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Research Department of Human Nutrition, Centre for Food Research (C.V., A.F., A.A.), The Royal Veterinary and Agricultural University, DK-1958 Frederiksberg C, Denmark; Division of Surgery, Karolinska Institute (E.N.), Danderyd Hospital, SE-182 88 Daderyd, Sweden; School of Biological Science (S.J.L., L.M.M.), University of Surrey, Guildford GU2 5XH, United Kingdom; Division of Gastroenterolgy (J.-P.G., C.B.), University Hospital, CH-4031 Basel, Switzerland; Department of Gastroenterology and Hepatology (P.M.H.), Karolinska Hospital, SE-171 76 Stockholm, Sweden; and Department of Medical Physiology, The Panum Institute (J.J.H.), University of Copenhagen, DK-2200 Copenhagen N, Denmark
Address all correspondence and requests for reprints to: Prof. Arne Astrup, Research Department of Human Nutrition, The Royal Veterinary and Agricultural University, Rolighedsvej 30, DK-1958 Frederiksberg C, Denmark. E-mail: ast{at}kvl.dk
Abstract
Seven studies have now been published pertaining to the acute effect of iv administration of glucagon-like peptide-1 (7–36) amide on ad libitum energy intake. In four of these studies energy intake was significantly reduced following the glucagon-like peptide-1 infusion compared with saline. In the remaining studies, no significant effect of glucagon-like peptide-1 could be shown. Lack of statistical power or low glucagon-like peptide-1 infusion rate may explain these conflicting results.
Our aim was to examine the effect of glucagon-like peptide-1 on subsequent energy intake using a data set composed of subject data from previous studies and from two as yet unpublished studies. Secondly, we investigated whether the effect on energy intake is dose dependent and differs between lean and overweight subjects.
Raw subject data on body mass index and ad libitum energy intake were collected into a common data set (n = 115), together with study characteristics such as infusion rate, duration of infusion, etc. From four studies with comparable protocol the following subject data were included if available: plasma concentrations of glucagon-like peptide-1, subjective appetite measures, well-being, and gastric emptying rate of a meal served at the start of the glucagon-like peptide-1 infusion.
Energy intake was reduced by 727 kJ (95% confidence interval, 548–908 kJ) or 11.7% during glucagon-like peptide-1 infusion. Although the absolute reduction in energy intake was higher in lean (863 kJ) (634–1091 kJ) compared with overweight subjects (487 kJ) (209–764 kJ) (P = 0.05), the relative reduction did not differ between the two groups (13.2% and 9.3%, respectively). Stepwise regression analysis showed that the glucagon-like peptide-1 infusion rate was the only independent predictor of the reduction in energy intake during glucagon-like peptide-1 (7–36) amide infusion (r = 0.4, P < 0.001). Differences in mean plasma glucagon-like peptide-1 concentration on the glucagon-like peptide-1 and placebo day (n = 43) were related to differences in feelings of prospective consumption (r = 0.40, P < 0.01), fullness (r = 0.38, P < 0.05), and hunger (r = 0.26, P = 0.09), but not to differences in ad libitum energy intake. Gastric emptying rate was significantly lower during glucagon-like peptide-1 infusion compared with saline. Finally, well-being was not influenced by the glucagon-like peptide-1 infusion.
Glucagon-like peptide-1 infusion reduces energy intake dose dependently in both lean and overweight subjects. A reduced gastric emptying rate may contribute to the increased satiety induced by glucagon-like peptide-1.
THE INTESTINAL HORMONE glucagon-like peptide-1 (GLP-1), released in response to food intake, has been proposed to act as a regulator of postprandial satiety (1, 2). In animal studies, acute administration of GLP-1 directly into the cerebrospinal fluid has been shown to reduce subsequent food intake (3, 4).
The acute effect of iv GLP-1 administration to humans has been studied by several groups (1, 5, 6, 7, 8, 9, 10). In four of these studies GLP-1 was found to produce a significant, and relatively large (10–32%), reduction in energy intake compared with saline (1, 6, 8, 9). In all of the remaining studies energy intake tended to be lowered following GLP-1 infusion (0.1–7%) (5, 7, 10). Differences in infusion rate, duration of infusion before the ad libitum meal, preload, or subject characteristics might explain these inconsistent findings.
To our knowledge, only one study has been performed in which appetite has been measured in subjects given GLP-1 over a longer period of time (11). In this study, GLP-1 was administered to six type II diabetic patients by a continuous sc infusion over a period of 48 h, during which food intake was fixed. There was, however, a tendency to a reduction in hunger and prospective consumption and an increase in satiety during the GLP-1 infusion (11). These findings suggest that continuous administration of GLP-1 to type II diabetics might serve two treatment purposes: 1) to increase insulin secretion and hereby improve blood glucose regulation (11, 12, 13, 14); and 2) to reduce food intake and to aid intended weight loss.
