Review
Non-nutritive sweeteners: Review and update
Padmini Shankar Ph.D., R.D. a,*, Suman Ahuja Ph.D. b
, Krishnan Sriram M.B.B.S., F.R.C.S(C), F.A.C.S. c
a
Department of Health and Kinesiology, Georgia Southern University, Statesboro, GA, USA
b
Department of Cooperative Research, Human Nutrition/Obesity Research, Lincoln University, Jefferson City, MO, USA
c
Division of Surgical Critical Care, Surgical Nutrition Section and Nutrition Support Team, Stroger Hospital of Cook County, Chicago, IL, USA
a r t i c l e i n f o
Article history:
Received 19 November 2012
Accepted 31 March 2013
Keywords:
Non-nutritive sweeteners
Obesity
Artiﬁcial sweeteners
Non-caloric sweeteners
Sugar substitutes
a b s t r a c t
Obesity has become an epidemic, not just in the United States, but also across the globe. Obesity is
a result of many factors including poor dietary habits, inadequate physical activity, hormonal
issues, and sedentary lifestyle, as well as many psychological issues. Direct and indirect costs
associated with obesity-related morbidity and mortality have been estimated to be in the billions
of dollars. Of the many avenues for treatment, dietary interventions are the most common.
Numerous diets have been popularized in the media, with most being fads having little to no
scientiﬁc evidence to validate their effectiveness. Amidst this rise of weight loss diets, there has
been a surge of individual products advertised as assuring quick weight loss; one such product
group is non-nutritive sweeteners (NNS). Sugar, a common component of our diet, is also a major
contributing factor to a number of health problems, including obesity and increased dental
diseases both in adults and children. Most foods marketed towards children are sugar-laden.
Obesity-related health issues, such as type 2 diabetes mellitus, cardiovascular diseases, and
hypertension, once only commonly seen in older adults, are increasing in youth. Manufacturers of
NNS are using this as an opportunity to promote their products, and are marketing them as safe for
all ages. A systematic review of several databases and reliable websites on the internet was
conducted to identify literature related to NNS. Keywords that were used individually or in
combination included, but were not limited to, artiﬁcial sweeteners, non-nutritive sweeteners,
non-caloric sweeteners, obesity, sugar substitutes, diabetes, and cardiometabolic indicators. The
clinical and epidemiologic data available at present are insufﬁcient to make deﬁnitive conclusions
regarding the beneﬁts of NNS in displacing caloric sweeteners as related to energy balance,
maintenance or decrease in body weight, and other cardiometabolic risk factors. Although the FDA
and most published (especially industry-funded) studies endorse the safety of these additives,
there is a lack of conclusive evidence-based research to discourage or to encourage their use on
a regular basis. While moderate use of NNS may be useful as a dietary aid for someone with
diabetes or on a weight loss regimen, for optimal health it is recommended that only minimal
amounts of both sugar and NNS be consumed.
Ó 2013 Elsevier Inc. All rights reserved.
Introduction
In recent years, increased obesity related mortality has
resulted in a surge of weight loss diets and products, and various
ﬁtness routines. It is widely understood that of the many
contributing factors, a high sugar/high fat diet is partly to be
blamed for the increasing obesity and related health issues such
as type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD),
hypertension, and certain cancers [1,2]. As a result of the many
negative health conditions associated with the intake of
excessive sugar, there has been an upsurge in the consumption of
NNS as an alternative [3]. Consumption of NNS-containing foods
has increased among people of all ages, with 28% of the total
population reporting intake. This trend is highly prevalent
among children, especially when it comes to beverage intake.
Analysis of National Health and Nutrition Examination Survey
data collected from 1999 to 2008 shows that NNS-containing
beverage use increased from 6.1% to 12.5% among children and
from 18.7% to 24.1% among adults [4]. A large variety of NNS are
available, and they are differentiated based on whether they are
high-intensity, low-calorie, high-potency, and/or non-nutritive
[3]. NNS are known to be at least 30 to 13,000 times sweeter in
taste compared with their natural counterpart, sugar (sucrose).
* Corresponding author: Tel.: 912-478-5785; fax: 912-478-0381.
E-mail address: pshankar@georgiasouthern.edu (P. Shankar).
