S P E C I A L
F E A T U R E
C l i n i c a l
R e v i e w
Non-Nutritive Sweeteners and their Role in the
Gastrointestinal Tract
Rebecca J. Brown and Kristina I. Rother
National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892-1645
Context: Non-nutritive sweeteners can bind to sweet-taste receptors present not only in the oral
cavity, but also on enteroendocrine and pancreatic islet cells. Thus, these sweeteners may have
biological activity by eliciting or inhibiting hormone secretion. Because consumption of non-nutritive sweeteners is common in the United States, understanding the physiological effects of these
substances is of interest and importance.
Evidence Acquisition: A PubMed (1960 –2012) search was performed to identify articles examining
the effects of non-nutritive sweeteners on gastrointestinal physiology and hormone secretion.
Evidence Synthesis: The majority of in vitro studies showed that non-nutritive sweeteners can elicit
secretion of gut hormones such as glucagon-like peptide 1 and glucose-dependent insulinotropic
peptide in enteroendocrine or islet cells. In rodents, non-nutritive sweeteners increased the rate
of intestinal glucose absorption, but did not alter gut hormone secretion in the absence of glucose.
Most studies in humans have not detected effects of non-nutritive sweeteners on gut hormones
or glucose absorption. Of eight human studies, one showed increased glucose-stimulated glucagon-like peptide 1 secretion after diet soda consumption, and one showed decreased glucagon
secretion after stevia ingestion.
Conclusions: In humans, few studies have examined the hormonal effects of non-nutritive sweeteners, and inconsistent results have been reported, with the majority not recapitulating in vitro
data. Further research is needed to determine whether non-nutritive sweeteners have physiologically significant biological activity in humans. (J Clin Endocrinol Metab 97: 2597–2605, 2012)
N
on-nutritive sweetener consumption, largely in the
form of diet soda, has been associated in epidemiological studies with numerous adverse metabolic outcomes, including weight gain, the metabolic syndrome,
and diabetes (1–7). In contrast, a small number of randomized, controlled trials involving these sweeteners have
generally shown neutral to mildly beneficial metabolic
outcomes with non-nutritive sweetener use, such as weight
stability or decreased weight regain after dieting (8 –10).
Certainly, epidemiological studies cannot demonstrate
causality, and one likely explanation for the observed correlation between weight gain and non-nutritive sweetener
use is that people at risk of weight gain may choose to
consume these sweeteners in an effort to reduce caloric
sugar consumption. Another potential explanation for
the epidemiological association between non-nutritive
sweetener use and weight gain, largely supported by
rodent data (11), is that training people to associate the
sensation of “sweetness” with foods or drinks that are
low in calories may cause them to overeat when presented with high-calorie, sugar-sweetened versions of
these foods and beverages.
Although non-nutritive sweeteners have generally been
considered metabolically inert, recent data suggest that
these sweeteners may have physiological effects that alter
appetite and/or glucose metabolism. Much of the research
discussed in this review was predicated by the discovery of
the structure of the sweet-taste receptor in 2001, followed
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright © 2012 by The Endocrine Society
doi: 10.1210/jc.2012-1475 Received February 22, 2012. Accepted May 11, 2012.
First Published Online June 7, 2012
Abbreviations: GIP, Glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; GLUT2, glucose transporter 2; 3OMG, 3-O-methyl glucose; PYY, peptide YY;
SGLT-1, Na⫹/glucose cotransporter.
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shortly by the demonstration that sweet-taste receptors, in
addition to being located on taste buds in the oropharynx,
are found in enteroendocrine cells of the gastrointestinal
tract (12, 13) and other tissues, such as the pancreas (14).
acesulfame-K, aspartame, neotame, saccharin, stevia, and
sucralose. Stevia is a botanically derived sweetener from
the Stevia rebaudiana plant and consists of related chemicals
called steviol glycosides; only the sweetest of these, rebaudioside A, is shown in Table 1. Typical concentrations of
sweeteners in carbonated beverages are also listed; these are
frequently lower than anticipated based on sweetness equivalence because many beverages contain more than one nonnutritive sweetener. The metabolic fate of non-nutritive
sweeteners varies from presumed excretion in a nonmetabolized manner (acesulfame-K, saccharin, sucralose) to intestinal breakdown into the sweetener’s components (e.g. aspartame becomes aspartic acid, phenylalanine, and
methanol) or deesterification (neotame) (20).
