A recent article by Aeberli et al. (1) concluded that moderate amounts of fructose and sucrose “clearly” and significantly alter hepatic insulin sensitivity and lipid metabolism compared with glucose. The authors’ data do not support their conclusions, however, due to experimental design limitations, data variability, and undemonstrated clinical significance at moderate fructose doses.

First, the authors properly reported baseline daily intake data for energy, sugars, and fibers in Table 3 of ref. 1 but neglected to do so for the crux of the article—the metabolic markers and measures of glucose metabolism reported in Tables 1 and 2 of ref. 1. Although the authors noted this limitation, as well as the short duration of the intervention (3 weeks), they should also have pointed out the significant limitation of such a low number of subjects (n ≤ 9). These limitations cloud the significance of their findings.

Second, there was surprising variability in the reported data. At the end of the 3-week intervention, the authors reported a significant decrease in hepatic glucose in the high fructose variable (18.9% energy as fructose), which was not observed in the remaining interventions. The lack of effect was surprising in comparison with the medium fructose variable (16.9% energy as fructose), which was nearly equivalent in fructose to the high fructose variable. In addition, there was no apparent fructose dose effect.

And according to the authors, sugar-sweetened beverages—especially those containing fructose—can result in alterations of hepatic glucose metabolism. However, no significant differences among treatments were seen on the glucose metabolic clearance rate, a parameter addressing whole-body glucose handling (mainly, in the muscle) (Table 2 of ref. 1). Further, fasting blood levels of glucose and insulin did not differ significantly among any of the sugars interventions.

Third, the authors report statistically significant differences between glucose, fructose, and sucrose interventions for several metabolic markers (LDL and total cholesterol, free fatty acids, leptin), but these lack both clinical significance—all fall within normal medical reference ranges (24)—and consistency versus dose (titration effect with increasing fructose exposure). It must also be questioned whether the small but statistically significant differences in anthropometrics have any real clinical importance at all.

Finally, the causal relationship between fructose and obesity alluded to in the authors’ introduction is now out of date. The statement that fructose intake increased between 1970 and 1997, while true, presents an incomplete and misleading picture of fructose consumption when augmented with U.S. Department of Agriculture historical and contemporary sweetener data (5). Fructose from added sugars reached a peak in 1999 and has been in substantive decline in the intervening 13 years; thus, there has been no causal relationship with obesity for over a decade. In fact, fructose consumption has been remarkably constant since 1920 at 39 ± 4 g/day/person (6).

In conclusion, Aeberli et al. do not demonstrate a clear and significant effect of fructose on hepatic insulin sensitivity and lipid metabolism because of experimental design limitations, data variability, and undemonstrated clinical significance at moderate fructose doses.

This work was supported by the Calorie Control Council (Atlanta, GA). J.S.W. has been a paid consultant for the Calorie Control Council (Atlanta, GA) and has been on the scientific advisory panel for the Corn Refiners Association (Washington, DC).

J.S.W. is founder and president of White Technical Research. No other potential conflicts of interest relevant to this article were reported.

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