0899-9007/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.nut.2013.03.024
Contents lists available at ScienceDirect
Nutrition
journal homepage: www.nutritionjrnl.com
Nutrition 29 (2013) 1293–1299
This intense sweetness allows for smaller portions to yield sugar
like sweetness in food products, thus enabling the manufacturer
to label them as virtually “sugar free” or “non-caloric” [3].
The increased incidences of obesity and related health issues,
mainly T2DM and CVD, have resulted in an increased production
and consumption of foods made with NNS. The fundamental
principle behind this upsurge in use of NNS is that individuals
struggling with obesity can enjoy foods and beverages without
the risk of consuming additional calories contributed by normal
sugar-based products. NNS can be found in almost any food
product such as beverages, ice cream, chewing gum, chocolate,
jams/jellies, yogurt, and salad dressings. Overzealous use of
these NNS brings to light the issue of safety, mainly with respect
to the maximum amounts of said NNS considered safe for human
consumption and whether there are any associated health issues
with the use of these laboratory-created sweeteners.
Since their discovery and introduction into the public market,
there has been much debate regarding the health advantages
and disadvantages of artiﬁcial sweeteners. The very ﬁrst
evidence of artiﬁcial sweetener–related health issues was
observed by the FDA before it banned a commonly used sugar
substitute known as cyclamate, which was deemed inappropriate
for consumption due to its carcinogenic effects evidenced
through many animal studies [5]. Since then, the NNS industry
has come a long way and consumers now have products safe for
consumption, even for kids. However, irrespective of advancements
in technology, it appears that scientiﬁc information
regarding these sweeteners and the established amounts
considered safe for consumption seem to be scarce. Hence,
through this review, we aim to establish scientiﬁc information
about the most commonly used artiﬁcial sweeteners in the food
industry. In reviewing these NNS, we will discuss issues
involving the sweetness factor compared with sucrose, FDArecommended
safety guidelines, health implications of
consuming these sweeteners, threat of a carcinogenic and/or
teratogenic effect, energy restriction, and other common issues
such as sweeteners acting as laxatives when consumed in excess.
Methods
Based on these factors, we decided to review the pros and
cons of consuming NNS, and to outline salient properties of
some of the most commonly used NNS to help clinicians counsel
their patients accordingly. A systematic review of several databases
including MEDLINE and PubMed, and reliable websites
on the internet was conducted from 1987 to 2012 to identify
literature related to NNS. The keywords used individually or in
combination, artiﬁcial sweeteners, non-nutritive sweeteners, noncaloric
sweeteners, obesity, sugar substitutes, diabetes, and cardiometabolic
indicators, were variously combined in the search list.
Role of non-nutritive sweeteners on glucose homeostasis
Non-nutritive sweeteners have been in use for decades for
both weight loss and in diabetic diets. In fact, the Academy of
Nutrition and Dietetics [6] suggests NNS may be used to enhance
the palatability of foods to help consumers increase their
consumption of certain foods to be included in their respective
dietary routines. However, the understanding thus far was that
NNS did not affect fasting glucose and insulin responses
in patients with TD2M supplemented with NNS, particularly
sucralose, to assist these patients in increasing compliance with
their dietary needs [7]. To better understand the effects of NNS
on glucose homeostasis, a recent study investigated the shortterm
effects of sucralose on glucose homeostasis and hunger
compared with water, sucrose, and sucrose combined with
sucralose in the liquid form [8]. Additionally, the study also
examined the effects of consuming the aforementioned treatment
beverages before consumption of a standardized breakfast
to determine the physiological responses elucidated by the body
in response to speciﬁc meals. The amount of sucralose used in
the study approximated that of what is in a regular soft drink.
Blood samples were collected at fasting, post-treatment, and
after breakfast; the study found no differences in subjective
responses, circulating triglycerides, or glucagon concentrations
among treatment groups over time. However, the study reported
signiﬁcant differences in insulin, glucose, and ghrelin concentrations
over time between the sucrose and non-sucrose treatments
regardless of their sucralose consumption. Thus, the
study concluded that sucralose may in fact be a relatively inert
NNS as far as evoking hunger signals and short-term glucose
homeostasis.