Given the chemical heterogeneity of these compounds,
it is not surprising that not all bind to the same ligand
binding domain of the sweet-taste receptor (21, 22). However, all non-nutritive sweeteners have the ability to activate the oropharyngeal sweet-taste receptors, thereby generating a signal that ultimately results in the conscious
perception of sweetness. Upon ligand binding to the receptor, associated G proteins, such as ␣-gustducin, are
activated, resulting in increased phospholipase C␤2,
which increases production of the second messengers inositol trisphosphate and diacylglycerol. This in turn leads
to activation of the taste-transduction channel, TRPM5
(transient receptor potential cation channel subfamily
M member 5, also known as long transient receptor
potential channel 5), resulting in increased intracellular
calcium and neurotransmitter release (16). There are
important species differences in the perception of sweet
compounds. For example, the non-nutritive sweetener
aspartame does not stimulate sweet-taste receptors in
the mouse, and thus mice do not exhibit behavioral
responses to aspartame (17).
Taste Perception
To understand the role of non-nutritive sweeteners in
physiology, it is critical to understand taste perception.
This has been thoroughly reviewed by others (15, 16), and
is briefly summarized here. The tongue contains three varieties of taste papillae—the fungiform, foliate, and circumvallate— each of which contains one to hundreds of
taste buds. The classic representation of the tongue as having regions specialized for differing tastes has been largely
debunked, with the observation that all of the five major
tastes [sweet, bitter, salty, sour, and umami (the taste of
“savory,” exemplified by monosodium glutamate and aspartate)] can be sensed in all regions of the tongue.
Sweet, bitter, and umami tastes are sensed via G protein-coupled taste receptors located on taste receptor cells
within taste buds and elsewhere in the oropharynx. Each
individual cell expresses a single receptor type (either
sweet, bitter, or umami), and thus is specialized to perceive
a single taste (17). These cells project to neurons in the
brain, permitting conscious awareness of taste. The sweet,
bitter, and umami receptors are heterodimeric receptors,
with the combination of subunits conveying their flavor
specificity. The umami taste receptor has a T1R1 and a
T1R3 subunit, whereas the sweet-taste receptor has a
T1R3 and a T1R2 subunit (15). The bitter taste receptor
family contains numerous binary combinations (⬃25 in
humans) of type 2 receptors. Because bitter tastants are
often toxins, the substantial heterogeneity of bitter receptors is likely due to the evolutionary advantages of being
able to detect a broad range of potentially toxic substances
(18). Sour taste is sensed via ion channels. The taste of
sodium salts is sensed at least in part via amiloride-sensitive sodium channels (19), but the sensory mechanisms for
other salts have not been identified.
The sweet-taste receptor can bind to chemicals of
widely varying structures, including the caloric sugars
(e.g. sucrose, glucose, and fructose), sweet proteins such as
thaumatin and monellin, and non-nutritive sweeteners.
Non-nutritive sweeteners are also known as “artificial
sweeteners” or “low-calorie sweeteners,” because some
(such as aspartame) have measurable caloric value, albeit
negligible at the concentrations used. Chemical and sensory properties of the six Food and Drug Administration
(FDA)-approved non-nutritive sweeteners (with sucrose
for comparison) are shown in Table 1. The sweeteners are:
Not Just in the Mouth?
