Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy normal-weight subjects.
ABSTRACT The sweet-taste receptor (T1r2+T1r3) is expressed by enteroendocrine L-cells throughout the gastrointestinal tract. Application of sucralose (a non-calorific, non-metabolisable sweetener) to L-cells in vitro stimulates glucagon-like peptide (GLP)-1 secretion, an effect that is inhibited with co-administration of a T1r2+T1r3 inhibitor. We conducted a randomised, single-blinded, crossover study in eight healthy subjects to investigate whether oral ingestion of sucralose could stimulate L-cell-derived GLP-1 and peptide YY (PYY) release in vivo.
Fasted subjects were studied on 4 study days in random order. Subjects consumed 50 ml of either water, sucralose (0.083% w/v), a non-sweet, glucose-polymer matched for sweetness with sucralose addition (50% w/v maltodextrin+0.083% sucralose) or a modified sham-feeding protocol (MSF=oral stimulation) of sucralose (0.083% w/v). Appetite ratings and plasma GLP-1, PYY, insulin and glucose were measured at regular time points for 120 min. At 120 min, energy intake at a buffet meal was measured.
Sucralose ingestion did not increase plasma GLP-1 or PYY. MSF of sucralose did not elicit a cephalic phase response for insulin or GLP-1. Maltodextrin ingestion significantly increased insulin and glucose compared with water (P<0.001). Appetite ratings and energy intake were similar for all groups.
At this dose, oral ingestion of sucralose does not increase plasma GLP-1 or PYY concentrations and hence, does not reduce appetite in healthy subjects. Oral stimulation with sucralose had no effect on GLP-1, insulin or appetite.
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ABSTRACT: As obesity continues to be a global epidemic, research into the mechanisms of hunger and satiety and how those signals act to regulate energy homeostasis persists. Peptide YY (PYY) is an acute satiety signal released upon nutrient ingestion and has been shown to decrease food intake when administered exogenously. More recently, investigators have studied how different factors influence PYY release and circulating levels in humans. Some of these factors include exercise, macronutrient composition of the diet, body-weight status, adiposity levels, sex, race and ageing. The present article provides a succinct and comprehensive review of the recent literature published on the different factors that influence PYY release and circulating levels in humans. Where human data are insufficient, evidence in animal or cell models is summarised. Additionally, the present review explores the recent findings on PYY responses to different dietary fatty acids and how this new line of research will make an impact on future studies on PYY. Human demographics, such as sex and age, do not appear to influence PYY levels. Conversely, adiposity or BMI, race and acute exercise all influence circulating PYY levels. Both dietary fat and protein strongly stimulate PYY release. Furthermore, MUFA appear to result in a smaller PYY response compared with SFA and PUFA. PYY levels appear to be affected by acute exercise, macronutrient composition, adiposity, race and the composition of fatty acids from dietary fat.Nutrition Research Reviews 06/2014; · 3.86 Impact Factor
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ABSTRACT: The consumption of low-calorie beverages has increased worldwide, mainly because of their combination of sweet taste without adding significant calories to the diet. However, some epidemiological studies have linked the higher consumption of low-calorie beverages with increased body weight gain.Current Opinion in Clinical Nutrition and Metabolic Care 07/2014; · 3.97 Impact Factor
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ABSTRACT: Increased energy consumption, especially increased consumption of sweet energy-dense food, is thought to be one of the main contributors to the escalating rates in overweight individuals and obesity globally. The individual's ability to detect or sense sweetness in the oral cavity is thought to be one of many factors influencing food acceptance, and therefore, taste may play an essential role in modulating food acceptance and/or energy intake. Emerging evidence now suggests that the sweet taste signaling mechanisms identified in the oral cavity also operate in the gastrointestinal system and may influence the development of satiety. Understanding the individual differences in detecting sweetness in both the oral and gastrointestinal system towards both caloric sugar and high intensity sweetener and the functional role of the sweet taste system may be important in understanding the reasons for excess energy intake. This review will summarize evidence of possible associations between the sweet taste mechanisms within the oral cavity, gastrointestinal tract and the brain systems towards both caloric sugar and high intensity sweetener and sweet taste function, which may influence satiation, satiety and, perhaps, predisposition to being overweight and obesity.Nutrients 09/2014; 6(9):3431-3450. · 3.15 Impact Factor
Effects of oral ingestion of sucralose on gut hormone response and appetite in healthy
Heather E. Ford BSc*, Veronique Peters PhD*, Niamh M. Martin PhD, Michelle L.
