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. 

### 

This work was supported by funding from the Swedish Cancer Foundation, the Strategic Research Areas–Stem Cell and Regenerative Medicine Foundation, the Karolinska Institute Foundation, the NOVO Nordisk Foundation, the Swedish Research Council, the Swedish Research Council, the National Natural Science Foundation of China, the Hong Kong Centre for Cerebro-Cardiovascular Health Engineering, the Horizon Europe grant-PERSEUS, Key R&D Program of Shandong Province, the National Natural Science Foundation of China, and State Key R&D Program of China. 

Cell Metabolism, Cao et al., “Sweetener aspartame aggravates atherosclerosis through insulin-triggered inflammation.” https://www.cell.com/cell-metabolism/fulltext/S1550-4131(25)00006-3.

Cell Metabolism (@Cell_Metabolism), published by Cell Press, is a monthly journal that publishes reports of novel results in metabolic biology, from molecular and cellular biology to translational studies. The journal aims to highlight work addressing the molecular mechanisms underlying physiology and homeostasis in health and disease. Visit http://www.cell.com/cell-metabolism. To receive Cell Press media alerts, contact press@cell.com.