The aim of the present study was 1) to examine the overall effect of GLP-1 on energy intake on the basis of a data set composed of subject data from the seven previously published studies as well as from two as yet unpublished studies, and 2) to investigate whether the effect on energy intake is dose dependent and/or differs between lean and overweight subjects. Furthermore, the relationship between differences in mean plasma concentration of GLP-1 and subjective sensations of hunger, prospective food consumption, and fullness were assessed using raw data from three of the studies with comparable protocols (1, 6, 10). Finally, data on gastric emptying rate from two of these studies (6, 10) were also included in the analysis.
Materials and Methods
Selection of studies
A Medline search was performed to identify all studies pertaining to the effect of iv GLP-1 infusion on subsequent food intake in humans. The following search words were used in combination: GLP-1 or glucagon-like peptide-1 and energy intake or food intake or appetite or satiety from 1966 to 2000. From this search 67 studies pertaining to humans were found. Six studies were selected as being suitable for the present meta-analysis (1, 5, 6, 7, 8, 9). One study involving GLP-1 administration was excluded because it differed markedly from the other studies. In this study, GLP-1 was administrated sc to type II diabetics during a 48-h period with fixed energy intake (11). Data from two unpublished studies performed by Christoph Beglinger et al. (unpublished results) and one study performed at our own institute (10) were included in the analysis.
Design of selected studies
All of the selected studies were randomized cross-over studies with iv infusion of either GLP-1 or placebo during an ad libitum meal. In one of the studies a 5% glucose solution was given as placebo (8) whereas saline was given in the remaining studies. The duration of infusion before the ad libitum meal varied from 0 to 240 min. In two of the studies infusion was stopped for 30 min before the ad libitum meal and resumed at the beginning of the meal (1, 10), whereas in the other studies the infusion was not disrupted. In the study where the ad libitum meal was served at the beginning of the infusion all subjects were fasting before the meal (5). In six studies a fixed preload meal (1.4–3.0 MJ) was served 4–6 h before the ad libitum meal (Refs. 1, 6, 7, 9 , and 10 ; Beglinger et al., unpublished results). In the last study, subjects were asked to eat their usual breakfast at home (8). In addition, 36 subjects followed a weight-maintaining standardized diet for 2 days before the examination (1, 10). The rate of infusion per kilogram of body weight was equal for all subjects within all studies, except one (10). In this study, subjects were given 0.75 pmol fat free mass (kg)-1/min-1, corresponding to a mean infusion rate of 0.5 pmol kg-1 min-1 (range, 0.45–0.52 pmol/kg-1·min-1). In this meta-analysis the mean infusion rate was used in replacement for the infusion rate calculated for each subject.
Collection of data
A letter was sent to the corresponding author of the seven relevant articles informing them about our plans for a meta-analysis and asking them to contribute to this by delivering raw data on the following variables: body mass index (BMI) and ad libitum energy intake on the placebo day and on the GLP-1 day.
The four studies by Näslund et al. (5, 6) and Flint et al. (1, 10) were selected for further analysis, as they followed comparable protocols with infusion lasting 3–4 h. In these studies appetite measures were assessed by the use of visual analog scales (VAS) throughout the infusion. Furthermore, plasma concentrations of GLP-1 were assessed in the same laboratory in three of the studies (1, 6, 10), and gastric emptying rate was assessed in three of the studies (5, 6, 10). From these studies raw data on gastric emptying, plasma GLP-1 concentration, and VAS scores were collected into a separate data file, together with the rest of the data material from these studies, to investigate the effect of GLP-1 infusion rate and GLP-1 plasma concentrations on gastric emptying, ad libitum energy intake, and VAS scores for appetite measures (hunger, fullness, prospective food consumption).
