Current Evidence on Noncaloric Sweeteners and their Health Implications

Overview

Use of artificial sweeteners has been rising in the U.S. for the last 50 years. Because artificial sweeteners deliver a sweet flavor without calories, these substitutes have been considered a solution to endemic problems such as obesity and diabetes, which are linked to high caloric and sugar intake. But over the same time period, average body weight in the U.S. has increased steadily, as it has been for well over 100 years, and any link between the two trends remains unclear.

For many consumers, artificial sweeteners, also known as low-calorie sweeteners (LCSs) or nonnutritive sweeteners (NNSs), raise concerns about toxicity or deleterious health effects. On November 16, 2015, PepsiCo Global Research and Development and the Academy's Sackler Institute for Nutrition Science presented a symposium on Current Evidence on Noncaloric Sweeteners and their Health Implications to consider existing research on sweeteners.

The evening began with a presentation by John Glendinning of Barnard College, who described mouse models that are used to study the roles of taste receptors in physiology and flavor perception. Although no published studies indicate that NNSs pose a risk to humans, the use of artificial sweeteners is controversial, and some opponents fear that metabolic disruption or addiction will result. Glendinning discussed the metabolic fate of NNSs in the intestinal tract and the different sensory mechanisms that mediate their detection in the mouth.

There are two signaling pathways for sweeteners in taste cells. One involves the canonical sweet-taste receptor T1r2+T1r3, and the other the K(ATP) signaling pathway. The importance of T1r2+T1r3 signaling to the attraction of mammals to sweeteners is well established. For instance, wild-type mice offered a choice between water and a sweetener solution (containing a sugar or NNS) show strong preference for the sweet taste. In contrast, T1r3 KO knockout mice (which lack the T1r3 subunit of T1r2+T1r3) show no attraction to the taste of the sweetener solution when offered the same choice.

Another important function of sweet taste is its contribution to a process called the cephalic-phase insulin release (CPIR). The process is elicited by the taste, smell, and visual appearance of foods, and causes a rapid spike in blood insulin even before food has been swallowed. The CPIR has been found to help mammals, including humans, maintain glucose homeostasis in the blood. Glendinning recently demonstrated that the taste of sugars (e.g., glucose and sucrose) but not of NNSs elicit CPIR in mice.

Glendinning explained that T1r2+T1r3 signaling is not required for mice to generate a normal CPIR. Indeed, T1r3 KO knockout mice show normal CPIR to oral stimulation with sugars. He found, however, that mice lacking a protein called Sur1 that is required for K(ATP) signaling exhibit normal behavioral attraction to sweeteners but show no CPIR to oral stimulation with sugars.

He emphasized that these observations are important for several reasons. First, they indicate that there are at least two signaling pathways for sugars in the taste system, each with a different function. T1r2+T1r3 signaling mediates behavioral attraction to sugars, whereas K(ATP) signaling is involved in taste-mediated CPIR. Second, the discovery of a novel taste signaling pathway for sugars provides opportunities to develop new drugs to control blood sugar in people with type 2 diabetes. Finally, because NNSs do not activate the K(ATP) signaling pathway, sugars are probably the main elicitors of CPIR.

Rick Mattes of Purdue University focused on some of the most common concerns related to artificial sweeteners: activation of reward centers in the brain, effects on metabolism and microbiota, secretion of gut peptide such as GLP-1, and stimulation of appetite and energy intake.

To start, Mattes rejected the idea that sweeteners are addicting. He reviewed the different avenues of neurological communication implicated in addiction; dopamine, the reward response in the brain, is exponentially lower during NNS consumption than it is for drugs deemed addictive. The literature discussing whether NNS consumption can change appetite or motivation to eat ranges widely and yields no consensus.

Mattes next discussed aspartame studies that monitored physical and metabolic outcomes, such as body weight, glucose levels, and cholesterol. In an animal study by Palmnas et al., mice on a regular diet with or without aspartame showed no significant differences in numerous outcome measures—body weight, percent body fat, or triglycerides. The mice only showed variation in glucose tolerance (measured via insulin tolerance test) in the short term. However, animals on a high-fat diet had a lower body weight when also given aspartame. (Both high-fat groups had much higher body weights than groups on a normal diet). A different research team (Suez et al.) also found that mice consuming an artificial sweetener (saccharin, compared to aspartame in the previous group) had higher blood glucose. These results suggest that replacing sugar with NNSs may not be an effective strategy for certain metabolic disorders or for glucose intolerance, but Mattes observed that there may be discrepancies in normalization and said both studies should be considered critically, despite publication in high-level journals. He also discussed the possible role of aspartame in dysregulating microbiota activity, although the studies cited do not directly assess the gut microbiota.