After the discovery of the structure of the sweet-taste receptor (17) and its G protein, gustducin (23), immunohistochemical techniques were used to identify sites of tissue
expression of these proteins outside of the oral cavity. It
was quickly learned that sweet-taste receptors were located in other regions of the gastrointestinal tract—most
notably, in enteroendocrine L cells (24, 25) and K cells
(26). Enteroendocrine cells are specialized cells of the gastrointestinal tract that secrete a variety of hormones. They
are sparse, comprising less than 1% of epithelial cells
within the intestine. In addition to the gastrointestinal mucosa, sweet-taste receptors have also been identified in
pancreatic ␤-cells (14), in the biliary tract (27), and in the
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TABLE 1. Chemical properties of FDA-approved non-nutritive sweeteners
Chemical name
Structure
Sweetness
Sweetness
Concentration at half
Mean concentration
(compared to
recognition
maximal sweetness
in carbonated soft
5% sucrose)
threshold
response (mmol/L)
drinks (mmol/L)
(mmol/L)
Sucrose
1
16.6
Not determined
329
Acesulfame-
140x
0.161
2.34
0.44
200x
0.0449
1.90
0.16
11,000x
0.00114
Not tested
Not tested
250x
0.013
0.21
Not tested
450x
0.0497
0.52
0.15
600x
0.00877
0.28
0.14
Potassium
(C4H4KNO4S)
Aspartame
(C14H18N2O5)
Neotame
(C2OH3ON2O5)
Rebaudioside A
(C44H70O23)
Saccharin
(C7H5NO3S)
Sucralose
(C12H19Cl3O8)
Sweetness data were obtained from psychophysical testing in human volunteers (58, 59). The sweetness recognition threshold is the lowest
concentration at which subjects identified the solution as sweet. For the non-nutritive sweeteners, subjects’ perception of sweetness reached a
maximum asymptotically. Thus, the concentration range from sweetness recognition to half maximal sweetness provides a sense of the biological
response range of sweet-taste receptors to individual sweeteners. Sucrose was not tested at high enough concentrations to determine maximal
sweetness. Mean concentrations of sweeteners in carbonated soft drinks were obtained from a sample of 19 beverages from Belgium (60).
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lungs (28). It is important to note, however, that conscious
perception of sweetness is conveyed only after activation
of oral sweet-taste receptors; sweet-taste receptors in the
gastrointestinal tract and other tissues do not convey taste.
The functional importance of sweet-taste receptors on enteroendocrine cells was recently investigated in two publications from the Beglinger group (25, 29) using the sweet-taste
inhibitor, lactisole. Lactisole [sodium 2-(4-methoxyphenoxy) propionate] inhibits sweet and umami taste perception
in primates by binding to the transmembrane domain of the
T1R3 receptor (30). In human psychophysical studies, lactisole decreased sweetness perception for 12 of 15 sweet compounds tested, including both caloric and non-nutritive
sweeteners (31). The Beglinger group studies demonstrated
that, in healthy humans, the addition of lactisole to an intragastric infusion of glucose decreased secretion of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) (both
made by L cells) by 24 to 47% and 15 to 27%, respectively.
In contrast, cholecystokinin secretion (from I cells, which are
not known to express sweet-taste receptors) was unaffected
by lactisole. These data support the idea that ligand binding
to sweet-taste receptors on L cells is partially responsible for
L-cell hormone secretion; there are undoubtedly sweet-taste
receptor-independent mechanisms as well.
Jang et al. (32) showed that the non-nutritive sweetener sucralose (the active ingredient in Splenda) stimulated GLP-1 secretion from a human L-cell line (NCIH716 cells) in a dose-dependent fashion. This GLP-1
secretion could be blocked by the sweet-taste inhibitor
lactisole, implying that sucralose was acting via sweettaste receptors. Similar results were published by Margolskee et al. (24), showing that sucralose stimulated
both GLP-1 and glucose-dependent insulinotropic peptide (GIP) secretion from a murine enteroendocrine cell
line (GLUTag cells); this effect was likewise blocked by
the sweet-taste inhibitor, gurmarin, implying that the
effect was sweet-taste receptor mediated. These results
were not confirmed in two other studies, however, in
which sucralose and another sweetener, acesulfame-K,
failed to increase GLP-1 in cultured mouse intestine
(33), or GIP secretion in isolated mouse K cells (34). The
concentrations of non-nutritive sweeteners used in
these in vitro studies (Table 2) were generally in the
upper half of, or well above, the expected dynamic response range of the sweet-taste receptor, and discrepant
results among the studies cannot be easily explained on
the basis of the sweetener concentrations used.