Sleeth BSc, Mohammad A. Ghatei PhD, Gary S. Frost PhD, Steve R. Bloom MD
Division of Diabetes, Endocrinology and Metabolism, Department of Medicine,
Hammersmith Campus, Imperial College London, UK.
Running head (38 characters): sweet taste receptors and gut hormones
* These authors contributed equally to the project.
Correspondence and request for reprints to Stephen R Bloom, Division of Diabetes,
Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine,
Hammersmith Hospital Campus, Imperial College London, 6th Floor, Commonwealth
Building, Du Cane Road, London, W12 0NN
Telephone number: +44(0)208 383 3242
Fax number: +44(0)208 383 8320
Email address: email@example.com
This research is funded by program grants from the MRC (G7811974) and Wellcome Trust
(072643/Z/03/Z) and by an EU FP6 Integrated Project Grant LSHM-CT-2003-503041. We
are also grateful for support from the NIHR Biomedical Research Centre funding scheme.
We thank Tate and Lyle for the provision of sucralose.
Abstract (234 words)
Background: The sweet taste receptor (T1r2+T1r3) is expressed by enteroendocrine L-cells
throughout the gastrointestinal tract. Application of sucralose (a non-calorific, non-
metabolisable sweetener) to L-cells in vitro stimulates glucagon-like peptide (GLP)-1
secretion, an effect that is inhibited with co-administration of a T1r2+T1r3 inhibitor.
Objective: We conducted a randomised, single-blinded, cross-over study in eight healthy
subjects to investigate whether oral ingestion of sucralose could stimulate L-cell derived
GLP-1 and peptide YY (PYY) release in vivo.
Methods: Fasted subjects were studied on four study days in random order. Subjects
consumed 50ml of either water, sucralose (0.083% w/v), a non-sweet, glucose-polymer
matched for sweetness with sucralose addition (50% w/v maltodextrin + 0.083% sucralose)
or a modified sham feeding protocol (MSF = oral stimulation) of sucralose (0.083% w/v).
Appetite ratings and plasma GLP-1, PYY, insulin and glucose were measured at regular time
points for 120 minutes. At 120 minutes, energy intake at a buffet meal was measured.
Results: Sucralose ingestion did not increase plasma GLP-1 or PYY. MSF of sucralose did
not elicit a cephalic phase response for insulin or GLP-1. Maltodextrin ingestion significantly
increased insulin and glucose compared to water (p<0.001). Appetite ratings and energy
intake were similar for all groups.
Conclusions: At this dose, oral ingestion of sucralose does not increase plasma GLP-1 or
PYY concentrations and hence, does not reduce appetite in healthy subjects. Oral stimulation
with sucralose had no effect on GLP-1, insulin, or appetite.
