhibitory effect on the release of PYY. Thus our data may reflect a negative feedback of GLP-1 on the function of the L-cells.
GLP-1 has been tried as a novel therapeutic for the treatment of
non-insulin-dependent diabetes mellitus (NIDDM) (32). There has,
however, been concern that the inhibitory effect of the peptide on
gastric functions may result in gastrointestinal side effects and
nutritional problems when the peptide is given at high doses (1.2 pmol · kg1 · min1).
When GLP-1 is infused at a rate of 0.8 pmol · kg1 · min1,
gastric emptying of a liquid meal is nearly complete after 240 min
(22). For comparison, the present study demonstrates that only 40% of
a solid meal is emptied after 180 min during infusion of GLP-1 at 0.75 pmol · kg1 · min1.
Thus the inhibitory effect of GLP-1 on gastric emptying seems more
profound for a solid than for a liquid meal. The plasma concentrations of C-terminal GLP-1 [comprising both intact GLP-1 and its primary metabolite, GLP-1-(936) amide (4)] are 40-80% higher than those seen under physiological conditions (27), indicating that the
infusion rate slightly exceeded the postprandial secretory rate. The
plasma concentrations of N-terminal GLP-1 (comprising exclusively the
intact, biologically active peptide) were also slightly above
postprandial levels (4) but similar to the plasma concentrations
required to normalize plasma glucose concentrations in patients with
NIDDM (5). The long-term effect of a profound inhibition of solid
gastric emptying as seen with GLP-1 is unknown. In terms of nausea,
infusion of GLP-1 during 8 h at the same rate as in the present study
did not result in nausea (23), and a continuous infusion at the rate of
1.2 pmol · kg1 · min1
for 1 wk did not result in any gastrointestinal side-effects or
diminished biological response (19).
In conclusion, our study demonstrates that intravenous administration of GLP-1 is a powerful inhibitor of gastric emptying in man, with secondary effects on the release of insulin, C-peptide, and glucagon, most likely through the inhibitory action of GLP-1 on gastric emptying resulting in lower plasma glucose concentrations. In addition, GLP-1 also seems to act on more distal parts of the gut as the release of PYY, which is colocalized with GLP-1 in the L-cells of the intestinal mucosa, is inhibited, suggesting a negative feedback mechanism.
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ACKNOWLEDGEMENTS |
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This study was supported by grants from the Swedish Medical Research Council (nos. 7916 and 13150), the Danish Medical Research Council, the Foundations of the Karolinska Institutet, the Professor Nanna Svartz Foundation, the Magnus Bergvall Foundation, the Tore Nilsson Foundation, the Ruth and Richard Juhlin Foundation, and the AMF-sjukförsäkrings Jubilée Foundation for Research in National Diseases.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: E. Näslund, Dept. of Surgery, Danderyd Hospital, SE-182 88 Danderyd, Sweden (E-Mail: Erik.Naslund{at}kir.ds.sll.se).
Received 26 February 1999; accepted in final form 21 May 1999.
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SUBJECTS AND METHODS
RESULTS
DISCUSSION
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) or saline (
) for 180 min.
P < 0.001 for time effect,
treatment effect, and time × treatment interaction effect,
respectively (ANOVA with repeated measures).