The majority of in vivo data have failed to confirm
effects of non-nutritive sweeteners on hormone secretion
observed in vitro. Fujita et al. (26) found that gastric gavage (thus bypassing lingual taste receptors) of four different non-nutritive sweeteners (acesulfame-K, stevia, dtryptophan, and sucralose) failed to increase GLP-1 or GIP
secretion in rats. It is notable that in this experiment, the
doses of sweetener given (1 g/kg) were 1000-fold in excess
of the concentrations typically found in commercial products such as diet sodas. Four similar experiments in healthy
humans showed no effect of oral sucralose (35, 36) or
intragastric sucralose, aspartame, or acesulfame-K on
GLP-1, PYY, ghrelin, or GIP secretion (37, 38). Taken
together, these data support the notion that non-nutritive
Non-Nutritive Sweeteners and Hormone
Secretion
Given that both non-nutritive and caloric sweeteners bind
to oral sweet-taste receptors, resulting in the conscious
sensation of sweetness, it is logical to hypothesize that
non-nutritive sweeteners could bind to sweet-taste receptors on enteroendocrine cells, likewise causing signal
transduction and downstream actions such as hormone
secretion. This possibility has been explored in multiple
systems, from cell lines to rodents to humans, with inconsistent results (Table 2– 4).
TABLE 2. Effects of non-nutritive sweeteners on gut hormones and glucose absorption: in vitro effects
Sweetener
Acesulfame-K
Saccharin
Sucralose
Concentration
2 mM (33)
50 mM (14)
50 mM (14)
0.2, 1, 5, 20 mM (32)
50 mM (24)
1 mM (34)
1 and 20 mM (33)
Model system
Cultured mouse intestine
MIN6 cells
MIN6 cells
NCI-H716 cells
GLUTag cells
Isolated mouse K-cells
Cultured mouse intestine
50 mM (14)
10 and 50 mM (14)
2.5 mM (43)
MIN6 cells
Isolated mouse islets
Isolated rat islets
Biological effect
No effect on GLP-1
Increased glucose-stimulated insulin secretion
Increased glucose-stimulated insulin secretion
GLP-1 secretion at 1 and 5 mM but not at 0.2 or 20 mM
GIP and GLP-1 secretion
No effect on GIP
No effect on GLP-1 at 1 mM. Increased GLP-1 at 20 mM
only in colon (not small bowel)
Increased glucose-stimulated insulin secretion
Increased glucose-stimulated insulin secretion
Increased glucose-stimulated insulin secretion
Measurable biological effects are italicized. NCI-H716 is a human L cell line; GLUTag is a mouse enteroendocrine cell line; MIN6 is a mouse
insulinoma (␤-cell) line.
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TABLE 3. Effects of non-nutritive sweeteners on gut hormones and glucose absorption: in vivo effects on animals
Sweetener
Acesulfame-K
Aspartame
D-tryptophan
Saccharin
Stevia
Sucralose
Dose
10 mM in drinking water ⫻ 2 wk (24)
1 g/kg (26)
Not reported (51)
1 mM in drinking water ⫻ 2 wk (24)
50 mg/kg (26)
20 mM ⫻ 2 wk (24)
Not reported (51)
1 g/kg (26)
0.03 g/kg/d (46)
2 mM in drinking water ⫻ 2 wk (24)
1 mM intestinal infusion (51)
1g/kg (26)
Model system
Mouse
Rat
Rat
Mouse
Rat
Mouse
Rat
Rat
Rat (T2D)
Mouse
Rat
Rat
Biological effect
Increased SGLT-1 expression
No effect on GIP or GLP-1
Increased GLUT-2-mediated glucose absorption
No effect on SGLT-1 expression
No effect on GIP or GLP-1
Increased SGLT-1 expression
Increased GLUT-2-mediated glucose absorption
No effect on GIP or GLP-1
Reduced glucose, insulin, and glucagon
Increased SGLT-1 expression and glucose absorption
Increased GLUT-2-mediated glucose absorption
No effect on GIP or GLP-1
Measurable biological effects are italicized. T2D, type 2 diabetes.
sweeteners in isolation are not a sufficient stimulus to
cause gut hormone secretion in vivo.