Keywords: obesity, sucralose, sweetener, gut hormone, appetite
Recently, there have been significant advances in our understanding of how hormonal signals
released from the gastrointestinal (GI) tract interact with circuits within the central nervous
system to control appetite and energy intake (Murphy and Bloom, 2006). The gut hormones
peptide YY (PYY) and glucagon-like peptide (GLP)-1 are co-secreted from intestinal
enteroendocrine L-cells and released post-prandially in proportion to the amount of energy
ingested (Adrian et al., 1985; Ghatei et al., 1983; Le Roux et al., 2006). PYY and GLP-1 have
both been shown to be satiety factors, reducing food intake when administered to rodents
(Batterham et al., 2002; Challis et al., 2003; Chelikani et al., 2005a; Chelikani et al., 2005b;
Chelikani et al., 2006; Halatchev et al., 2004; Talsania et al., 2005) and to humans
(Batterham et al., 2002; Degen et al., 2005; Flint et al., 1998; Gutzwiller et al., 1999; Le
Roux et al., 2006). The incretin effect of GLP-1, augmentation of insulin secretion in
response to an oral glucose load, has been well characterised (Elrick et al., 1964). Secretion
of PYY and GLP-1 is regulated by a complex neuro-humoral system in addition to direct
nutrient contact with specific receptors expressed by intestinal L-cells. However, the
mechanisms by which luminal nutrients stimulate the release of GLP-1 and PYY from L-cells
remain poorly understood. 39
The two proteins T1r2 and T1r3 form a heterodimer and function together as a general sweet-
taste receptor (Li et al., 2002; Nelson et al., 2001). T1r2+T1r3 is coupled to the G-protein
gustducin, which mediates transduction of sweet taste signals (Wong et al., 1996). T1r, and
the alpha subunit of gustducin (α-gust), are co-localised with GLP-1 and PYY in
enteroendocrine L-cells of the intestinal brush border membranes (Jang et al., 2007;
Rozengurt et al., 2006; Sutherland et al., 2007). Recently, a key role for α-gust and a
functioning sweet-taste receptor in glucose stimulated GLP-1 secretion from the L-cell has
been demonstrated (Jang et al., 2007). Application of sucralose (a non-calorific, non-
metabolisable sweetener) to human L-cells in vitro stimulated GLP-1 secretion and this effect
was inhibited with co-administration of a T1r3 inhibitor. This evidence supports a new
signaling mechanism which regulates gut hormone secretion via the sweet-taste receptor
T1r2+T1r3 in the GI tract.
One proposed factor in the increasing prevalence of obesity and type 2 diabetes is an
increased consumption of processed foods containing high levels of sucrose and fructose
(Bray et al., 2004; Elliott et al., 2002; Raben et al., 2002). To offset this, the food industry has
attempted to replace sugars with artificial sweeteners. The ability of non-calorific sweeteners
to enhance endogenous gut hormone release would represent a potentially exciting
opportunity for their addition to foods as agents to control glucose homeostasis and appetite
regulation in populations at risk of type 2 diabetes and obesity.
The aim of this study is to investigate whether oral ingestion of sucralose, at a dose that
would be consumed in a normal diet, increases circulating GLP-1 or PYY concentrations in
Subjects and Methods
Eight normal-weight, healthy volunteers were locally recruited. All were non-smokers, aged
22-27y (seven females and one male) with a stable body weight and a body mass index
ranging from 18.8 to 23.9 kg/m2. Persons who disliked the study food, who had food allergies
or food restrictions, who were taking medication that was likely to affect taste, smell or
appetite or who reported recent weight loss or weight cycling were excluded. Subjects were
screened using the standard Dutch Eating Behaviour questionnaire (Van Strien et al., 1986)
and SCOFF questionnaire (Morgan et al., 2000) and were excluded if they demonstrated
abnormal eating behaviour. Female volunteers attended all study days within the follicular
stage of the menstrual cycle.
The study was conducted with local ethical approval (project registration number:
07/Q0406/62). Written informed consent was obtained from all volunteers and the study was
performed in accordance with the Declaration of Helsinki.
The study had a randomised, single-blinded, cross-over design. Subjects were randomly
assigned to receive one of four solutions on four separate study sessions. Study sessions
lasted from 0830h until 1230h with at least three days between sessions. Subjects were asked
to refrain from drinking alcohol and to keep evening meals and activity levels as similar as
possible the day before each test session and to fast from 2100h, consuming only water.
