Artificial, or low-calorie sweeteners (LCSs) such as sucralose are found in thousands of food and beverage products, but whether they have negative effects on the brain and metabolism is a continued topic of hot debate, with reported studies generating conflicting results. An international team of investigators headed by scientists at Yale University School of Medicine has now carried out a study in human volunteers that may explain the discrepancies in previous results. The new research found that participants who drank fruit-flavored beverages sweetened with sucralose alone, showed no changes in brain or metabolic responses. However, when the study volunteers drank sucralose-sweetened drinks to which another, tasteless carbohydrate had been added, they exhibited adverse changes in insulin sensitivity and decreased brain responses to sweet taste, measured using functional magnetic resonance imaging (fMRI).

“When we set out to do this study, the question that was driving us was whether or not repeated consumption of an artificial sweetener would lead to a degrading of the predictive ability of sweet taste,” said Dana Small, PhD, a neuroscientist who is a professor of psychiatry and the director of the Modern Diet and Physiology Research Center at Yale University. “This would be important because sweet-taste perception might lose the ability to regulate metabolic responses that prepare the body for metabolizing glucose or carbohydrates in general.” What Small and colleagues unexpectedly discovered, and have now reported in Cell Metabolism, is that “… consuming sucralose with, but not without, a carbohydrate rapidly impairs glucose metabolism.” As they concluded in their report, “This raises the possibility that the combination effect may be a major contributor to the rise in the incidence of type 2 diabetes and obesity.” Their results are described in a paper titled, “Short-Term Consumption of Sucralose with, but Not Without, Carbohydrate Impairs Neural and Metabolic Sensitivity to Sugar in Humans.”

Low calorie sweeteners are present in thousands of food and beverage products, the authors wrote. However, there is “significant controversy” over the effects of consuming LCSs on health. Different human studies have linked LCS either with diabetes and weight gain or, conversely, with a reduction in body mass index and weight loss, or found no link to these measures. Studies in animals have also been inconsistent. It’s a puzzle that needs solving, the authors continued. “Given the growing use of LCSs, especially in relation to the obesity and diabetes pandemics, it is of pressing importance to resolve the controversy surrounding LCS consumption.”

To do this the team designed a study to test the theory that consuming sweet foods and beverages without calories “uncouples” the brain’s perception of sweet taste from energy intake. This would result in diminished physiological responses even when regular calorie-containing sugar is consumed, which could ultimately lead to weight gain, glucose intolerance, and diabetes. “… it has been suggested that uncoupling sweet taste from energy receipt leads to a weakening of conditioned responses to sweet taste,” the investigators noted. “In this case, sweetness-elicited conditioned responses, such as release of incretins, which help regulate glucose metabolism, are hypothesized to be reduced, leading to the subsequent development of glucose intolerance.

The trial enrolled 45 volunteers between the ages of 20 and 45 who didn’t normally consume low-calorie sweeteners. The sweeteners were consumed as fruit-flavored beverages with added sucralose and fruit-flavored beverages with added table sugar for comparison. In what was intended to be a control group: some of the volunteers had the carbohydrate maltodextrin added to their sucralose drinks. This was the “combo” group. The researchers chose the non-sweet carbohydrate maltodextrin, to control for the calories of sugar without adding more sweet taste to the beverage. All of them were of healthy weight and had no metabolic dysfunction. Other than consuming seven beverages in the lab over a two-week period, they didn’t make any changes to their diet or other habits. The investigators conducted studies on the volunteers before, during, and after the testing period, and carried out fMRI scans to look at changes in the brain in response to sweet tastes, as well as other tastes like salty and sour. They also measured taste perception and did an oral glucose tolerance test to look at insulin sensitivity.

A parallel study was conducted with adolescents, aged 13–17 years, “since adolescents go through a period of transient insulin resistance, a time of increased preference for sweet beverages, and of intensive brain development,” the authors noted. However, the trial was ended early when it was found that two of the adolescents in the the sucralose-carbohydrate combination group exhibited skyrocketing fasting insulin levels.

The authors reasoned that if the uncoupling hypothesis was correct, then participants in the group consuming LCS-sweetened beverages, but not in the group consuming sugar-sweetened beverages, or the group consuming beverages with LCS plus maltodextrin, should exhibit reduced insulin sensitivity coupled with decreased brain and sensory responses to sweet, but not to sour, salty, or savory taste. “The uncoupling hypothesis states that uncoupling sweet taste from energy results in an impaired ability to use sweet taste to guide feeding. If so, we reasoned that brain response to sweet, but not the other tastes, should change,” they noted.

What they unexpectedly found was that it was the control, combo group consuming the LCS plus maltodextrin beverages that showed changes in brain response to sweet taste, and in insulin sensitivity and glucose metabolism. “The subjects had seven low-calorie drinks, each containing the equivalent of two packages of Splenda, over two weeks,” said Small. “When the drink was consumed with just the low-calorie sweetener, no changes were observed; however, when this same amount of low-calorie sweetener was consumed with a carbohydrate added to the drink, sugar metabolism and brain response to sugar became impaired.”

Given the surprising result, the researchers added a second control group, in which the participants drank beverages with maltodextrin alone. They found no evidence that consuming just maltodextrin-containing beverages over the seven-day period alters insulin sensitivity and glucose metabolism.

“Collectively, the findings from the two human studies refute the hypothesis that uncoupling sweet taste from caloric content causes metabolic dysfunction or decreases in the potency of sweet taste as a conditioned stimulus,” the team concluded. “Rather, the results reveal that metabolic dysfunction, coupled with reduced central sensitivity to sweet taste, occurs when an LCS is repeatedly consumed with, but not without, a carbohydrate … they suggest that sucralose consumption alters the metabolism of simultaneously consumed glucose to rapidly produce deleterious effects on metabolic health.”

And as to why these effects occurred, Small reasoned, “Perhaps the effect resulted from the gut generating inaccurate messages to send to the brain about the number of calories present. The gut would be sensitive to the sucralose and the maltodextrin and signal that twice as many calories are available than are actually present. Over time, these incorrect messages could produce negative effects by altering the way the brain and body respond to sweet taste.”

She further noted that a subset of previous studies evaluating artificial sweeteners had involved mixing the sweeteners with plain yogurt, and that adding carbohydrates from the yogurt may have led to the same effects as those that were seen with added maltodextrin. This could explain why previous findings about artificial sweeteners have been conflicting.

And if, as the authors suggested, the combination of LCS with carbohydrate is contributing to the incidence of type 2 diabetes and obesity, “… the addition of LCSs to increase the sweetness of carbohydrate-containing food and beverages should be discouraged and consumption of diet drinks with meals should be counseled against.

As Small said, “Previous studies in rats have shown that changes in the ability to use sweet taste to guide behavior can lead to metabolic dysfunction and weight gain over time … We think this is due to the consumption of artificial sweeteners with energy … Our findings suggest that it’s okay to have a Diet Coke once in a while, but you shouldn’t drink it with something that has a lot of carbs … If you’re eating French fries, you’re better off drinking a regular Coke or—better yet— water. This has changed the way that I eat, and what I feed my son. I’ve told all my friends and my family about this interaction.”

Future studies will look at whether other artificial sweeteners, as well as more natural sweeteners like stevia, have the same effects as sucralose. Small, who also directs Yale’s newly formed division of nutritional psychiatry, expects that many of them will. “It’s hard to say, because we still don’t fully understand the mechanism,” she concluded. “That’s also something we hope to study further, especially in mice.”

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