Non-nutritive sweeteners and their inﬂuence on weight control
Because NNS are alternatives to table sugar and its calories,
theoretically, NNS would only aid in weight loss if compensatory
sugar intake does not occur. Of concern is the appetite-promoting
effect of NNS. Rats administered liquids containing saccharin
consumed more food and gained more weight compared with
rats given liquids containing glucose. The common perception
that NNS may promote weight loss by reducing calories is
misguided because consumption of saccharin-sweetened liquids
increased overall food intake [9]. Furthermore, positive correlations
between NNS consumption and increased body mass index
in children and adolescents have been reported in several observational
studies [10–12]. However, there is a lack of conclusive
evidence to state that NNS may be the cause of weight gain in
children [13]. A second study found no evidence to link NNS use
to weight gain in adults either [14]. Management of obesity is
multifactorial, and no adequate evidence exists to target NNS use
as an effective strategy in weight management. Other factors
associated with modern lifestyle behaviors and genetics may be
confounding inﬂuences that promote weight gain.
A Western diet and sedentary lifestyle encouraging energydense
foods have resulted in a surge of chronic diseases that
have led to an interest in gene–diet interactions within the
clinical and scientiﬁc community. Understanding this gene–diet
interaction can help promote diet modiﬁcations and reduction of
obesity-related health disorders based on genetic makeup. Of all
the energy-dense foods, it appears that consumption of sugarsweetened
foods and beverages may have the most effect on
gene–diet-related patterns of obesity [15].
Saccharin
Saccharin has been on the market for more than 100 y and
is the oldest NNS. It was discovered by Remsen and Fahlberg
at John Hopkins University in 1879. This non-caloric sweetener
is 200 to 700 times sweeter than sugar. It is marketed under the
brand names Sweet’N LowÒ, Sugar TwinÒ, and Necta SweetÒ.
In the food industry, it is commonly used in soft drinks, baked
goods, jams, canned fruit, candy, salad dressing, dessert toppings,
and chewing gum, in addition to being used as a tabletop
sweetener. It also is used in other household products such as
toothpaste, lip gloss, mouthwash, vitamins, and pharmaceuticals.
An important characteristic of saccharin is that its sweetening
power is not reduced when heated, which makes it an excellent
P. Shankar et al. / Nutrition 29 (2013) 1293–12991294
candidate as an additive in low-calorie and sugar-free products.
Saccharin is not metabolized in the gastrointestinal (GI) tract and
therefore does not affect blood insulin levels [16], which makes
saccharin a viable sugar substitute for patients with diabetes.
The Adequate Dietary Intake (ADI) for saccharin is set at 5 mg/
kg body weight per day for adults and children. As per a 2010
report in Current Oncology [17], one would have to drink about
800 twelve-ounce diet sodas containing saccharin to reach doses
that can induce carcinogenesis. The ADI also means that one can
“safely consume 8.5 tabletop sweetener packets nearly every day
over his or her lifetime.” It seems highly unlikely that any population
would exceed the ADI for such intense sweeteners,
considering the average user of saccharin ingests less than
1ounce of the sweetener each year. In a Belgian study, no risk for
exceeding the ADIs established for saccharin and other similar
sweeteners was found among individuals older than age 15 y [18].
However, a survey of the usage pattern of saccharin in edible
products in India found that in all age groups consumption
exceeds the ADI, with the most susceptible group being the 6- to
10-y age group, who exceeded the ADI by 54% through the
consumption of ice candy and crushed ice. Intake of foods containing
saccharin is high in India, as it is the cheapest and most
widely used NNS product. Furthermore, a habitual intake of
pan masala and pan betel products resulted in an excessive
consumption of saccharin with an estimated maximum daily
intake that exceeded the ADI by 137% [19]. Thus, overconsumption
is possible in some settings warranting further study.
Since its introduction into the market, saccharin has been
researched extensively to determine its carcinogenic potential.
Studies in the 1970s and 1980s reported bladder cancer in rats
given high doses of saccharin, which prompted the FDA in 1981
to pass a mandate that products containing saccharin carry
a label warning about its potential as a human carcinogen [20].
However, it was later found that the cancer-causing mechanisms
in rodents are not applicable to humans. Furthermore, clinical
studies conducted since then have shown no association between
saccharin consumption and cancer in humans [21]. As
a result, in 2000, saccharin was delisted from the National
Toxicology Report on Carcinogens and labels no longer have to
display such warning [22].
A case–control study in Italy examined the association
between saccharin and other NNS and gastric, pancreatic, and
endometrial cancers between 1991 and 2004. The results of this
study indicate that consumption of NNS products such as
saccharin and aspartame are not associated with the risk for
neoplasms in the population studied [23].