Statistics
The traditional meta-analysis is made exclusively on summary data that are published in original articles. Typically, the aim of a meta-analysis is to create a systematic overview of the effect of a specific treatment (for instance, the effect of ad libitum intake of low-fat diets on body weight) (15). In this type of meta-analysis the original studies are randomized, placebo-controlled intervention studies, including an intervention group that receives the treatment of the study and a control group either receiving placebo or a conventional treatment. However, studies investigating the physiological effect of a short-term intervention such as the effect of GLP-1 infusion on the subsequent ad libitum energy intake are typically performed as cross-over studies where the subject serves as their own control. The essential parameters in a meta-analysis are the mean and the 95% confidence interval (CI) for the mean difference in the outcome measure between the intervention and the control group. These measures are then weighted according to the size of the study, and an overall mean and 95% CI for all studies is then estimated. When the study is designed as a randomized, placebo-controlled intervention, the mean and the CI for the difference between the two intervention groups is easily estimated from the mean and the CI of the outcome measure for each of the two groups. However, to include cross-over studies in a meta-analysis one needs to include the mean and CI of the within-subject differences between the two treatments. The effect of the treatment is typically tested using a paired sample t test. Most often, however, mean and CI for the outcome measure is reported separately for the two interventions whereas CI for the within-subject difference between the two treatments is not reported in the article, and cannot be calculated from the reported data. Therefore, when performing a meta-analysis including cross-over studies one will need either raw data for all subjects or summary measures of the within-subject differences between the two treatments. Because we were able to obtain raw data from all studies, we decided to perform only an analysis on individual subject data, that is creating a large data set including raw data from all subjects and examining these data as data from a single study using study-specific circumstances such as infusion rate, duration of infusion, size of test meal, or pre load as covariates together with BMI. One of the studies included in this meta-analysis examined the dose-response relationship between GLP-1 infusion rate and reduction in energy intake compared with the placebo. The subjects in this study were subjected to one control infusion of 5% glucose solution and three intervention infusions of GLP-1 of 0.325, 0.75, and 1.50 pmol/kg-1 ·min-1. When including data from this study into the meta-analysis, the same subject and the same control measurements are included three times and the fact that these are repeated measurements was not taken into account. However, because the aim of the present analysis was to examine the dose-response relationship between GLP-1 infusion rate and reduction in ad libitum energy intake, it is obvious that relevant information would be lost if we excluded some of the data. Therefore, we chose to include data from all three infusion rates in the primary analysis, but to repeat the analysis using only data from either the high, medium, or low infusion rate. All statistical procedures in the present meta-analysis were performed using SPSS 10.0 for Windows (SPSS, Inc., Chicago, IL). The relationship between GLP-1 infusion rate and change in ad libitum energy intake compared with the control was tested using bivariate correlation analysis (using Pearson coefficient of correlation) and stepwise linear regression. Data pertaining to the effect of GLP-1 infusion rate or GLP-1 plasma concentration on subjective appetite measures, gastric emptying rate, and reported well-being were analyzed in the same manner.
Subjects
All subjects were male. In five of the studies only healthy lean
subjects (BMI, 20.1–26.9 kg/m2) were included
(Table 1
). Of the remaining four studies,
three included only healthy overweight subjects (BMI, 30.0–51.1
kg/m2), whereas one study was performed on 12
lean and overweight type II diabetics (BMI, 24.2–36.3
kg/m2). For the purpose of examining the effect
of GLP-1 on lean and overweight subjects separately, BMI
was used to divide the subject data into two groups: BMI less than 25
and BMI 25 or greater. One lean subject suffering from type II diabetes
was found to have a higher energy intake (1.3 MJ greater) on the day of
GLP-1 infusion compared with the placebo day. Data from
this subject was included in the overall data analysis, but excluded
when analyzing overweight and lean separately, because the inclusion of
this subject in the lean group could lead to a false conclusion when
comparing the sensitivity toward the hormone between lean and
overweight subjects. Eleven overweight type II diabetics were include
in the analysis with the overweight subjects.
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In three of the included studies (n = 44, but data are missing from one subject in Ref. 10) plasma concentrations of GLP-1 were assessed during the infusion using RIAs specific for both the C- and the N-terminal of the molecule as described previously (1, 6, 10). Here, we only include plasma concentrations assessed by the assay specific for the C-terminal. Two summary measures were calculated and incorporated in the analysis, namely the mean GLP-1 concentration during the time between the preload and the ad libitum meal and the mean concentration during the last hour before the ad libitum meal.
Gastric emptying
In three of the studies gastric emptying was assessed by adding
1.5 g acetaminophen to the preload meal (6, 10) or the ad libitum meal served at the beginning of
the infusion (5). Blood samples were taken every 30 min
during the following 3–5 h to assess the rate of absorption of
acetaminophen, which is known to depend almost exclusively
on the rate of gastric emptying (16, 17). For the purpose
of the present meta-analysis, gastric emptying was estimated by
incremental postprandial area under the curve (AUC) for plasma
acetaminophen, incremental peak value (
peak), and time
to peak for plasma concentrations of acetaminophen, as
described previously (10).
Subjective ratings using VAS
From the three studies measuring plasma concentrations of
GLP-1 during the infusion VAS scores for hunger, fullness,
and prospective food consumption were included in the present analysis.
Additional VAS scores for nausea from one study and well-being from
another study (6, 10) were pooled into a common data set
to assess possible side effects of GLP-1. For appetite
ratings, the numeric difference between the measurement immediately
after ingestion of the preload and immediately before the ad
libitum meal, the -value, was used as the only outcome measure.
For side effects, a mean value for the same period was also included.
