Swapping out sugar for Splenda triggers a strange, potentially dangerous effect on the body if the swap is paired with food high in carbohydrates, suggests new research.

It turns out artificial sweeteners and carbs — when consumed together — trip up the brain and mess with metabolism. These effects can lead to insulin intolerance, diabetes, and weight gain. This research suggests that downing a diet soda isn't so bad for you if consumed alone. What could be bad for health is when the drink comes with a side of fries.

Input: We ate Impossible Foods' faux pork and it was good as hell

“If you're going to have a diet drink, don't have it with French fries,” co-author Dana Small, a researcher at Yale University, tells Inverse. “Have the diet drink by itself and if you're going to have a diet drink, give an hour on either side and it should be fine, at least in small quantities.”

The study was published Tuesday in the journal Cell Metabolism.

This research also posits that, if you’re on a sugar detox or aim to skip sugar-related calories, artificial sweeteners may not help as much as you think. Anytime you increase the sweetness of anything and it's not actual sugar, it could have a negative impact, Small says.

“The finding that we saw could be the tip of the iceberg in the sense that there are many, many things where the sensory properties and the energetic properties are mismatched or combined and created and processed, unlike anything in the natural food environment," Small explains.

Sweet experiment

Small and her team recruited a group of 45 healthy young adults who didn’t regularly consume artificial sweeteners. All of the participants maintained a healthy weight and showed no signs of metabolic dysfunction.

The participants were randomly assigned into three groups and, over the course of a two week period, visited Small's lab 13 times. By the end of the study, each participant drank seven fruit-flavored beverages mixed by the researchers.

One group drank beverages sweetened with the artificial sweetener sucralose (zero-calories, 0.06 grams of sucralose adding up to about two packets of Splenda). Sucralose goes by the brand name Splenda and is one of the most common artificial sweeteners. It’s 600 times sweeter than table sugar, the FDA says, and has been on the market since 1998.

Sucralose goes by the brand name Splenda. Other popular artificial sweeteners, such as Equal (pictured), contain aspartame. Mike Mozart

Another group drank beverages with regular table sugar (120 calories, 30.38 grams of sugar) and, as a control, the final group consumed drinks including both an artificial sweetener and added carbs — a non-sweet substance called maltodextrin (120 calories, 31.83 grams of maltodextrin). Each drink was the size of a typical soda can (355 milliliters or about 12 ounces).

Before and after they downed their drinks, the participants went through a barrage of tests measuring brain activity, taste perception, and metabolic function. The scientists also used functional magnetic resonance (fMRI) scanning to look at how the participant's brains responded to sweet, savory, salty and sour tastes. The researchers also documented the group’s taste perception and did an oral glucose tolerance test to look at insulin sensitivity.

Conscious uncoupling

At the start of the study, the researchers wanted to test the “uncoupling hypothesis.” This hypothesis works off the idea that we've evolved to have a special relationship with sugar: We want sweet food, like fruit, because sweet food gives us energy. But when we consume something that is sweet that doesn't contain calories — like artificial sweetener — the body becomes consumed. The taste is there, but the calories that give us energy are not.

In this case sweetness, Small explains, "is no longer a useful clue." According to the hypothesis, this confusion causes the body to stop producing insulin and metabolizing sugar — which it normally would if the sweetness was paired with calories. This can lead to metabolic dysfunction and weight gain.

But Small’s results disprove this theory: If the uncoupling hypothesis were correct, the group who drank artificially-sweetened drinks would have experienced negative brain and metabolic changes.

That didn't happen: Only the group that drank the carb-artificial sweetener combo showed changes in the brain’s response to sweet taste and impaired insulin sensitivity or sugar metabolism. This result shocked the researchers so much, that they conducted an additional test where participants drank beverages with the added carbs (maltodextrin) only.

On their own, sucralose, sugar, or carb-heavy drinks didn’t seem to have negative metabolic and neurologic effects. Only the artificial sweetener-carbohydrate mixture disrupted the brain’s sugar response and kicked off downstream metabolic changes.

The sweetener-carbo group participants' brains also showed decreased activity in the parts of the brain linked to regulating metabolism and processing rewards. These participants also because slightly insensitive to insulin.

Taken together, the results suggest carbs and sucralose work together to confuse the brain and set off a cascade of miscommunication through the body.

Since the brain’s response to sugar is “blunted” the body can’t metabolize sugar properly. In turn, if this blunting effect happens regularly, it can make it difficult for the brain and body to recognize sugar and respond appropriately.

Small describes this as a "circuit change." This neural circuit change is adaptive in the sense that the body’s trying to understand how to process nutrients, but it is getting inaccurate signals, Small says. Whether the brain would eventually be able to self-correct isn't clear, since the study was only for two weeks.

Rethinking artificial sugar

While no one in this study was at risk of becoming diabetic, the results do suggest that people who habitually eat or drink artificial sweeteners with a side of carbs may have a greater risk of Type 2 diabetes or becoming obese, Small explains.

Whether other common artificial sweeteners — from aspartame to stevia — could also ignite this disruptive effect when paired with carbs isn't known, but Small predicts research will reveal similar results.

Artificial sweeteners, Small points out, aren't necessarily used by food and drink companies because they are trying to make "diet" products — it's because they're artificial sweeteners are less expensive than sugar. In turn, her research suggests it's time to rethink how healthy a "diet" version of a product (containing artificial sweeteners) is compared to foods and drinks that contain actual sugar.

To be the healthiest you can be, Small advises you avoid process foods and eat naturally. But if you're in the mood for a treat, pair your pizza slice with a sugary drink like a Sprite — and not a Diet Coke.

Abstract: There is a general consensus that overconsumption of sugar-sweetened beverages contributes to the prevalence of obesity and related comorbidities such as type 2 diabetes (T2D). Whether a similar relationship exists for no- or low-calorie ‘‘diet’’ drinks is a subject of intensive debate and controversy. Here, we demonstrate that consuming seven sucralose- sweetened beverages with, but not without, a carbohydrate over 10 days decreases insulin sensitivity in healthy human participants, an effect that correlates with reductions in midbrain, insular, and cingulate responses to sweet, but not sour, salty, or savory, taste as assessed with fMRI. Taste perception was unaltered and consuming the carbohydrate alone had no effect. These findings indicate that consumption of sucralose in the presence of a carbohydrate rapidly impairs glucose metabolism and results in longer-term decreases in brain, but not perceptual sensitivity to sweet taste, suggesting dysregulation of gut-brain control of glucose metabolism.