In a recent study, rats that consumed saccharin-sweetened
liquids had an increased food intake and gained more body
weight than rats that consumed glucose-sweetened liquids [9].
The ﬁndings of this study have major implications on public
health, given that people are consuming foods containing NNS in
an effort to lose weight. This study, although not done on
humans, challenges the popular notion that use of intense NNS
help in weight loss due to the calorie deﬁcit. In another study,
the same authors reported that in addition to increased energy
intake and weight gain, use of NNS also caused accumulation of
body fat and weaker caloric compensation [24].
Saccharin is the oldest and most researched of all NNS. It
bears the FDA stamp of approval in suggested quantities by being
a food additive on the Generally Recognized as Safe (GRAS) list
[25]. GRAS is a term designated to any substance added to food as
an additive that is considered to be generally safe for human
consumption. Despite its questionable carcinogenic history,
currently there is not enough evidence that identiﬁes it as
a carcinogenic agent and it appears to be safe for consumption
among children and adults, including pregnant women and
patients with diabetes when quantities consumed are within
the ADI recommendations.
Aspartame
Aspartame was originally discovered by James Schalatter,
a chemist, who was working on an anti-ulcer drug. It is the
methyl ester of the two amino acids, aspartic acid and phenylalanine.
Although discovered in 1965, aspartame was not approved
by the FDA until 1981 [26]. It is sold under the brand
names EqualÒ, NutraSweetÒ, and Natra TasteÒ. Because it is
made from amino acids, it provides 4 kcal/g. Aspartame is 200
times sweeter than sucrose and therefore very small amounts
are required for sweetening foods, thus making its caloric
contribution insigniﬁcant. According to the FDA, the acceptable
daily intake of aspartame for humans is 50 mg/kg body weight,
for both adults and children [27]. Aspartame is used as a sweetener
in many products including chewing gum, diet soda, dry
drink mixtures, yogurt and pudding, and instant tea and coffee.
The ﬂavor proﬁle of aspartame is found to be highly acceptable.
In a study on the effects of artiﬁcial sweeteners on food intake
and satiety, aspartame was found by participants to have a more
pleasant taste compared with stevia or sucrose [28]. Furthermore,
aspartame does not elicit the same response as sugar does
in the brain or the pancreas. A magnetic resonance imaging
study showed a decline in activity of the hypothalamus part of
the brain after ingestion of sucrose, whereas aspartame does not
show similar response. It is suggested that for a hypothalamic
reaction to occur there should be the combined stimuli of sweet
taste and energy content, as found in sweetened caloric beverages.
In the pancreas, aspartame does not stimulate an insulin
response as sugar does [29].
Aspartame is metabolized to phenylalanine, aspartic acid,
and methanol in the GI tract. People with the genetic disorder,
phenylketonuria, must exercise caution because they cannot
break down phenylalanine to tyrosine, and therefore must avoid
aspartame [26]. Because of aspartame’s effects on these patients,
the FDA requires all aspartame products to have a label stating
the containment of phenylalanine [6]. Common side effects reported
from aspartame consumption include dizziness, headaches,
GI issues, and mood changes [30].
There are mixed reports about the safety of aspartame. All of
the studies funded by the industry vouch for its safety, whereas
92% of independently funded studies report that aspartame can
cause adverse health effects [31]. Several studies have reported
aspartame to be a trigger in causing headaches, with some
people being more susceptible to this malady [32–34]. There are
still many claims that a number of health problems are associated
with consumption of aspartame including, but not limited
to: Alzheimer’s disease, attention-deﬁcit disorders, birth defects,
cancer, diabetes, Gulf War syndrome, and lupus [27]. Aspartame
can promote seizures in susceptible animal models by increasing
phenylalanine levels in the brain. A similar effect is probable in
human beings with seizures caused by increased phenylalanine
[35]. In pregnant rats, aspartame proved to be nephrotoxic by
causing alterations in the morphology of renal structures in the
fetus and by causing decreased fetal body weight [36]. No
association was found between aspartame consumption and the
risk for common neoplasms such as gastric, pancreatic, and
endometrial cancers among Italian people [23]. Aspartame
intake during pregnancy and lactation was not found to increase
risk for brain tumors among children [37]. Aspartame remains
P. Shankar et al. / Nutrition 29 (2013) 1293–1299 1295
one of the most controversial and widely used artiﬁcial sweeteners
today.