As described above, in two of the studies the infusion was stopped for
30 min before the ad libitum meal. The differences in
hunger, fullness, prospective food consumption, well-being
and mean well-being between the 2 test days were calculated as:
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Results
Overall effect of GLP-1 on ad libitum energy intake
When pooling the 147 observations a mean reduction in ad
libitum energy intake of 727 kJ (95% CI, 908–548 kJ)
(P < 0.001) or 11.7% (95% CI, 8.1–15.3%)
(P < 0.001) was seen during GLP-1
infusion compared with the control infusion (Fig. 1). The mean GLP-1
infusion rate for all observations was 0.89
pmol/kg-1·min-1. The
mean ad libitum energy intake during the placebo treatment
was significantly higher in healthy lean subjects (n = 99; 6.4 MJ)
(95% CI, 6.1–6.8 MJ) than in overweight subjects (n = 47; 3.7
MJ) (95% CI, 3.3–4.2 MJ) (P < 0.001). In lean
subjects the mean infusion rate was 0.9
pmol/kg-1·min-1, and
the average reduction in ad libitum intake was 863 kJ (95%
CI, 634-1091 kJ) or 13.2% (95% CI, 9.7–16.7%) (P <
0.001 for both). In merely overweight subjects (n = 36) the mean
infusion rate was 0.67
pmol/kg-1·min-1, and
the reduction in ad libitum intake was, on average, 252 kJ
(95% CI, 15–489 kJ) (P < 0.04) or 4.5% (95% CI,
-5% to 14.0%) (NS). When including data from overweight type II
diabetic subjects (n = 11) the mean infusion rate was 0.86
pmol/kg-1·min-1, and
the reduction in ad libitum intake was, on average, 487
(95% CI, 764–209 kJ) (P = 0.001) or 9.3% (95% CI,
0.8–17.3%) (P < 0.04). Although a difference in
ad libitum energy intake was found between lean and
overweight subjects (P = 0.05), the percentage
reduction in energy intake was similar between the two groups.
Furthermore, when excluding the six subjects for whom the ad
libitum meal was served at the beginning of the infusion
(5) the mean difference in ad libitum energy
intake was 556 kJ (95% CI, 247–865) (P = 0.001) or
10.5% (0.93–20.1%) (P < 0.04) for overweight
subjects (n = 41), which was not significantly different from lean
subjects. Both the absolute and the relative reduction in ad
libitum energy intake was greater for overweight subjects with
noninsulin-dependent diabetes mellitus (NIDDM) compared with merely
overweight subjects (P < 0.05 for both).
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In the overall data set the reduction in ad libitum
energy intake correlated with the GLP-1 infusion rate
(Fig. 2A) (r = 0.40,
P < 0.001). The analysis was repeated including data
from only one of the three infusion rates applied to the subjects in
the dose-response study by Gutzwiller et al.
(8). The strength of the relationship remained when
results obtained during medium and low infusion rates were excluded
(r = 0.46, P < 0.001). However, it was reduced,
but still significant, when the data obtained during the high infusion
rate was excluded (r = 0.21, P = 0.023 when
including data from a medium infusion rate, and r = 0.22,
P = 0.021 when including data from a low infusion
rate). The relationship between infusion rate and reduction in energy
intake in lean subjects was similar to that seen in the overall data
set (r = 0.42, P < 0.001) (Fig. 2B). In the group
of merely overweight subjects no correlation was seen. However, when
including data from overweight type II diabetics, the same correlation
was seen in overweight subjects as in lean subjects (r = 0.47,
P = 0.001) (Fig. 2B). By the SPSS procedure "curve
fitting" it was tested whether the relationship between the
GLP-1 infusion rate and reduction in energy intake was
best described by a linear, logarithmic, inverse, or quadratic model.
In the overall data set, as well as in lean subjects, the fit of the
model was slightly improved by applying the quadratic model compared
with the linear (Table 2). By stepwise
linear regression analysis the GLP-1 infusion rate was
found to be the only independent predictor of the reduction in energy
intake, whereas BMI, duration of infusion, and duration of time between
preload and ad libitum meal did not contribute any further.
This was seen both in the overall data set and in the lean and
overweight subjects. When repeating the analysis with residuals from
the quadratic model describing the relationship between infusion rate
and reduction in ad libitum intake (Table 2) as the
dependent variable neither BMI, duration of infusion, or duration of
time between preload and ad libitum meal turned out
significantly in the stepwise regression analysis (data not shown). In
six of the studies a fixed test meal was served several hours before
the ad libitum meal. Stepwise regression showed no
relationship between the size of the test meal and the reduction in
subsequent ad libitum intake.