Mattes described a study by Jang et al., which focused on GLP-1, a peptide important in appetite signaling. The researchers showed that in cell culture the NNS sucralose increases GLP-1 levels compared to glucose and sucrose, and that expression of GLP-1 can be reversed with lactisole (a sweet-receptor inhibitor). There is poor consensus in the field, however, as to whether sucralose changes the levels of GLP-1, blood glucose, or insulin in animals and humans. Mattes briefly compared three papers showing conflicting results. The research is inconclusive despite the initial excitement surrounding cell-based experiments.

Swithers and Davidson proposed in 2008 that conditioning from consistent NNS consumption would cause the body to adapt and reduce the cephalic response to foods containing NNSs, despite the sweet taste, because of the absence of sugar. The authors propose that this mechanism would lead to insufficient insulin production upon the reintroduction of sugar, deregulating metabolism and leading to weight gain by uncoupling CPIR from sugar detection. In that study, animals given inconsistent chow diets (sometimes low fat, sometimes high fat) experienced the highest weight gain. However, this finding was never recapitulated in human studies. Dietary inconsistency has not been shown to lead to behavioral changes or to overeating.

The final studies Mattes examined were epidemiological. The two studies were themselves meta-analyses, which compared final outcomes, such as a change in BMI. Both studies reported a benefit to including nonnutritive sweeteners instead of water in weight-loss regimens, though neither discriminated between NNS compounds.

Gary Foster of Weight Watchers International noted that recommendations promoting decreased sugary-drink consumption often lead to increased consumption of NNS-containing drinks, not increased water intake. According to the U.S. Department of Agriculture's 2015 Report on Dietary Guidelines, "there is insufficient evidence (due to paucity of data) to recommend the use of low-calorie sweeteners as a strategy for long-term weight loss." The report reviewed three meta-analyses that included 39 studies, mostly on aspartame. While some trials showed that replacing sugary drinks with NNS-containing drinks led to decreases in body weight and lower risks of heart disease and diabetes, the overall results lacked rigor and consistency.

Foster described a trial he conducted at Temple University, published in the journal Obesity, which tested the effects of consuming NNSs or water during a weight-loss regime. Over 300 adults were enrolled in the year-long study, and subjects participated in weight-loss programs, including regular exercise and guided calorie restriction, while drinking 24oz of either water or NNS-containing soft drinks daily. Consumption of other drinks, including full-calorie soft drinks, was not limited. Participants attended weekly support meetings, followed caloric recommendations set individually on the basis of resting metabolic rate, and provided self-reported food and drink intake.

At 12 weeks the participants consuming NNSs had lost 2 kg more body weight on average, and more participants in that cohort had lost 5% of body weight or more. The NNS cohort also had lower cholesterol and LDL levels, and reported less hunger in general. At 52 weeks, among participants who completed the weight-loss regime, those in the NNS cohort lost an average of 5 kg more weight than those drinking water (8.39 kg vs. 3.39 kg lost). Both groups achieved maximum mean weight loss after about 6 months, but the NNS group regained less weight afterwards. Foster proposed that the water group may lack satisfying sweetness and consume excess calories as a result, but it is not possible to prove this hypothesis on the basis of the data gathered.

Editor's note: The initial (12-week) findings from this study were discussed in commentary by Stephen Anton published in Obesity. (Can Non-Nutritive Sweeteners Enhance Outcomes of Weight Loss Interventions?) Anton noted the need for research on potential mechanism(s) for the superior effects of NNSs on weight loss outcomes.

The speakers agreed that there is generally no evidence that artificial sweeteners present harm to users who consume approximately 2 servings daily. They also noted the evidence that drinking beverages containing artificial sweeteners might improve weight-loss results. The field suffers from a paucity of studies and inconsistent results, partly because there is a lack of government funds for research into sweeteners. A few recent studies have measured effects on the gut microbiota directly. The focus of most of the work presented at this meeting was general health and weight maintenance. The speakers stressed the need for more research funding in this area. Artificial sweeteners are widely used; understanding their benefits and risks is a public health imperative.

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Presentations available from:
Gary D. Foster, PhD (Weight Watchers International Inc.)
John Glendinning, PhD (Barnard College)
Rick Mattes, PhD, MPH, RD (Purdue University)
Moderator: Kiyah Duffey, PhD (Virginia Tech)

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Presented by

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How to cite this eBriefing

The New York Academy of Sciences. Current Evidence on Noncaloric Sweeteners and their Health Implications. Academy eBriefings. 2016. Available at: www.nyas.org/Sweeteners-eB

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This is a CME-accredited program.

CME Accreditation
This activity has been approved for 2.0 CPE and CHES credit by the Clinical Directors Network Inc. through the joint sponsorship of PepsiCo and the Sackler Institute for Nutrition Science and the New York Academy of Sciences. The Clinical Directors Network Inc. is accredited by the American Academy of Family Physicians to provide continuing education. The evaluation form to obtain CME credit is available here.