Acesulfame-K
Acesulfame-K was discovered in 1967 by the pharmaceutical
company, Hoechst. This high-intensity sweetener is about 200
times sweeter than the table sugar sucrose [38]. It is used in
more than 100 countries in more than 5000 products [39]. In the
United States, acesulfame-K was initially permitted only in foods
such as sugar-free baked goods, chewing gum, and gelatin
desserts. In July 1998, this non-caloric sweetener was approved
for use in soft drinks by the FDA [40]. Acesulfame-K is sold under
the brand names SunetteÒ, Sweet OneÒ, and Swiss SweetÒ [41].
Acesulfame-K is heat stable and can be used in cooking and
baking.
The ADI for acesulfame-K is 15 mg/kg body weight. In the
United States, actual consumption is about 20% of the ADI over
a lifetime [42]. As such, typical amounts of acesulfame-K and
other artiﬁcial sweeteners consumed by the average population
are quite low that toxicity is highly unlikely. In Portuguese
teenagers, the highest estimated daily intake of acesulfame-K
and aspartame was from soft drinks. However, the amount
consumed was well below the ADI and this population was noted
to be at low risk for any adverse effects arising from use of these
artiﬁcial sweeteners [43].
Being a blended product comprising of an organic acid and
potassium, acesulfame-K typically is found in food products in
combination with other artiﬁcial sweeteners, which helps in
developing an optimal ﬂavor proﬁle [44]. It is usually combined
with aspartame or sucralose to provide a synergistic sweetening
effect. Such combinations not only provide a “more sugar-like
taste” but also decrease the total amount of sweetener used
[41]. Concerns about the safety proﬁle of blends of artiﬁcial
sweeteners are addressed in a study that found no synergistic
genotoxic effects when acesulfame-K was used in combination
with aspartame in mice [45].
Acesulfame-K is excreted by the kidneys after it passes
through the body unchanged [44]. One of the byproducts of
acesulfame-K’s breakdown in the body is acetoacetamide, which
is toxic at high doses. However, the amount of acesulfame-K used
to sweeten a beverage is very small and as such does not pose
a safety hazard [46].
Widespread concerns exist about the safety of acesulfame-K,
since it was tested in the 1970s when “the standard criteria for
the design of animal carcinogenesis bioassays were still under
development” [47]. The FDA approved acesulfame-K despite
inadequate and poor-quality toxicity tests. Although acesulfameK
was nominated twice for testing in 1996 and 2006 in the
National Toxicology Program (NTP) bioassay program, the
motion was rejected by NTP and the product has not been subjected
to such testing.
Sucralose
Sucralose, an artiﬁcial sweetener discovered in 1976, was
granted FDA approval in 1998 for use as a sugar substitute in 15
food and beverage categories. Marketed under the brand name
SplendaÒ, sucralose has a taste proﬁle very similar to sugar and
has no unpleasant aftertaste, an undesirable trait found in many
other NNS. Extensive testing has established an excellent safety
proﬁle for sucralose, allowing it to be used among all population
groups, including pregnant and nursing mothers [48].
Sucralose is a highly intense sweetener that is 600 times
sweeter than table sugar. It is made by selective substitution of
chlorine for hydroxyl groups on a sucrose core. This compound is
not recognized by the body as a carbohydrate due to being poorly
absorbed during the digestion process. It passes through the
body relatively unchanged with insigniﬁcant amounts being
absorbed in the GI tract. Eventually, it is eliminated in the feces
unchanged [44]. Sucralose is exceptionally stable and is able to
retain its sweetness when subjected to high heat and acidity
[49]. In the food industry, it is widely used as a NNS and is found
in more than 4000 products in the United States [50]. Sucralose is
also used as a sweetener in more than 80 countries today [51].
In a study comparing the sensory proﬁle of several sweeteners,
it was found that sucralose is most similar to table sugar
[52], but unlike table sugar, sucralose does not promote tooth
decay. In 2006, the FDA approved the use of a health claim
regarding sucralose and the non-promotion of dental caries [53].
The safety proﬁle of sucralose has been extensively reviewed
and has been reported to be non-carcinogenic and nongenotoxic.
Furthermore, due to its lack of bioreactivity and bioaccumulation
in humans and animal models, sucralose is
considered to be safe for long-term use [54].