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The relationship between plasma GLP-1 concentrations
and subjective measures of appetite was examined in 42 subjects. No
relationship was seen between the difference in ad libitum
energy intake and mean GLP-1 concentration between the 2
test days (neither during the whole period between preload and the
ad libitum meal or during the last hour before the ad
libitum meal). On the other hand, the difference in
GLP-1 concentration between the 2 test days correlated
with the difference in fullness (r = -0.38 P =
0.013) and prospective food consumption (r = 0.40,
P = 0.008) (Fig. 3, A and B) and
tended to correlate with the difference in hunger (r = 0.26,
P = 0.09) (Fig. 3C). Finally, no correlation was found
between difference in ad libitum energy intake and
fullness (r = 0.25 P = 0.09), prospective
food consumption (r = 0.1, P = 0.5), or hunger
(r = 0.1, P = 0.5).
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The studies from which data on gastric emptying was obtained were
all performed on overweight subjects (n = 31). In the pooled data
set, peak and incremental AUC for acetaminophen were
reduced (P < 0.001 for both), and time to peak was
increased (P < 0.01) on the day with
GLP-1 infusion compared with the placebo day. As seen in
Table 3, the reduction in peak and
incremental AUC was much higher in the studies using 0.75
pmol/kg-1·min-1
compared with the study using 0.50
pmol/kg-1·min-1,
suggesting a nonlinear relationship between infusion rate and reduction
in gastric emptying rate. In the 24 subjects for whom plasma
GLP-1 concentrations had been assessed, the difference in
mean plasma GLP-1 concentration on the two interventions
was related to both the percentage reduction in peak (r = 0.65
for the quadratic model, r = 0.63 for the linear model,
P = 0.001 for both) and incremental AUC (r = 0.77
for the quadratic model, r = 0.71 for the linear model,
P < 0.001 for both) (Fig. 4, A and B) but not to differences in
time to peak.
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peak and AUC
acetaminophen and the reduction in ad libitum
intake during GLP-1 infusion. This was tested using only
the data from Flint et al. (10) and
Näslund et al. (6) (n = 25). In the
last study (5), the ad libitum meal was served
as a preload, and subsequently the emptying rate for this meal was
assessed. Therefore, it would not give any meaning to include this in
the analysis. Side effects of GLP-1 infusion
In two of the studies VAS scores on either well-being or feelings of nausea were included. Neither in the separate studies nor in the pooled data set (n = 25) were there any signs of side effects of the GLP-1 infusion.
Discussion
The present meta-analysis is the first combined analysis of data from previous studies of the effect of iv GLP-1 infusion on appetite regulation, gastric emptying, and well-being in humans. From this meta-analysis it is evident that GLP-1 infusion inhibits ad libitum energy intake and that the effect is dose dependent, as previously indicated in the study by Gutzwiller et al. (8).
It is well documented that obesity may be associated with a reduction of the postprandial GLP-1 response (18, 19, 20, 21). Although the present analysis shows a somewhat lesser absolute reduction in energy intake following similar GLP-1 infusion rate in overweight compared with lean subjects, this difference is mainly due to the fact that the overall ad libitum intake was lower in obese subjects. Furthermore, from the stepwise regression analysis it is seen that BMI is not an independent determinant of the effect of GLP-1 and that the linear coefficient for reduction of energy intake during GLP-1 infusion is 1.4 MJ per pmol/kg-1·min-1 in lean and 1.1 MJ per pmol/kg-1·min-1 in overweight subjects, which would indicate that the sensitivity is equal in the two subject groups. Finally, the difference between lean and overweight subjects was somewhat reduced when excluding data from the study, in which the ad libitum meal was served at the beginning of the infusion. In this study, ad libitum energy intake was similar on the 2 test days (5). It is not possible to conclude whether this finding is related to GLP-1 being increasingly effective with time.
Both the absolute and the relative reduction in energy intake seemed to be greater in overweight subjects with NIDDM compared with merely overweight subjects. This finding might indicate a greater sensitivity to the satiating effect of GLP-1 in NIDDM. However, the observations made in NIDDM patients originated from the same study (9), and it is, therefore, not possible to distinguish a possible effect of the diabetes status from the effect of the study.
Although a linear relationship was shown between reduction in the ad libitum energy intake and GLP-1 infusion rate in both the whole group and the two subgroups the quadratic model was found to fit the data better, suggesting that the effect of increasing the GLP-1 dose is greater at a high rate than at a low rate of infusion. Thus, this observation might also indicate a rather weak effect at the more "physiological" levels of GLP-1.
From the pooled data set describing the relationship between plasma concentrations of GLP-1 and appetite measures, it was clear that increased plasma levels of GLP-1 reduced the feelings of hunger and prospective food consumption and increased the feeling of fullness. However, no relationship was seen between the differences in plasma GLP-1 concentration and ad libitum intake on the 2 test days. This might be explained by a large intraindividual variation in ad libitum energy intake, which might also explain the lack of correlation between differences in ad libitum energy intake and differences in subjective feelings of appetite reported by VAS scores, or that other, unmeasured factors were more important in determining energy intake.
