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A tale of two sugars—fructose and glucose cause differing metabolic effects

Researchers have found that the sugars fructose and glucose cause different metabolic effects and health outcomes in mice, but only in animals eating a high-fat diet. Overconsumption of high-fat foods and sugar-sweetened beverages is a risk factor for developing obesity, type 2 diabetes, and nonalcoholic fatty liver disease. Most food and beverages are sweetened with table sugar and/or high-fructose corn syrup, both of which contain fructose and glucose. Though both sugars promote fat build-up in the liver, the liver metabolizes fructose and glucose differently. It is unclear whether those differences lead to different health outcomes, and there is scientific debate about whether one sugar or the other is less harmful to people’s health. In a new study, researchers sought to tease out whether there are metabolic differences when mice consume similar caloric amounts of fructose and glucose.

To do this, researchers added fructose or glucose to the drinking water of male mice for 10 weeks, keeping their total caloric intake similar. There were no major health differences when the animals ate a standard, low-fat diet—both groups gained similar amounts of weight and had mild accumulation of fat in their livers compared to control mice drinking only water. However, the story was different in mice eating a high-fat diet. In those mice, fructose consumption caused them to have more obesity and other indicators of metabolic dysfunction (e.g., reduced tolerance to glucose, impaired insulin signaling) compared to mice drinking the same caloric levels of glucose. Surprisingly, glucose appeared to protect animals eating a high-fat diet: their glucose tolerance and sensitivity to insulin were similar to control mice eating a standard chow diet, and they did not gain more weight than animals eating a high-fat diet alone even though they were consuming extra calories from the glucose. In mice eating a high-fat diet, both fructose and glucose led to the accumulation of high levels of liver fat, but experiments suggested that the underlying mechanisms leading to fat accumulation differed between the two sugars. Because fructose was associated with poor metabolic outcomes as described above, the researchers next studied a protein called ketohexokinase (KHK) that is involved in the first step of fructose metabolism. They found that Khk gene activity in the liver was increased in mice consuming fructose compared to animals consuming glucose or water. Experimentally decreasing the activity of the Khk gene in the liver resulted in improved health outcomes in fructose-consuming mice eating a high-fat diet—e.g., they had less weight gain, improved glucose tolerance, and less fatty liver compared to animals with normal Khk gene activity eating the same diet. Extending their observations to people, the researchers found that KHK gene activity and protein levels were higher in liver biopsy samples from obese adolescents with more advanced fatty liver disease compared to adolescents with no or less severe fatty liver disease. Taken together, these findings suggest that KHK may be a target for treating fatty liver disease in people.

This research has found that, in mice eating a high-fat diet, fructose leads to poor metabolic outcomes, whereas glucose appears to be protective. Further research could determine whether the observed differences between the two sugars hold true in women and men, and if adjusting sweetener use could have beneficial health effects.


Softic S, Gupta MK, Wang GX…Kahn CR.  Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signalingJ Clin Invest 127: 4059-4074, doi: 10.1172/JCI94585, 2017.
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