Our group examined this question using a slightly different design, testing whether non-nutritive sweeteners in
a commercially available diet soda could change gut hormone secretion in combination with caloric sugars (39).
Healthy adolescents and young adults drank either caffeine-free Diet Rite cola or carbonated water, followed 10
min later by an oral glucose load in a randomized, crossover design. We found that the plasma GLP-1 area under
the curve after glucose ingestion was 34% higher after diet
soda compared with carbonated water (P ⫽ 0.029). This
finding was replicated in patients with type 1 diabetes, in
whom the GLP-1 area under the curve was 43% higher in
the diet soda condition, but not in those with type 2 diabetes (40). These data imply that diet soda (presumably via
the non-nutritive sweeteners) enhances glucose-stimulated GLP-1 secretion, although it is not clear from the
experiment whether this effect was mediated via sweettaste receptors on enteroendocrine cells, lingual sweettaste receptors, or another mechanism altogether. In ad-
dition, the clinical significance of this finding is not clear
because insulin levels were not statistically different between the two conditions, and other GLP-1 effects, such as
satiety and gastric emptying, were not measured. It is noteworthy that these findings were not confirmed by another
study, which found no difference in plasma GLP-1 during
intraduodenal infusion of 4 mM sucralose vs. saline in
combination with glucose (41). Data from Gerspach et al.
(29) support the idea that sweet-taste sensing is less important for GLP-1 secretion after intraduodenal vs. intragastric delivery of glucose, potentially accounting for the
differing results in the two studies. Wu et al. (42) studied
the effects of sucralose before a solid meal (powdered potatoes with 20 g glucose and egg yolk) and reported no
effect on GIP or GLP-1 secretion; however, there was no
unsweetened control.
Pancreatic ␤-cells, although located outside the intestinal epithelium, may be considered enteroendocrine cells.
In 2009, Nakagawa et al. (14) identified sweet-taste receptors in MIN6 cells (a mouse insulinoma cell line frequently used to study ␤-cell function) and in mouse islets.
TABLE 4. Effects of non-nutritive sweeteners on gut hormones and glucose absorption: in vivo effects on humans
Sweetener
Acesulfame-K
Acesulfame-K ⫹ sucralose
in diet cola
Dose
220 mg (25)
26 mg acesulfame-K ⫹
46 mg sucralose (39, 40)
Subjects
Healthy
Healthy, T1D, T2D
Aspartame
Stevia
169 mg (25)
1 g (47)
Healthy
T2D
Sucralose
41.5 mg (35)
62 mg (25)
80 and 800 mg (37)
960 mg (41)
Healthy
Healthy
Healthy
Healthy
85 mg (36)
60 mg (42)
Healthy
Healthy
Biological effect
No effect on PYY or GLP-1
Increased glucose-stimulated GLP-1 in healthy
and T1D, but not T2D. No effect on insulin,
glucose, GIP, or PYY
No effect on PYY or GLP-1
Decreased glucagon and blood glucose.
No effect on GLP-1 or GIP
No effect on PYY or GLP-1
No effect on PYY or GLP-1
No effect on GIP or GLP-1
No effect on glucose-stimulated
GLP-1 or glucose absorption rate
No effect on ghrelin, glucagon, insulin, or glucose
No effect on mixed-meal stimulated GLP-1, GIP
Measurable biological effects are italicized. NCI-H716 is a human L cell line; GLUTag is a mouse enteroendocrine cell line; MIN6 is a mouse
insulinoma (␤-cell) line. T1D, Type 1 diabetes; T2D, type 2 diabetes.
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FIG. 1. A model of intestinal glucose absorption in the fasting or low luminal carbohydrate state (A) or after a high-carbohydrate meal, with or
without non-nutritive sweeteners (B). In the low luminal carbohydrate state, glucose is largely transported from the gut lumen into the enterocyte
via SGLT-1. Glucose may pass in a bidirectional manner between the enterocyte and the bloodstream via GLUT2 located on the basolateral
membrane, depending on the plasma glucose concentration and the metabolic needs of the enterocyte. In the presence of high luminal
carbohydrate, glucose binds to sweet-taste receptors on enteroendocrine L cells, initiating a signal transduction cascade that results in GLP-1 and
GLP-2 release. GLP-2 may cause up-regulation of SGLT-1 via enteric neurons. GLP-1 may act in a paracrine manner on nearby enterocytes to upregulate apical GLUT2. Non-nutritive sweeteners can also bind to enteroendocrine sweet-taste receptors, causing GLP-1 release (in vitro) and
increased intestinal glucose uptake (in rodents).
