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Artificial sweetener triggers insulin spike leading to blood vessel inflammation in mice
From diet soda to zero-sugar ice cream, artificial sweeteners have been touted as a guilt-free way to indulge our sweet tooth. However, new research publishing in the Cell Press journal Cell Metabolism on February 19 shows that aspartame, one of the most common sugar substitutes, may impact vascular health. The team of cardiovascular health experts and clinicians found that aspartame triggers increased insulin levels in animals, which in turn contributes to atherosclerosis—buildup of fatty plaque in the arteries, which can lead to higher levels of inflammation and an increased risk of heart attacks and stroke over time.
The research was inspired by a can of diet soda during a project meeting. “One of my students was sipping on this sugar-free drink, and I said, ‘Why don't you look into that?’” recalls senior author Yihai Cao, who studies chronic diseases related to blood vessel disorders at Karolinska Institute in Sweden.
Previous research has linked consumption of sugar substitutes to increased chronic disorders like cardiovascular disease and diabetes. However, the mechanisms involved were previously unexplored.
For this study, the researchers fed mice daily doses of food containing 0.15% aspartame for 12 weeks—an amount that corresponds to consuming about three cans of diet soda each day for humans. Compared to mice without a sweetener-infused diet, aspartame-fed mice developed larger and more fatty plaques in their arteries and exhibited higher levels of inflammation, both of which are hallmarks of compromised cardiovascular health.
When the team analyzed the mice’s blood, they found a surge in insulin levels after aspartame entered their system. The team noted that this wasn’t a surprising result, given that our mouths, intestines, and other tissues are lined with sweetness-detecting receptors that help guide insulin release. But aspartame, 200 times sweeter than sugar, seemed to trick the receptors into releasing more insulin.
The researchers then demonstrated that the mice’s elevated insulin levels fueled the growth of fatty plaques in the mice’s arteries, suggesting that insulin may be the key link between aspartame and cardiovascular health. Next, they investigated how exactly elevated insulin levels lead to arterial plaque buildup and identified an immune signal called CX3CL1 that is especially active under insulin stimulation.
“Because blood flow through the artery is strong and robust, most chemicals would be quickly washed away as the heart pumps,” says Cao. “Surprisingly, not CX3CL1. It stays glued to the surface of the inner lining of blood vessels. There, it acts like a bait, catching immune cells as they pass by.”
Many of these trapped immune cells are known to stoke blood vessel inflammation. However, when researchers eliminated CX3CL1 receptors from one of the immune cells in aspartame-fed mice, the harmful plaque buildup didn't occur. These results point to CX3CL1’s role in aspartame’s effects on the arteries, says Cao.
Looking ahead, Cao and his team plan to verify their findings in humans. Cao also foresees CX3CL1 as a potential target for chronic conditions beyond cardiovascular disease, given that blood vessel inflammation is involved in stroke, arthritis, and diabetes.
“Artificial sweeteners have penetrated almost all kinds of food, so we have to know the long-term health impact,” says Cao.
Expert Reaction
These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.
Oliver Jones is Professor of Chemistry at RMIT University in Melbourne, Australia
I have several concerns about this study.
The authors claim that the consumption of Aspartame by adults and children "often exceeds those levels recommended by the FDA" This is extremely unlikely in my view. The FDA-acceptable daily intake of Aspartame is 50 mg per kg of body weight per day. I weigh 80 kg, so this means this means the FDA-based safe dose for me is 4000 mg (or 4 grams) of Aspartame per day, every day, for life. Given a diet drink contains about 200 mg of Aspartame, I would have to drink the equivalent of 20 cans of diet soda a day to get this dose. A child of 40 kg would have to drink 10 cans a day, every day. Even then, the 50 mg/kg dose has a safety factor of 100 built-in.
The study design also has some issues. The main one is that the authors used a particular type of lab mouse called an ApoE mouse, which is bred to be prone to heart disease. They also fed it a high-fat, high-cholesterol diet, which itself increases the risk of heart disease. They also don’t seem to have measured how much of the Aspartame water the mice drank, or the Aspartame level in the blood, so it is unknown what the mice actually received.
To my mind, the author's admission that feeding mice that are already genetically susceptible to heart disease with a high-fat, high-cholesterol diet that is known to cause heart disease "diminishes clinical relevance" is somewhat of an understatement.
Contrary to the paper's claims, it is quite well-established that Aspartame doesn't stimulate glucose or insulin levels in humans.
Aspartame is essentially just two common amino acids (aspartic acid and phenylalanine) joined together. In the gut, it is broken down to aspartic acid and phenylalanine. There is no reason to think amino acids from Aspartame would be worse than those from any other source.
