International Journal of Obesity (2011) 35, 748–749 & 2011 Macmillan Publishers Limited All rights reserved 0307-0565/11 www.nature.com/ijo
LETTERS TO THE EDITOR Fructose as cause of metabolic syndrome is poorly supported International Journal of Obesity (2011) 35, 748; doi:10.1038/ ijo.2010.170; published online 31 August 2010
In a recent paper, Perez-Pozo et al.1 concluded that high doses of fructose raise blood pressure and cause features of metabolic syndrome, and that fructose may therefore have a role in the current epidemics of obesity and diabetes. Their conclusion is poorly supported and should not be used to inform the public debate on fructose for three reasons. First, the study is weakened through lack of a rigorous double-blind experimental design. That investigators and staff knew throughout the study which participants were receiving allopurinol makes it impossible to rule out the prospect of subjective bias from experimental subjects, analysts and study principals. Second, the experimental design lacked a proper control. The authors administered fructose±allopurinol to human subjects to test the hypothesis that excessive fructose intake can induce the features of metabolic syndrome and that the induction is reversible. Their failure to provide an appropriate non-fructose comparison group invalidates all conclusions about fructose. Third, the amount of dietary þ supplementary fructose in experimental diets (55 g þ 200 g ¼ 34% of the total energy) is nearly quadruple the mean (9.1% of the total energy) and double the 95th percentile (o18% of the total energy) human fructose intakes recently established by Marriott et al.2 Such macronutrient excess is atypical of the human fructose experienceFcharacterized instead by moderate fructose intake in the presence of equivalent amounts of glucoseFand further diminishes the clinical relevance of this study.
Thus, the conclusion by Perez-Pozo et al. that excessive fructose consumption could have a causal role in the metabolic syndrome is inadequately supported by the current work. The weak experimental design fails to demonstrate a unique role for fructose vis-a`-vis other nutritive sugars, lacks a suitable control, is not doubleblinded and relies on exaggerated fructose exposures. It would be inappropriate to use this study to inform the public debate on fructose.
Conflict of interest The author is a consultant to the food and beverage industry in the area of nutritive (caloric) sweeteners. He has advised research institutes, food industry councils, trade organizations, national health associations, governmental agencies and individual companies. JS White White Technical Research, Argenta, IL, USA E-mail:
[email protected]
References 1 Perez-Pozo SE, Schold J, Nakagawa T, Sanchez-Lozada LG, Johnson RJ, Lillo JL. Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response. Int J Obes (Lond) 2010; 34: 454–461. 2 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.
Response to Dr White International Journal of Obesity (2011) 35, 748–749; doi:10.1038/ijo.2010.197; published online 21 September 2010
The primary purpose of our study was to determine the role of uric acid in fructose-mediated metabolic effects, and as such our study compared the effects of fructose supplemen-
tation with or without allopurinol (a xanthine oxidase inhibitor). The reason we used high doses of fructose was to ensure the robust metabolic effects that would better allow distinction of the role of uric acid. Although the study was single blinded, the laboratory tests were performed by technicians blinded to the two groups and the blood pressure readings were made by an automated 24 h
Letters to the Editor
749 ambulatory blood pressure equipment. Hence, all results consisted of ‘hard’ data. An important finding in our study was the observation that fructose can raise blood pressure and that this was uric acid dependent. These studies are consistent with epidemiological studies1,2 and a recent clinical trial.3 We agree that inclusion of a glucose control group would have been beneficial. However, a carefully performed clinical trial by Stanhope et al.4 has already documented that fructose, but not glucose, induces features of metabolic syndrome in humans. Experimental studies have also documented that fructose is distinct from glucose in its ability to induce metabolic syndrome and that this is independent of energy intake.5,6 These data are consistent with a recent meta-analysis that found that high-fructose corn syrup-containing beverages increase the risk for metabolic syndrome and diabetes.7 Our finding that we induced metabolic syndrome in 25% of adults within 2 weeks is of great concern. Although we agree that the rapidity of this induction is likely because of the large doses of fructose used in this study, it raises the specter that lower doses of fructose may cause similar effects over a longer period of time and would be consistent with the observation that obesity and metabolic syndrome develop over years in humans. For example, although it takes only 2 months to induce insulin resistance with 60% fructose in rats, studies show that a 15% fructose diet can induce insulin resistance in 15 months.8 In conclusion, we believe our study makes an important contribution on the role of excessive fructose in inducing metabolic syndrome and on the role of fructose-induced hyperuricemia in the blood pressure response. Although the doses of fructose used in the study were large, we must remember that some groups, such as young adults and children, are ingesting as much as 20–30% of their diet as added sugars. Other groups, such as African Americans and Hispanic Americans, are ingesting disproportionately higher amounts of fructose-containing sugars. When one further notes that the coexistent glucose can enhance fructose absorption in the intestine, our study gains additional clinical relevance. Hence, we strongly recommend public health measures to reduce the intake of fructose-containing sugars in the population; we believe this will have a major
benefit to prevent obesity, diabetes and hypertension, with overall benefits to cardiovascular health.
Conflict of interest Dr Johnson has a lay book, The Sugar Fix (Rodale, Simon and Schuster) and is also listed as an inventor on several patent applications related to blocking the effects of fructose to induce obesity and metabolic syndrome. All other authors declare no conflict of interest. SE Perez-Pozo, J Schold, T Nakagawa, LG Sanchez-Lozada, RJ Johnson and J Lopez-Lillo Department of Medicine, University of Colorado, Aurora, CO, USA E-mail:
[email protected]
References 1 Nguyen S, Choi HK, Lustig RH, Hsu CY. Sugar-sweetened beverages, serum uric acid, and blood pressure in adolescents. J Pediatr 2009; 154: 807–813. 2 Jalal DI, Smits G, Johnson RJ, Chonchol M. Increased fructose associates with elevated blood pressure. J Am Soc Nephrol 2010; 21: 1543–1549. 3 Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on the blood pressure of adolescents with newly diagnosed essential hypertension. JAMA 2008; 300: 922–930. 4 Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL et al. Consuming fructose-sweetened, not glucosesweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 2009; 119: 1322–1334. 5 Gersch MS, Mu W, Cirillo P, Reungjui S, Zhang L, Roncal C et al. Fructose, but not dextrose, accelerates the progression of chronic kidney disease. Am J Physiol 2007; 293: F1256–F1261. 6 Roncal CA, Reungjui S, Sanchez-Lozada LG, Mu W, Sautin YY, Nakagawa T et al. Combination of captopril and allopurinol retards fructose-induced metabolic syndrome. Am J Nephrol 2009; 30: 399–404. 7 Hu FB, Malik V, Popkin BM, Bray GA, Despres JP, Willett W. Sugar sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis. Diabetes Care 2010, e-pub ahead of print 6 August 2010. 8 Blakely SR, Hallfrisch J, Reiser S, Prather ES. Long-term effects of moderate fructose feeding on glucose tolerance parameters in rats. J Nutr 1981; 111: 307–314.
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