In MIN6 cells, the non-nutritive sweeteners sucralose, saccharin, and acesulfame-K stimulated insulin secretion in
the presence of glucose at low concentration (3 mM), and
sucralose augmented glucose-stimulated insulin secretion
across a range of glucose concentrations, from 3 to 25 mM.
Consistent with known intracellular signaling mechanisms in lingual taste cells, sucralose increased intracellular Ca2⫹, and this effect was blocked by the sweet-antagonist gurmarin, implying that it was mediated via sweettaste receptors. In isolated mouse islets, sucralose
enhanced glucose-stimulated insulin secretion at low glucose concentrations (2.8 mM), but not at high glucose concentrations (20 mM). Although non-nutritive sweetener
concentrations within islets in vivo have not been measured, the 10 to 50 mM concentrations used in these experiments are likely to be an order of magnitude above
what might be found in humans, thus bringing into question the biological relevance of these results. However, in
rat islets, 2.5 mM saccharin, a concentration that might
conceivably be achieved by high levels of consumption in
humans, was shown to increase basal insulin secretion
(43). The effects on islet hormone secretion of the plantderived sweetener, stevia, and its sweetest component
molecule, rebaudioside A, have been extensively studied
by the Hermansen group. Their work suggests that this
class of compounds enhances glucose-stimulated insulin
secretion via inhibition of ATP-sensitive K-channels (44,
45) and lowers blood glucose in both rodents (46) and
humans (47) with type 2 diabetes primarily by suppressing
glucagon release.
Non-Nutritive Sweeteners and Intestinal
Glucose Absorption
Dietary glucose is absorbed across the enterocytes of the
intestinal wall via the active Na⫹/glucose cotransporter
(SGLT-1) on the apical (luminal) membrane and the passive glucose transporter 2 (GLUT2) on the basolateral
membrane of the enterocyte (Fig. 1A). In order for intestinal transport to adapt to dietary glucose concentrations,
there must be a glucose sensing mechanism present in the
gastrointestinal tract; the sweet-taste receptor is one such
sensor (13, 24). Glucose binding to sweet-taste receptors
on intestinal enteroendocrine cells causes secretion of
GLP-1, GLP-2, and GIP, which in turn may act as neural
or paracrine signals to nearby enterocytes, causing upregulation of SGLT-1 (48) (Fig. 1B). Kellett et al. (49) have
proposed that intestinal glucose absorption can be further
increased at high glucose concentrations (over 30 mM) by
insertion of GLUT2 at the apical membrane of the enterocyte. The functional importance of apical GLUT2 in intestinal glucose absorption has been questioned, however,
because humans with GLUT2 deficiency (Fanconi Bickel
syndrome) do not have significant carbohydrate malabsorption. In contrast, humans with SGLT-1 deficiency
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(glucose-galactose malabsorption) have severe carbohydrate malabsorption, emphasizing the functional importance of this glucose transporter (50).
Margolskee et al. (24) studied the role of non-nutritive
sweeteners in the regulation of intestinal glucose absorption in mice, demonstrating that sucralose, acesulfame-K,
and saccharin (but not aspartame, which is not sensed as
sweet by rodents) up-regulated SGLT-1. This up-regulation resulted in a 1.9-fold increase in SGLT-1-mediated
glucose transport measured in vitro. In 2007, Mace et al.
(51) showed that these sweeteners could double the in vivo
rate of intestinal glucose absorption in rats by increasing
GLUT2 insertion into the apical membrane of enterocytes.
