Q&A: 'Toxic' effects of sugar: should we be afraid of fructose?
Luc Tappy


Are there harmful consequences of these features of fructose metabolism?

At a high level of intake, yes, and one of these is increased cardiovascular risk. Paradoxically this in part came to light because of a strong interest, in the 1980s, in the use of pure fructose as a sweetener for type 2 diabetic patients. This was proposed on the grounds that fructose might be less harmful than sucrose or glucose because, unlike glucose, it causes little hyperglycemia after eating (postprandial hyperglygemia), and is metabolized independently of insulin. Furthermore, it enhances energy expenditure compared to similar doses of glucose, which was thought to help prevent weight gain.

However, many short-term studies showed that substituting fructose for starch in the diet of type 2 diabetic patients was associated with an increase in plasma triglyceride concentrations (both fasting and postprandial), raising the possibility that any beneficial effect on glycemic control may be counterbalanced by pro-atherogenic effects of hypertriglyceridemia.

If high fructose intake can be responsible for the development of obesity and the associated metabolic disorders that constitute metabolic syndrome, wouldn't this show up in epidemiological studies?

The answer to this question is not straightforward. Several large cohort studies have included a dietary evaluation and a medical follow-up, but their interpretation is problematic, for several reasons. First, until recently, fructose as such did not appear in nutritional databases, and these studies therefore looked at a variety of different variables, some evaluating the effects of calculated total sugar intake, others the effects of calculated fructose intake, while others examined the effects of specific food groups (sugar-sweetened beverages, sweets) that contribute substantially to total fructose intake. Second, the results vary according to how statistical analyses were performed. On one hand, some studies used a statistical analysis that was not adjusted for total energy intake, and documented a positive correlation with obesity. Some of these same studies, however, reported that obesity was associated not only with sugar-sweetened beverages and sweet intakes, but also with the consumption of potatoes and meat. On the other hand, some investigators argued that, in order to conclude that fructose (or sugar) is a major determinant of obesity, it is necessary to establish a positive correlation that is independent of total energy intake. These studies searched for a relationship between obesity and sugar intake expressed as a percentage of total calorie intake and generally failed to observe a significant positive correlation, or even reported a negative correlation. Furthermore, although these studies reported that the incidence of diabetes, dyslipidemia, liver disorders, or high blood pressure correlated positively with sugar intake, these relationships were no longer observed after adjusting for total body weight.


Metabolism of fructose in the liver. The majority of fructose in the portal vein is taken up by the liver to be converted into glucose, glycogen, and lactate. A small portion may be either oxidized within hepatocytes or converted into fatty acid, which will be either secreted as very low density lipoprotein-triglyceride (VLDL-TG) particles or stored as intrahepatocellular lipids (IHCL). Only a minor portion escapes liver uptake and reaches the systemic circulation; blood fructose concentrations therefore remain very low even after ingestion of a large fructose load.

Putative mechanisms that may link excessive fructose intake to the development of metabolic disorders in the long term. Stimulation of hepatic de novo lipogenesis may lead to the deposition of fat within the liver, which may secondarily be involved in hepatic insulin resistance. Hepatic de novo lipogenesis may also cause an increase in VLDL-TG secretion and ectopic deposition of lipids in skeletal muscle, and contribute to muscle insulin resistance through the generation of muscle lipid metabolites. Fructose metabolism in the liver increases uric acid synthesis, and the ensuing hyperuricemia can secondarily be responsible for endothelial cell dysfunction, impaired insulin-induced vasodilation and a consequent failure to increase muscle blood flow after a meal, leading to muscle insulin resistance. In addition, the metabolism of fructose in liver cells can cause the formation of reactive oxygen species (ROS), which can activate nuclear factor (NF)κB, causing inflammation-linked insulin resistance. Finally, fructose can increase the translocation of bacterial endotoxin (lipopolysaccharide (LPS)) into the portal blood, causing endotoxin-mediated stimulation of inflammation. TNF, tumor necrosis factor.

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