Calorie Control Council Response to Abdelmalek et al

Underpowered and unphysiologic design weakens fructose

Abdelmalek MF, Lazo M, Horska A, Bonekamp S, Lipkin EW, Balasubramanyam A, Bantle JP, et al. Underpowered and unphysiologic design weakens fructose—ATP/NAFLD associations. Hepatology. 2012

In “Underpowered and unphysiologic design weakens fructose—ATP/NAFLD associations,” Abdelmalek et al.1 assessed fructose as a risk factor for NAFLD by measuring depletion and replenishment of ATP. Their assessment is fraught with problems — and is of little value in evaluating human risk — for the following reasons.

First, the authors acknowledged this was a pilot study with insufficient power to support judgments of significance. It was thus surprising when they nevertheless reported differences of significance between experimental variables and used them to draw inferences about fructose.

Second, the depletion of hepatic ATP as a result of parenteral administration of fructose is a well known phenomenon.2Shortly after fructose infusion, an elevated but transient rate of hepatic ATP consumption is observed due to the initial phosphorylation of fructose; however, ATP is rapidly regenerated as fructose metabolites flow through glycolytic pathways. Consequently, the degree of ATP depletion following an intravenous fructose challenge lacks relevance as a physiological means to examine the effects of dietary fructose, which is always consumed orally. And ATP depletion/regeneration should not be viewed in isolation as the consequence of a single nutrient. For perspective, hundreds of metabolic reactions use ATP at any given time and the body goes to great lengths to ensure a steady supply, regenerating an estimated 65 kg/d.3

Third, subject fructose consumption reported in Table 1 (range 12.7-24 g/d) was considerably lower than recent NHANES-based estimates of 45 and 73 g/d for mean and 95th percentile intakes, respectively.4 In this light, assigning subjects to “low” (<15 g/d) and “high” (=15 g/d) fructose consumption categories appears arbitrary and out of touch with real-world fructose intakes.

And finally, recent studies by Sun et al.5 and Wang et al.6critically evaluated subjects from the NHANES data base and a large number of human controlled feeding studies, respectively, and reported that while hypercaloric fructose intake may increase uric acid, no uric acid-increasing effect of ordinary orisocaloric fructose intake in normal and diabetic subjects was found.

The authors failed to demonstrate that fructose is a specific and unique risk factor for ATP depletion, uric acid increase and NAFLD under typical conditions of human oral fructose intake and exposure. Since by design their study lacked sufficient power to discern significant differences and lacked physiologic relevance, it should have little bearing on future public health policy.


1. Abdelmalek MF, Lazo M, Horska A, Bonekamp S, Lipkin EW, Balasubramanyam A, Bantle JP, et al. Higher dietary fructose is associated with impaired hepatic ATP homeostasis in obese individuals with type 2 diabetes. Hepatology 2012.
2. Van den Berghe G. Metabolic effects of fructose in the liver. Curr Top Cell Regul 1978;13:97-135.
3. Mathews CK, Van Holde KE, Appling DR, Anthony-Cahill SJ. Biochemistry. 4th ed. Toronto: Pearson, 2013.
4. Marriott BP, Cole N, Lee E. National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr 2009;139:1228S-1235S.
5. Sun SZ, Flickinger BD, Williamson-Hughes PS, Empie MW. Lack of association between dietary fructose and hyperuricemia risk in adults. Nutr Metab (Lond) 2010;7:16.
6. Wang DD, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Cozma AI, Mirrahimi A, et al. The Effects of Fructose Intake on Serum Uric Acid Vary among Controlled Dietary Trials. J Nutr 2012;142:916-923.