Zero-calorie sweeteners can still lead to diabetes and obesity, according to new research.
The study shows that common artificial sweeteners used in zero-calorie drinks and other products can change how the body processes fat and energy.
Increased awareness of the health consequences of eating too much sugar has led to a dramatic increase in the consumption of zero-calorie artificial sweeteners in recent years.
But researchers have found that sugar replacements can also cause health changes that are linked with diabetes and obesity, which they suggests that switching from regular to diet drinks may be a case of 'out of the frying pan, into the fire.'
Artificial sweeteners are one of the most common food additives worldwide, frequently consumed in diet and zero-calorie drinks and other products.
While some previous studies have linked artificial sweeteners with negative health consequences, earlier research has been mixed and raised questions about potential bias related to study sponsorship.
The new study is the largest examination to date that tracks biochemical changes in the body - using an approach known as unbiased high-throughput metabolomics -after consumption of sugar or sugar substitutes.
The American research team also looked at impacts on heart health by studying how the substances affect the lining of blood vessels. The studies were conducted in rats and cell cultures.
Lead researcher Dr Brian Hoffmann, assistant professor in the department of biomedical engineering at the Medical College of Wisconsin and Marquette University, said: "Despite the addition of these non-caloric artificial sweeteners to our everyday diets, there has still been a drastic rise in obesity and diabetes.
"In our studies, both sugar and artificial sweeteners seem to exhibit negative effects linked to obesity and diabetes, albeit through very different mechanisms from each other."
The researchers fed different groups of rats diets high in glucose or fructose, or aspartame or acesulfame potassium - common zero-calorie artificial sweeteners.
After three weeks, they saw "significant" differences in the concentrations of biochemicals, fats and amino acids in blood samples.
The researchers said that the results suggest artificial sweeteners change how the body processes fat and gets its energy.
And they found acesulfame potassium seemed to accumulate in the blood, with higher concentrations having a more harmful effect on the cells that line blood vessels.
Dr Hoffmann said: "We observed that in moderation, your body has the machinery to handle sugar; it is when the system is overloaded over a long period of time that this machinery breaks down.
"We also observed that replacing these sugars with non-caloric artificial sweeteners leads to negative changes in fat and energy metabolism."
The researchers cautioned that the results do not provide a clear answer whether sugar or artificial sweeteners are worse.
Dr Hoffmann said It is well known that high dietary sugar is linked to negative health outcomes and the study suggests artificial sweeteners do, too.
He added: "It is not as simple as 'stop using artificial sweeteners' being the key to solving overall health outcomes related to diabetes and obesity.
"If you chronically consume these foreign substances - as with sugar - the risk of negative health outcomes increases.
"As with other dietary components, I like to tell people moderation is the key if one finds it hard to completely cut something out of their diet."
Dr Hoffmann presented the findings at the American Physiological Society (APS) annual meeting in San Diego.