On arrival at the study centre subjects were asked to be seated and to relax for 30 minutes
following placement of the intravenous cannula. After two baseline blood samples subjects
completed one of four experimental manipulations. Subjects ingested, in a single swallow,
50mL of either water (W), sucralose (S; 0.083% w/v, 2mmol/L Splenda®, Tate and Lyle
PLC, Southampton, UK) or the positive control maltodextrin (MD) which was matched for
sweetness with sucralose (50% w/v Polycose®, Abbott Laboratories Ltd, US, plus 0.083%
sucralose). Each was followed by a one minute period of modified-sham-feeding (MSF)
protocol of the same solution that was swallowed. The fourth experimental manipulation was
designed to ascertain the involvement of stimulation of the sweet-taste receptors within the
oral cavity independently of the sweet-taste receptors throughout the GI tract. In this instance
subjects consumed 50mL water followed by the one-minute MSF of the sucralose solution
(WS; 0.083% w/v sucralose). The test solutions used are described in Table 1. The MSF
protocol involved drawing the solution up into the mouth through a straw, moving it around
in the mouth and then spitting it out, doing so repeatedly until the entire volume of 200mL
was finished and the one minute time limit was up. In order to investigate the cephalic effects
of sucralose, the MSF was performed after ingestion of the test solution to ensure that no
residual sucralose would be swallowed with the subsequent ingestion of water in the WS
The dose of sucralose was chosen to represent a normal dietary load and the total volume
ingested was kept to a minimum, as it is known that ingestion of large volumes of water
alone can induce a gut hormone response (Christofides et al., 1979). Maltodextrin (a five
polymer chain of glucose) was used to assess the effect of glucose on gut hormone release
without the potential confounder of high concentrations of glucose effecting gastric emptying.
The expectorate from the MSF was weighed to ensure compliance with the protocol. Blood
samples and visual analogue scores (VAS) pertaining to subjective feelings of appetite, were
taken for a further two hours. After the last blood sample at 120 minutes, a test meal of
known energy content was given in excess and subjects were asked to eat until comfortably
full. Energy intake was calculated from the weight of food eaten.
Two baseline blood samples were taken at -15 and 0 minutes before consumption of test
solutions, then further samples were taken at 15, 30, 45, 60, 90 and 120 minutes after
consumption of test solutions. For analysis of the cephalic phase insulin release (CPIR) and
the cephalic phase GLP-1 response, blood samples were also taken at 2, 4, 6, 8 and 10
minutes for insulin and GLP-1 analysis only. Blood was collected in lithium heparin tubes
containing 5000 kallikrein units of aprotinin (200µL; Trasylol; Bayer) and immediately
centrifuged at 4ºC. Plasma was separated and stored at -20ºC until analysis.
Subjective feelings of appetite were assessed at -15, 0, 15, 30, 45, 60, 90 and 120 minutes
using VAS (Flint et al., 2000) with questions pertaining to desire to eat, hunger and
prospective food consumption. Subjects were also asked to score the palatability and
sweetness of the test solutions. Subjects marked their answers to the questions on scales of
100mm in length anchored at either end with the most positive and the most negative
response. The distance along the scale that the subjects placed their mark was measured from
one end and the reading in millimeters was recorded.
All samples were assayed in duplicate and in a single assay to eliminate inter assay variation.
Plasma PYY and GLP-1 were assessed using an established in-house radioimmunoassay
(RIA) described previously (Adrian et al., 1985; Kreymann et al., 1987). The detection limit
of the PYY and GLP-1 assays was 2.5pmol/L and 7.5pmol/L with an intra-assay coefficient
variation (CV) of 5.8% and 5.4% respectively. Insulin was measured using Axsym analyser
(Abbott Diagnostics, Maidenhead, UK). Sensitivity was 7 pmol/L with an intra-assay CV of
2.6%. Plasma glucose was measured using an Abbott Architect ci8200 analyser (Abbott
Diagnostics, Maidenhead, UK). Sensitivity was 0.3mmol/L and intra-assay CV was 1%.
All data are represented as mean values ± SEM. Plasma hormone and glucose concentrations
were adjusted from baseline and represented as time course from change from baseline.
Incremental area under the curve (iAUC) was calculated over baseline by the trapezoidal rule.