There have been some claims that sucralose may negatively
affect health. One controversial study found it to cause adverse
effects in the GI tract [55]. Rats that consumed SplendaÒ for 12
wk had a signiﬁcant decrease in beneﬁcial gut bacteria with
resulting weight gain, increased fecal pH due to decreased
production of short-chain fatty acids by colonic bacteria, and
enhanced expression of cytochromes in the body that can
potentially affect bioavailability of nutrients and drugs. Furthermore,
the stated changes in the GI tract occurred even when the
rats were fed sucralose at low doses approved by the FDA for
human consumption [55]. However, these results were widely
criticized, with an expert panel report citing that the study is
“deﬁcient in several critical areas” and that the conclusions from
the study are not “scientiﬁcally valid” [56].
Sucralose has been deemed safe for consumption by patients
with diabetes because it has no effect on carbohydrate metabolism
[57]. This NNS does not change the rate of glucose absorption
from the small intestine; nor does it increase glycemic
response or levels of incretin hormones such as glucagon-like
peptide-1 and glucose-dependent insulinotropic polypeptide
in healthy humans given an intraduodenal/intragastric infusion
[58,59]. Furthermore, sucralose did not stimulate insulin release
or slow gastric emptying, thereby maintaining glucose homeostasis
in the study population [59]. Other study ﬁndings
indicate that sucralose had no effect on appetite in healthy,
normal-weight adults [60]. NNS have been purported to increase
insulin resistance, which could lead to weight gain. However, in
a study comparing the body’s response to sucrose and sucralose,
sucralose did not raise blood sugar levels or increase insulin
resistance [61].
Because NNS are widely used by the public including women
of childbearing potential, concern exists about its possible teratogenic
effects. No adverse effect on normal fetal development
was observed in pregnant rats and rabbits when fed sucralose
during organogenesis [62]. However, some potential adverse
health effects are reported from sucralose use. Case studies have
identiﬁed sucralose to be a causative agent in triggering migraine
headaches [63,64]. In a hypothetical report, sucralose is suggested
to be the most likely cause in the increased incidence of
inﬂammatory bowel disease among Canadians due to its inhibiting
action on gut bacteria, gut barrier function, and digestive
protease enzymes [65].
P. Shankar et al. / Nutrition 29 (2013) 1293–12991296
Sucralose is one of the most researched and reviewed food
additives today. Based on its strong safety background, it is even
promoted for use among children. It is recommended that it be
used in children’s foods to reduce sugar calories, which could be
an effective strategy to combat childhood obesity [50], which is
one of the most challenging public health concerns today.
Tagatose
Over the last few years, numerous NNS have been added
to the list, one of them being a ketohexose also known as Dtagatose.
Tagatose is a fructose isomer that is commonly found in
milk and milk products. In comparison with sucrose and other
sugars, it has been reported that tagatose produces a lower
glycemic response and virtually zero calories [66]. This sweetener
has been examined for its safety and functional properties
as a bulk sweetener [8,67]. For an artiﬁcial sweetener to be
considered a staple in commercial food products, the two qualities
that render it useful for consumption are safety and taste. A
study investigating D-tagatose as a bulk sweetener reported that
this sweetener not only has physical attributes identical to that of
sucrose, but, the sweetness was comparable to sucrose as well. In
fact, this study reported that trace amounts of D-tagatose are
commonly found in certain milk products [8]. Another study
reported that per FDA laws and policies, D-tagatose was found to
contain no toxic, carcinogenic, or teratogenic compounds or
effects upon consumption [8]. A common problem associated
with consumption of most artiﬁcial sweeteners is the fact that
they can act as laxatives and although the FDA does not label
a laxative effect as toxic, it does require that food manufacturers
using sugar substitutes in their products label cautionary information
regarding the possibilities of a laxative effect and
subsequently print amounts/serving sizes safe for consumption
to avoid such health issues [8]. In an experimental study, rats
were fed a diet comprising of 20% (wt:wt) D-tagatose. The
researchers evaluated both a stool-softening as well as a laxative
effect induced by the sweetener. The results revealed that
a laxative effect was observed only upon inducing higher doses.