The gastric emptying rate was reduced during GLP-1
infusion in all the three studies from which data on gastric emptying
were included. The percentage reduction in emptying rate was much more
pronounced during the high infusion rate (0.75
pmol/kg-1·min-1)
compared with the lower dose (0.50
pmol/kg-1·min-1), and
the percentage reduction in emptying rate increased with increasing
plasma GLP-1 levels. The procedure for assessing gastric
emptying by adding acetaminophen to the preload differed
slightly between the studies using the high and the low infusion rate.
In the study using the low infusion rate (10)
acetaminophen was added to yogurt, whereas in the two
studies using the high infusion rate it was added to a glass of water,
which the subjects drank during or at the end of the preload (5, 6). However, as shown recently by Näslund et
al. (16), acetaminophen dissolved in
water and given with a meal follows the same emptying pattern as a
solid phase marker. The relation between increase in mean plasma
GLP-1 induced by the GLP-1 infusion and the
concomitant reduction in peak and AUC for plasma
acetaminophen (Fig. 4
, A and B) seems to reflect a
nonlinear dose-response relationship, even though it could be argued
that clustering of the data might lead to false conclusions, and that
differences in study design might be a confounder. However, this
finding of a dose-response relationship between GLP-1
infusion rate and reduction in gastric emptying is supported by
previous findings in lean subjects (22).
In contrast to what might be expected, no correlation was seen between the reduction in gastric emptying and ad libitum energy intake during treatment with GLP-1. However, this analysis was performed on data from 25 subjects from only two original studies (6, 10), and in one of these studies no significant difference in ad libitum energy intake was seen (10).
Well-being was not affected by the GLP-1 infusion in the overall data set including data from 25 subjects. This is in agreement with the findings in the two original studies (6, 10) and with studies from which raw data were not included (7, 8, 9). Furthermore, in the original studies, GLP-1 was shown not to affect palatability rating of the ad libitum meal (1, 5, 6, 10) or food preferences (5, 7).
GLP-1 has for several years been regarded as a promising agent in the treatment of type II diabetes. GLP-1 is known to be an important incretin hormone stimulating insulin secretion during hyperglycemia and may hereby improve the regulation of plasma glucose in type II diabetics without the risk of hypoglycemia (11, 12, 14, 23). Obesity is the most important cause of type II diabetes, and even a moderate weight reduction is known to improve insulin sensitivity, making weight reduction the primary goal in the treatment of this disease (24). The present meta-analysis confirms that GLP-1 is able to reduce ad libitum energy intake and increase satiety both in lean and overweight subjects, without affecting general well-being. Treatment with the GLP-1 agonist, exendin-4, has been shown to decrease food intake, fat deposition, and increase glucose tolerance in Zucker fatty rats (25). Taken together, these findings suggest that GLP-1 or GLP-1 agonists could be extremely valuable in the treatment of type II diabetics and merely obese in humans.
Acknowledgments
Footnotes
Abbreviations: BMI, Body mass index; CI, confidence interval; GLP-1, glucagon-like peptide-1 (7–36) amide; NIDDM, noninsulin-dependent diabetes mellitus; VAS, visual analog scale.
Received March 8, 2001.
Accepted May 30, 2001.
References
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P. J Larsen Mechanisms behind GLP-1 induced weight loss The British Journal of Diabetes & Vascular Disease, November 1, 2008; 8(2_suppl): S34 - S41. [Abstract] [PDF]
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C. W. Chia and J. M. Egan Incretin-Based Therapies in Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3703 - 3716. [Abstract] [Full Text] [PDF]
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 A. C. Nilsson, E. M. Ostman, J. J. Holst, and I. M. E. Bjorck Including Indigestible Carbohydrates in the Evening Meal of Healthy Subjects Improves Glucose Tolerance, Lowers Inflammatory Markers, and Increases Satiety after a Subsequent Standardized Breakfast J. Nutr., April 1, 2008; 138(4): 732 - 739. [Abstract] [Full Text] [PDF]
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O. B. Chaudhri, K. Wynne, and S. R. Bloom Can Gut Hormones Control Appetite and Prevent Obesity? Diabetes Care, February 1, 2008; 31(Supplement_2): S284 - S289. [Abstract] [Full Text] [PDF]
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 M. M. Huizinga Weight-Loss Pharmacotherapy: A Brief Review Clin. Diabetes, October 1, 2007; 25(4): 135 - 140. [Abstract] [Full Text] [PDF]