The authors would appear to think little work has been done on safety testing in Aspartame; this is just not true. All food ingredients are rigorously tested and safety assessed before they are approved for use. Aspartame is one of the most researched ingredients in the world. It is just that a lot of the data is in safety assessments for regulatory approval, not the academic literature.
Finally, even if Aspartame did cause some increase in cardiovascular risk (which this study does not prove), then that risk would likely be very small compared to things like high fat/high sugar diets and lack of exercise, etc.
In short, I don’t think this study itself gives us more reason to worry about diet drinks or aspartame.
Dr Ian Musgrave is a Senior Lecturer in the Faculty of Medicine, School of Medicine Sciences, within the Discipline of Pharmacology at the University of Adelaide.
Artificial sweeteners play a role in people’s attempts to control their calorie intake and reduce weight. However artificial sweeteners have come under attack for several false assertions about their health effects. However, a recent concern is that their sweetness may have an impact through the body’s sensors for sweetness that causes inappropriate hormone responses.
A new paper suggests that stimulation of these sweetness sensors may stimulate too high a release of insulin, leading to adverse effects on the blood vessels. However, it is unlikely to be of direct relevance to humans. This study was done in mice that were genetically engineered to lack a key lipid transporter, then fed a high-fat diet to stimulate the formation of fatty plaques in their blood vessels. These mice were then fed a control solution or aspartame in a dose equivalent to 3 cans of aspartame-containing drink a day for 12 days, and then their blood vessels were inspected for fatty plaque build-up.
Aspartame-treated mice had more fatty plaque in their blood vessels, and the experiments suggested that their insulin signalling was disordered.
While these experiments are elegant, the relevance of these experiments to humans is unclear. Genetically engineered mice on a diet specifically designed to accelerate plaque formation is unlikely to replicate the biology and dietary situation of most humans. Importantly, in the blood vessel experiments, the effects of an equivalently sweet dose of sugar was not studied, nor the effect of the reduction in calorie intake by the amount of aspartame consumed.
While the study may have given us a new target for treating plaque build-up in one of the body's inflammatory molecules, it does not suggest people should give up their artificially sweetened drinks.
Dr Yutang Wang is a Senior Lecturer in the School of Applied and Biomedical Sciences at Federation University Australia
Artificial sweeteners are often considered a healthier alternative to sugar and are commonly found in a variety of foods and drinks, including soft drinks, baked goods, and frozen desserts. Many people turn to these sugar substitutes to cut down on calories, avoid blood sugar spikes, or prevent tooth decay. However, a recent study published in the esteemed journal Cell Metabolism casts doubt on their safety.
The research exposed mice to aspartame, a popular artificial sweetener, and found that it caused direct damage to the inner lining of blood vessels. This damage made the blood vessel walls “stickier,” leading to an increase in inflammatory cells, which in turn contributed to the build-up of plaque in the arteries. This condition, called atherosclerosis, is a key factor in cardiovascular disease, including heart attacks and strokes.
While earlier studies had suggested a connection between artificial sweeteners and cardiovascular risks, this new research provides compelling evidence that these sweeteners directly cause cardiovascular disease. Though the study does have some limitations—such as being conducted in mice and testing only one sweetener— it adds weight to the growing body of research urging caution. It may be time to reconsider our consumption of artificially sweetened products. Reducing their intake could be a simple yet powerful step to protect ourselves from heart attacks and strokes.
Professor Mark L Wahlqvist AO is Emeritus Professor and Head of Medicine at Monash University and Monash Medical Centre. He is also Past President of the International Union of Nutritional Sciences
New findings about the biological effects of the dipeptide, a so-called non-nutritive sweetener, aspartame, discovered by accident in 1965 by a chemist licking his finger underscore important limitations in food and nutrition science as applied to health.
The first is that small molecules like dipeptides would have little or no biological consequence or food safety concern. But controversy has dogged this and other substitutes for sugar since their first approvals decades ago, That was in 1983 for aspartame by the FDA in the USA, confirmed in 2023. But IARC (International Agency for Research on Cancer) and WHO/FAO found that there was ‘limited evidence’ that it could cause cancer, and that intake should not exceed 40 mg per kg body weight per day.
In the meantime, evidence that its substitution for sugar in the prevention and management of obesity has been unconvincing, as for similar substitutions. After all this time, convincing evidence from the Karolinska Institute in Stockholm with colleagues in China that aspartame can adversely affect arterial health by inflammatory damage is disturbing.
We need to be clear that sweetness recognition is one thing, and energy (calorie) regulation another. Receptors for sweetness occur throughout the body; the idea that one effect was necessarily linked to another was flawed, and ‘playing‘ with sweetness to deal with energy metabolism has proven biologically fraught. We should stop the inappropriate use of sugar substitutes.