The effect of non-nutritive sweeteners on glucose absorption in humans was examined by Ma et al. (41). In healthy
adults, they found no difference in intestinal glucose absorption during intraduodenal infusion of 4 mM sucralose vs.
saline in combination with glucose. In this study, the rate of
intestinal glucose absorption was measured by adding a nonmetabolizable glucose analog, 3-O-methyl glucose (3OMG),
to the intestinal perfusate. 3OMG is absorbed across enterocytes identically to glucose and is subsequently excreted by
the kidney over 48 h (52). Serum levels of 3OMG over 2–3
h after ingestion can thus be used as a proxy for the rate of
intestinal glucose absorption. Because this is an indirect measure, however, it may be less sensitive than direct measures of
intestinal glucose absorption used in rodent studies. At the
current time, there is insufficient evidence to support an effect
of non-nutritive sweeteners on intestinal glucose absorption
in healthy humans.
Non-Nutritive Sweetener Effects on the
Microbiome
Connections between nutrition, gut microbial communities,
and specific aspects of our health, such as the function of the
immune system and the development of obesity, are under
intense investigation (53, 54). A bidirectional influence of
nutritional components such as non-nutritive sweeteners on
the gut microbiome and vice versa is highly likely. For example, rodent studies have shown that germ-free animals
up-regulate their sweet-taste receptors and glucose transporters in the proximal small intestine and preferentially consume nutritive compared with non-nutritive sweeteners (55).
Abou-Donia et al. (56) suggested that sucralose may alter the
microbiome of rats and furthermore reported that sucralose
up-regulated intestinal enzymes important for drug metabolism. To date, there are no published studies in humans
examining these questions.
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Conclusions
The identification of sweet-taste receptors in enteroendocrine cells, both in the intestinal epithelium and the pancreas, has led to important insights into the mechanisms
underlying glucose sensing, glucose transport, and hormone secretion. Non-nutritive sweeteners have allowed
researchers to distinguish effects that are mediated via
sweet-taste receptors (that bind to non-nutritive sweeteners) from effects mediated by other glucose sensors and
transporters, such as SGLT-1. Given the epidemiological
data associating non-nutritive sweetener use with weight
gain and diabetes, it is intriguing to speculate that intestinal sweet-taste receptors might provide a mechanistic
link. Egan and Margolskee (57) proposed that non-nutritive sweeteners binding to intestinal sweet-taste receptors
would lead to increased GLP-1 secretion, which in turn
would increase insulin secretion and lower blood glucose,
and thus increase appetite and induce weight gain. Corkey
(43) raised a similar provocative hypothesis in the 2011
Banting Lecture, speculating that non-nutritive sweeteners and other food additives might induce pancreatic ␤-cell
hypersecretion, leading to hepatic insulin resistance and
increased fat accumulation, both key components of obesity and type 2 diabetes.
Although most in vitro data support the idea that nonnutritive sweeteners can increase hormone secretion by
enteroendocrine cells or pancreatic ␤-cells, the available in
vivo data have generally not supported this. In both rodents and humans, non-nutritive sweeteners in the absence
of metabolizable sugars have not altered hormone secretion in vivo. When given in combination with metabolizable sugars, non-nutritive sweeteners increased intestinal
glucose absorption in rodents, but not humans. One human study showed that non-nutritive sweeteners may increase GLP-1 when given in combination with metabolizable sugars, but this finding needs to be replicated. To
date, solid evidence for a clinically relevant role of nonnutritive sweeteners on gut hormones or glucose metabolism in humans remains to be established. Ongoing and
future clinical studies will hopefully soon provide answers
to the highly relevant questions about the effects of nonnutritive sweeteners on gut hormones, glucose metabolism, and ultimately human weight regulation.
Acknowledgments
We thank Allison Sylvetsky for critical review of the manuscript.
Address all correspondence and requests for reprints to:
Rebecca J. Brown, M.D., Building 10, Room 7C-432A, 9000
Rockville Pike, Bethesda, Maryland 20892-1645. E-mail:
[email protected].
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Brown and Rother
Non-Nutritive Sweeteners and the Gut
J Clin Endocrinol Metab, August 2012, 97(8):2597–2605
This work was supported by the intramural research program
of the National Institute of Diabetes and Digestive and Kidney
Diseases.
Disclosure Summary: The authors have no conflicts of
interest.
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