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 J. J. Holst The Physiology of Glucagon-like Peptide 1 Physiol Rev, October 1, 2007; 87(4): 1409 - 1439. [Abstract] [Full Text] [PDF]
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 T. J Little, M. Horowitz, and C. Feinle-Bisset Modulation by high-fat diets of gastrointestinal function and hormones associated with the regulation of energy intake: implications for the pathophysiology of obesity Am. J. Clinical Nutrition, September 1, 2007; 86(3): 531 - 541. [Abstract] [Full Text] [PDF]
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 A. N. Pilichiewicz, R. Chaikomin, I. M. Brennan, J. M. Wishart, C. K. Rayner, K. L. Jones, A. J. P. M. Smout, M. Horowitz, and C. Feinle-Bisset Load-dependent effects of duodenal glucose on glycemia, gastrointestinal hormones, antropyloroduodenal motility, and energy intake in healthy men Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E743 - E753. [Abstract] [Full Text] [PDF]
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 S. A. McKennon and R. K. Campbell The Physiology of Incretin Hormones and the Basis for DPP-4 Inhibitors The Diabetes Educator, January 1, 2007; 33(1): 55 - 66. [Abstract] [Full Text] [PDF]
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 R K. Campbell Rationale for Dipeptidyl Peptidase 4 Inhibitors: A New Class of Oral Agents for the Treatment of Type 2 Diabetes Mellitus Ann. Pharmacother., January 1, 2007; 41(1): 51 - 60. [Abstract] [Full Text] [PDF]
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 E. Naslund and J. G. Kral Impact of Gastric Bypass Surgery on Gut Hormones and Glucose Homeostasis in Type 2 Diabetes Diabetes, December 1, 2006; 55(Supplement_2): S92 - S97. [Abstract] [Full Text] [PDF]
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J. Bowen, M. Noakes, and P. M. Clifton Appetite Regulatory Hormone Responses to Various Dietary Proteins Differ by Body Mass Index Status Despite Similar Reductions in ad Libitum Energy Intake J. Clin. Endocrinol. Metab., August 1, 2006; 91(8): 2913 - 2919. [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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R. Morinigo, V. Moize, M. Musri, A. M. Lacy, S. Navarro, J. L. Marin, S. Delgado, R. Casamitjana, and J. Vidal Glucagon-Like Peptide-1, Peptide YY, Hunger, and Satiety after Gastric Bypass Surgery in Morbidly Obese Subjects J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1735 - 1740. [Abstract] [Full Text] [PDF]
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T. J. Little, A. N. Pilichiewicz, A. Russo, L. Phillips, K. L. Jones, M. A. Nauck, J. Wishart, M. Horowitz, and C. Feinle-Bisset Effects of Intravenous Glucagon-Like Peptide-1 on Gastric Emptying and Intragastric Distribution in Healthy Subjects: Relationships with Postprandial Glycemic and Insulinemic Responses J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1916 - 1923. [Abstract] [Full Text] [PDF]
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M. C. Riddle and D. J. Drucker Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1 Diabetes Care, February 1, 2006; 29(2): 435 - 449. [Full Text] [PDF]
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B.-J. Kim, O. D. Carlson, H.-J. Jang, D. Elahi, C. Berry, and J. M. Egan Peptide YY Is Secreted after Oral Glucose Administration in a Gender-Specific Manner J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6665 - 6671. [Abstract] [Full Text] [PDF]
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 N. M. Neary, C. J. Small, M. R. Druce, A. J. Park, S. M. Ellis, N. M. Semjonous, C. L. Dakin, K. Filipsson, F. Wang, A. S. Kent, et al. Peptide YY3-36 and Glucagon-Like Peptide-17-36 Inhibit Food Intake Additively Endocrinology, December 1, 2005; 146(12): 5120 - 5127. [Abstract] [Full Text] [PDF]
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S. Stanley, K. Wynne, B. McGowan, and S. Bloom Hormonal Regulation of Food Intake Physiol Rev, October 1, 2005; 85(4): 1131 - 1158. [Abstract] [Full Text] [PDF]
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 I. M. Brennan, K. L. Feltrin, M. Horowitz, A. J. P. M. Smout, J. H. Meyer, J. Wishart, and C. Feinle-Bisset Evaluation of interactions between CCK and GLP-1 in their effects on appetite, energy intake, and antropyloroduodenal motility in healthy men Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1477 - R1485. [Abstract] [Full Text] [PDF]
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P. K. Chelikani, A. C. Haver, and R. D. Reidelberger Intravenous infusion of glucagon-like peptide-1 potently inhibits food intake, sham feeding, and gastric emptying in rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2005; 288(6): R1695 - R1706. [Abstract] [Full Text] [PDF]