However, with the doses administered, the rats had normal
stools and it appears that the D-tagatose was well tolerated over
a period of 3 d [67]. Similar tests, when performed on humans,
revealed that the mean laxative threshold value when consuming
D-tagatose was approximately 40 g per meal over a single
meal. However, additional studies are required to attest to these
ﬁndings [67]. Another study reported that humans can easily
tolerate up to 75 g of D-tagatose as long as it is equally distributed
over three meals [8]. It also was reported that after carefully
controlled experimental studies, D-tagatose could be used safely
in products to assist with weight loss as well as diabetes because
this sweetener effectively had a zero energy value as revealed via
metabolic experimental studies [8,67]. One study even reported
possible anti-aging properties induced by D-tagatose by way of
animal subjects (rats) on D-tagatose, demonstrating consistently
low plasma glucose and insulin levels compared with those fed
a regular glucose diet [68]. Of course, extensive human studies
would be required to justify the anti-aging properties of this
sugar substitute. Finally, it has been reported that tagatose might
have pharmaceutical capabilities, especially in treating patients
with diabetes. A Phase III clinical trial is in place to investigate the
mechanisms and efﬁcacy of tagatose in reducing hemoglobin A1c
levels. Although, the trials are still under way, human studies
have suggested that tagatose could be the new potential antidiabetic
drug because of its effects on postprandial hyperinsulinemia
and hyperglycemia in individuals with T2DM [69].
Nonetheless, it appears that at this time D-tagatose has been
successfully used in chocolate and chewing gum, however,
whether it may be approved as a sugar substitute safe for
consumption on a regular basis and an appropriate replacement
for table top sugar will depend on approvals from the FDA and
other such entities.
Sugar alcohols
Sugar alcohols are saccharide derivatives obtained by replacing
an aldehyde group with a hydroxyl group. Additionally,
sugar alcohols also are classiﬁed as hydrogenated monosaccharides
most commonly known as sorbitol, mannitol, and
xylitol; hydrogenated disaccharides such as isomalt, maltitol,
and lactitol; and as mixtures of hydrogenated mono-di- and/or
oligosaccharides such as hydrogenated starch hydrolysates
[70]. It is the limited digestion and absorption associated with
sugar alcohols that make them a primary choice of ingredients in
sugar- and energy-restricted foods [70]. Several factors affect the
digestion and absorption of sugar alcohols, one being gastric
transit time and the fact that sugar alcohols might get fermented
by gut bacteria, thus allowing limited absorption and to a certain
extent, some sugar alcohols may escape the process of absorption
completely [70]. However, unlike other NNS, it is important
to note that with sugar alcohols that make it as far as the distal
intestine, they will be subjected to some amount of fermentation
thus leading to production of hydrogen, methane, carbon
dioxide, and small amounts of short-chain fatty acids. Of all the
gaseous matter produced, likelihood of short-chain fatty acids
being converted to small amounts of energy are very plausible.
Although the energy available from sugar alcohols is 15% to 25%
lower than glucose, the conversion of energy to adenosine
triphosphate is almost as efﬁcient as that of glucose [70]. Thus,
for these reasons, the 1990 European Council Directives established
an energy value for sugar alcohols for the purpose of food
labeling [71].
Although sugar alcohols are widely used in foods, limited
research is available to determine the metabolic effects of these
sweeteners in humans [72]. A recent study investigated the
metabolic effects of lactitol and xylitol in comparison with
glucose on plasma insulin, glucose, and C-peptide in eight
healthy, non-obese men. It was observed that upon ingestion of
25 g of lactitol or xylitol, plasma insulin, glucose, and C-peptide
concentrations were not affected as dramatically as with ingestion
of glucose [72]. In fact, this study also reported that glycemic
indices of lactitol and xylitol were found to be –1 and 7 compared
with 100 g of glucose. Finally, the effects of consumption of these
sugar alcohols on carbohydrate and lipid oxidation is very
minimal compared with glucose [72]. Hence, it might be worth
exploring use of these sugar alcohols in food products marketed
to patients with diabetes and individuals considering energyrestricted
diets.