Data for energy intake and iAUC were tested for normality and analysed using repeated
measures one-way ANOVA with Bonferroni’s test for post hoc comparisons (GraphPad
Prism 4.03 Software, San Diego, USA). In all cases P<0.05 was considered to be statistically
Validation of MSF
After all test solutions, the expectorate weight was greater than the weight of the MSF
solutions sipped due to the addition of saliva indicating a successful MSF with minimum
swallowing of test solutions.
The water solution was significantly less sweet than the remaining three test solutions (70.9 ±
3 mm [WS], P<0.001; 65.9 ± 10.8 mm [S], P<0.01; 73.1 ± 8 mm [MD], P<0.001 vs. 5.9 ± 2
mm [W]; n=8). The WS, S and MD solutions were rated as having the same sweetness and
palatability (42.8 ± 8.9 mm [WS]; 36.8 ± 10 mm [S]; 38.1 ± 8.5 mm [MD], 26.1 ± 6 mm [W];
Appetite and food intake
For the two hour period following administration of the test solutions, there was no
significant difference in the iAUC(0-120min) of subjective feelings of appetite (Table 2). Two
hours after consumption of test solutions, there was no significant difference in energy intake
or water intake at the buffet meal (Table 2).
Hormones and glucose
Plasma insulin and GLP-1 did not show any significant change during the first 10 min after
the MSF of any solution (Table 2). iAUC(0-120min) for plasma GLP-1 and PYY concentrations
were similar in all four groups. The MD group had a significantly higher iAUC(0-120min) of
insulin and glucose concentrations compared with water, but there was no difference between
any other solution tested (Figure 1 and Table 2).
In the present study, we show that oral ingestion of a common dietary dose of the non-
calorific, artificial sweetener sucralose does not increase plasma GLP-1 or PYY
concentrations nor does it affect subjective feelings of appetite or energy intake at the next
meal in healthy volunteers. This study mimics the physiological intake of a sweetened
solution. Our data are in accord with recently published human data (Ma et al., 2009) and in
vivo rat data (Fujita et al., 2009) in which sucralose ingestion failed to stimulate a rise in two
circulating incretin hormones, GLP-1 and the K cell derived glucose-dependent
insulinotropic polypeptide (GIP). Ma et al. administered sucralose nasogastrically to healthy,
normal weight volunteers and observed no effect on plasma GLP-1 or GIP concentrations
(Ma et al., 2009). Similarly, Fujita et al. demonstrated in rats that in contrast to sucrose
gavage, oral gavage of sucralose did not induce a rise in plasma GLP-1 (Fujita et al., 2009).
The only other published study to investigate the acute effect of oral sweetener ingestion on
gut hormone release in humans used the sweetener aspartame. Although, ingestion of
encapsulated aspartame was associated with a reduction in subsequent food intake, this effect
did not seem to be mediated by GLP-1 release (Hall et al., 2003). We chose not to
encapsulate sucralose in our study, as it remains intact throughout the GI tract and very little
is absorbed (Grice and Goldsmith, 2000). Therefore, sucralose may stimulate receptors on
more distal L cells throughout the GI tract.
We did not observe a plasma GLP-1 response following ingestion of maltodextrin plus
sucralose. GLP-1 response to glucose seems to be dependent on glucose been present in the
distal duodenum where L-cells are present (Parker et al., 2010). In this experiment we used
relatively low amount of a glucose polymer which is cleared efficiently in the proximal
duodenum before it can elicit a gut hormone response.
Oral ingestion of two non-calorific sweeteners, sucralose plus acesulfame K, followed by an
oral glucose tolerance test, produces higher plasma peak GLP-1 concentrations compared to
ingestion of water followed by an oral glucose tolerance test in healthy normal weight
subjects (Brown et al., 2009). Consistent with this sucralose plus glucose has an additive
stimulatory effect on GLP-1 secretion from murine primary L-cells compared to sucralose or
glucose alone (Reimann et al., 2008). Taken together these studies suggest that non-calorific
sweeteners and sugars may act synergistically to stimulate GLP-1 release from L-cells. In the
current study, the maltodextrin solution was matched for sweetness by addition of sucralose.