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 M. K. Badman and J. S. Flier The Gut and Energy Balance: Visceral Allies in the Obesity Wars Science, March 25, 2005; 307(5717): 1909 - 1914. [Abstract] [Full Text] [PDF]
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K. Wynne, S. Stanley, B. McGowan, and S. Bloom Appetite control J. Endocrinol., February 1, 2005; 184(2): 291 - 318. [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.-P. Gutzwiller, L. Degen, D. Matzinger, S. Prestin, and C. Beglinger Interaction between GLP-1 and CCK-33 in inhibiting food intake and appetite in men Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2004; 287(3): R562 - R567. [Abstract] [Full Text] [PDF]
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 K.G. Murphy and S.R. Bloom Gut hormones in the control of appetite Exp Physiol, September 1, 2004; 89(5): 507 - 516. [Abstract] [Full Text] [PDF]
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J. A. Lovshin, Q. Huang, R. Seaberg, P. L. Brubaker, and D. J. Drucker Extrahypothalamic Expression of the Glucagon-Like Peptide-2 Receptor Is Coupled to Reduction of Glutamate-Induced Cell Death in Cultured Hippocampal Cells Endocrinology, July 1, 2004; 145(7): 3495 - 3506. [Abstract] [Full Text] [PDF]
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C. de Graaf, W. A. Blom, P. A. Smeets, A. Stafleu, and H. F. Hendriks Biomarkers of satiation and satiety Am. J. Clinical Nutrition, June 1, 2004; 79(6): 946 - 961. [Abstract] [Full Text] [PDF]
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K. Wynne, S. Stanley, and S. Bloom The Gut and Regulation of Body Weight J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2576 - 2582. [Abstract] [Full Text] [PDF]
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J. Korner and L. J. Aronne Pharmacological Approaches to Weight Reduction: Therapeutic Targets J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2616 - 2621. [Full Text] [PDF]
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S. Madsbad, O. Schmitz, J. Ranstam, G. Jakobsen, and D. R. Matthews Improved Glycemic Control With No Weight Increase in Patients With Type 2 Diabetes After Once-Daily Treatment With the Long-Acting Glucagon-Like Peptide 1 Analog Liraglutide (NN2211): A 12-week, double-blind, randomized, controlled trial Diabetes Care, June 1, 2004; 27(6): 1335 - 1342. [Abstract] [Full Text] [PDF]
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 S. Stanley, K. Wynne, and S. Bloom Gastrointestinal Satiety Signals III. Glucagon-like peptide 1, oxyntomodulin, peptide YY, and pancreatic polypeptide Am J Physiol Gastrointest Liver Physiol, May 1, 2004; 286(5): G693 - G697. [Abstract] [Full Text] [PDF]
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M. A. Cohen, S. M. Ellis, C. W. Le Roux, R. L. Batterham, A. Park, M. Patterson, G. S. Frost, M. A. Ghatei, and S. R. Bloom Oxyntomodulin Suppresses Appetite and Reduces Food Intake in Humans J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4696 - 4701. [Abstract] [Full Text] [PDF]
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G. S. Meneilly, N. Greig, H. Tildesley, J. F. Habener, J. M. Egan, and D. Elahi Effects of 3 Months of Continuous Subcutaneous Administration of Glucagon-Like Peptide 1 in Elderly Patients With Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2835 - 2841. [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. C. Howarth, E. Saltzman, M. A. McCrory, A. S. Greenberg, J. Dwyer, L. Ausman, D. G. Kramer, and S. B. Roberts Fermentable and Nonfermentable Fiber Supplements Did Not Alter Hunger, Satiety or Body Weight in a Pilot Study of Men and Women Consuming Self-Selected Diets J. Nutr., October 1, 2003; 133(10): 3141 - 3144. [Abstract] [Full Text] [PDF]
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R. Gros, X. You, L. L. Baggio, M. G. Kabir, A. M. Sadi, I. N. Mungrue, T. G. Parker, Q. Huang, D. J. Drucker, and M. Husain Cardiac Function in Mice Lacking the Glucagon-Like Peptide-1 Receptor Endocrinology, June 1, 2003; 144(6): 2242 - 2252. [Abstract] [Full Text] [PDF]
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J. M. Egan, G. S. Meneilly, and D. Elahi Effects of 1-mo bolus subcutaneous administration of exendin-4 in type 2 diabetes Am J Physiol Endocrinol Metab, June 1, 2003; 284(6): E1072 - E1079. [Abstract] [Full Text] [PDF]
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K. E. Mayo, L. J. Miller, D. Bataille, S. Dalle, B. Goke, B. Thorens, and D. J. Drucker International Union of Pharmacology. XXXV. The Glucagon Receptor Family Pharmacol. Rev., March 1, 2003; 55(1): 167 - 194. [Abstract] [Full Text] [PDF]
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G. A. Bray The Underlying Basis for Obesity: Relationship to Cancer J. Nutr., November 1, 2002; 132(11): 3451S - 3455. [Abstract] [Full Text] [PDF]
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