Stevia
Stevia, a natural NNS, is a glycoside isolated from the plant
Stevia Rebaudiana Bertoni and has been widely used in Japan for
more than 20 y [73,74]. Recently, stevia has been marketed as
a no-calorie sweetener in baked goods and soft drinks. Studies
have indicated possible hypotensive roles performed by stevia
[74], in addition to some suggesting stevia increases insulin
sensitivity and glucose tolerance in humans [28]. As far as safety
issues concerning stevia, no negative side effects have been reported
thus far. In fact, very recently stevia was approved for use
P. Shankar et al. / Nutrition 29 (2013) 1293–1299 1297
as a sweetener by the Joint Food and Agriculture Organization/World
Organization Expert Committee on Food Additives
[28]. A recent study evaluated the taste responses of rodents
(mice and rats) to both stevia and saccharin. It was reported that
both mice and rats responded strongly to stevia compared with
other non-caloric sweeteners, mainly aspartame and cyclamate
[73]. Such experiments provide a new understanding of the
effectiveness of these products. Of course, animal data would
have to be tested in humans before any conclusions on the safety
and efﬁcacy of these products are to be claimed. The very ﬁrst
study [28] that investigated the effects of stevia on food intake,
satiety, and postprandial glucose and insulin responses in
humans reported that participants who consumed products
made with stevia had a lower total caloric intake compared with
those consuming sucrose. Furthermore, consumption of stevia
signiﬁcantly lowered insulin levels compared with both aspartame
and sucrose, thus suggesting that using stevia in place of
sucrose might be an effective way of managing food intake and
satiation concerns. This study also reported that individuals
consuming stevia had signiﬁcantly lower postprandial glucose
responses compared with those on aspartame and sucrose [28].
These ﬁndings suggest promising avenues for both manufacturers
and individuals turning to products made with artiﬁcial
sweeteners to combat the twin epidemics of obesity and T2DM.
Conclusion
Consumers often do not have adequate information about
NNS. The pieces of information they are provided often are
contradictory depending on the motive and investment of the
body, industry, or agency providing the information. Although
the FDA and most published (especially industry-funded) studies
endorse the safety of these additives, there is a lack of conclusive
evidence-based research to discourage or to encourage their use.
However, consumers should be advised to employ a cautious
attitude when using artiﬁcial sweeteners. When using any new
product, it is important to monitor for symptoms related to
allergies or intolerance, which may occur even when very small
amounts are consumed. It is highly unlikely that U.S. consumers
will exceed the ADI established for NNS. As these products have
been on the market for decades, with consumption patterns on
the rise and no reported adverse health problems affecting large
numbers of people, their continued popularity and increased use
are to be expected.
The clinical and epidemiologic data available at present are
insufﬁcient to make ﬁrm conclusions regarding the beneﬁts of
NNS displacing caloric sweeteners in energy balance maintenance
or decrease of body weight or cardiometabolic risk factors.
As a result of scarce epidemiologic and clinical data on the
pros and cons of consuming NNS, very few recommendations
regarding consumption of artiﬁcial sweeteners are made available.
However, the Academy of Nutrition and Dietetics recommends
using artiﬁcial sweeteners in moderation, in conjunction
with a healthy diet based on the recommendations provided in
the Dietary Guidelines for Americans [6]. Given the sudden rise
in obesity and related health issues, it is crucial that clinicians
and scientists pursue research involving use of artiﬁcial sweeteners
to understand their effects on energy consumption,
appetite, satiety, body mass index, weight management,
biochemical parameters such as insulin, glucose, leptin, cortisol,
and ﬁnally the effects of artiﬁcial sweeteners on food cravings.
A recent scientiﬁc statement issued jointly by the American
Heart Association and the American Diabetes Association adds
credibility to this assertion [75]. A more recent publication
emphasizes that obesity is not related to sugar consumption [76].
Weight management depends more on total calorie restriction
rather than avoidance of caloric sweeteners. However, the use of
NNS as an adjunct to dietary management in diabetes, in an
attempt to optimize glycemic control, is more acceptable and
practiced more frequently.
For optimal health it is recommended that only minimal
amounts of both sugar and NNS be consumed. Today, there is
renewed emphasis on eating fresh, local, and natural foods to
maintain good health and promote sustainability. This calls for
a balanced diet that includes whole grains, vegetables, fruits,
legumes, nuts and seeds, low-fat dairy and lean meats, and
avoidance or minimal inclusion of processed foods and additives.
If these general principles of lifestyle are followed, artiﬁcial
sweeteners, like the sugars they replace, will have an
insigniﬁcant role in our diet and our lives.
Acknowledgments
We would like to thank Alexandra Tracchio and Shannon
Cearley for their help in preparation of the manuscript.
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