Therefore we cannot exclude a synergistic effect of maltodextrin and sucralose on plasma gut
hormone concentrations, if a gut hormone response had occurred. It would be interesting to
compare the effects of maltodextrin alone, without any match for sweetness, to the
combination of maltodextrin plus sucralose to assess any additive effect of sucralose and
maltodextrin on GLP-1 release.
Furthermore, we show that sucralose ingestion does not affect plasma glucose and insulin.
This is consistent with previous human studies in which no effect on plasma glucose and
insulin was observed following ingestion of encapsulated sucralose in diabetic patients (Grotz
et al., 2003) or following intragastric infusion of sucralose in healthy subjects (Ma et al.,
2009). Similarly, oral gavage of sucralose in rats did not improve glucose homeostasis
following an intraperitoneal glucose tolerance test (Fujita et al., 2009), suggesting that there
was no incretin effect mediated by the sucralose gavage.
Our study is the first to investigate the cephalic phase GLP-1 and insulin responses to
sucralose. We demonstrate that stimulation of the oral cavity with a sucralose-sweetened
solution does not lead to an early (0-10 min) increase in plasma GLP-1 and does not affect
subsequent food intake. This is in keeping with previous studies which have not demonstrated
a cephalic phase GLP-1 response to either ingestion of a mixed meal (Ahren and Holst, 2001)
or to a sham fed meal (Luscombe-Marsh et al., 2009). Furthermore, we show that sucralose
does not elicit a preabsorptive insulin response. This is consistent with previous studies using
a similar MSF protocol to assess the ability of non-calorific sweeteners such as aspartame and
saccharin to induce a CPIR in humans (Abdallah et al., 1997; Teff et al., 1995).
The concentration of sucralose used in the present study (2mmol/L) was chosen to be both
palatable and within the dose range (1-5mmol/L) previously shown to trigger GLP-1 release
from intestinal L-cells in vitro (Jang et al., 2007). However, with ensuing dilution in the gut
lumen post-ingestion, it is possible that the concentration of sucralose reaching the small
intestine was below 2mmol/l, which may have been insufficient to stimulate GLP-1 secretion.
An alternative explanation for our findings is that sucralose does not stimulate GLP-1 release
from intestinal enteroendocrine cells. In support of this, recent in vitro studies failed to
demonstrate an effect of sucralose on GLP-1 (Reimann et al., 2008) from enteroendocrine
cells using a similar sucralose concentration to that used in the current study. Furthermore, a
recent in vivo study has shown that intragastric infusion of up to 40mmol/L sucralose does
not induce GLP-1 secretion in humans (Ma et al., 2009). Together with our data, these studies
suggest that there is no measurable acute enhancement of GLP-1 or PYY release in vivo
following oral ingestion of sucralose. The reason for the apparent disparity of the effect of
sucralose on gut hormone release in vitro and in vivo is not clear and requires further
In summary, we have shown that oral ingestion of sucralose does not elicit a cephalic phase
GLP-1 or insulin response nor increase post-ingestive plasma GLP-1 or PYY concentrations,
and therefore does not subsequently affect appetite. Our findings, using a dietary dose of
sucralose, do not support the proposal that stimulation of the sweet taste receptor in the GI
tract can stimulate release of GLP-1 and PYY from enteroendocrine L-cells.
We thank Mandy Donaldson and John Meek for glucose and insulin assays, the Sir John
McMichael research centre for Clinical Investigation and Research, Hammersmith Hospital
and the volunteers. V.P. is funded through a European Union framework 6 Marie Curie
fellowship (NuSISCO). N.M.M. is funded by a HEFCE Clinical Senior Lecturer Award.
Contributions of the authors:
H.E.F. and V.P. designed the experiment, collected and analysed data and wrote the
manuscript. N.M.M. helped with the writing of the manuscript. M.S. contributed to the data
analysis. M.A.G, G.S.F and S.R.B. provided significant advice.
Conflict of interest:
The authors do not declare any conflict of interest.
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