Gastrointestinal symptoms developed in half of the subjects who consumed 50 g of fructose alone on an empty stomach.The current dose of 54 ± 4 g resulted in a similar proportion reporting mild symptoms, although not significantly greater than with glucose. Attempts to reduce malabsorption were made by concurrent foodstuff consumption.The impact on outcomes of any malabsorption is unclear. There are no reliable biomarkers for fructose or glucose absorption. The presence of symptoms did not impact on weight.

We acknowledge some limitations of our study. First, a large amount of monosaccharide was supplied to provide the subjects with 25% of their energy requirements. Similar energy contributions, however, are feasible within habitual dietary patterns. According to the Low Income Diet and Nutrition Survey, nonmilk extrinsic sugars provide low-income UK men with 14.6% ± 8.8% of their energy intakes, with an upper 2.5% percentile contribution of 34.1%.A further issue was that the monosaccharides were provided as their constituent powders as opposed to either incorporated into the matrix of a foodstuff, or as a constituent of sucrose. This resulted in a nutrient, as opposed to dietary pattern, comparison. However, there is no evidence that fructose differs in its metabolic outcomes when provided as a hexose or when bound to glucose in sucrose.Other issues included the lack of cross-over between the groups, which weakened analyses between the monosaccharides. The relatively short-term nature of the intervention means that an effect with a longer dietary alteration cannot be excluded. The hyperinsulinemic euglycemic clamp was performed only in a representative subset of the group, and the study was not specifically powered for this assessment. Hyperinsulinemia, however, was stably reproduced at all 4 assessments with concentrations similar to those found in obese postprandial subjects.During the hypercaloric period foodstuffs were not provided, and hence nutrient intakes were not regulated precisely. Ad libitum energy overfeeding is the standard dietary method used in related studies.It improves the translatability of the findings into dietary intakes but fails to exclude for potential confounders. The magnitude of these would be predicted to be small in this study because habitual intakes of macronutrients, including fructose, were identical between the groups ( Supplementary Table 1 ). Finally, it was not ethical to perform histologic analyses via serial liver biopsies.

Excessive fructose intake induces the features of metabolic syndrome in healthy adult men: role of uric acid in the hypertensive response.

The sharply defined cohort reduced variation in the baseline metabolic state but it also limited the translatability of the findings. The cohort did, however, represent a substantial proportion of the UK adult male population. Forty-eight percent of UK males have both a waist size greater than 94 cm and a BMI between 25 and 35 kg/mand 72% of UK males report drinking less than 21 units of alcohol a week.Only men were recruited because sex appears to impact fructose metabolism via hormonal or anthropometric mechanisms.

Ali A, Becker E, Chaudhury M, et al. Health Survey for England etc 2006. Edited by Craig R & Mindell J. Published by the National Health Service Information Centre, Leeds, UK.

Interpretation

34 Malik V.S.

Schulze M.B.

Hu F.B. Intake of sugar-sweetened beverages and weight gain: a systematic review. We compared the effects of high intakes of glucose or fructose in isocaloric and hypercaloric conditions with predictable weight changes. The isocaloric period not only maintained weight, but also levels of leptin, rates of glycogen synthesis (nonoxidative glucose disposal), and serum and ectopic TAG stores. The hypercaloric period altered all of these parameters with increased HTGC, and liver volume, biochemistry, and Pi content. Energy balance appeared to be the key determinant of outcomes. The lack of change in HTGC during the isocaloric period and increase in the hypercaloric period suggests an exquisite hepatic sensitivity to excess energy, as opposed to a specific monosaccharide. Interestingly, satiety was unaltered despite the weight gain during the hypercaloric period. This reinforces the notion of hidden calories in drinks.

31P metabolites; and whole-body substrate oxidation. This was more than just maintenance of the status quo because the hypercaloric period resulted in a clear hepatic challenge. The responses to the challenge were markedly similar in both groups ( 6 Livesey G. More on mice and men: fructose could put brakes on a vicious cycle leading to obesity in humans. 35 Sievenpiper J.L.

Carleton A.J.

Chatha S.

et al. Heterogeneous effects of fructose on blood lipids in individuals with type 2 diabetes: systematic review and meta-analysis of experimental trials in humans. 4 Stanhope K.L.

Schwarz J.M.

Keim N.L.

et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. , 36 Ngo Sock E.T.

Le K.A.

Ith M.

et al. Effects of a short-term overfeeding with fructose or glucose in healthy young males. , 37 Chong M.F.

Fielding B.A.

Frayn K.N. Mechanisms for the acute effect of fructose on postprandial lipemia. , 38 Tilg H.

Hotamisligil G.S. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. 4 Stanhope K.L.

Schwarz J.M.

Keim N.L.

et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. , 12 Bantle J.P.

Raatz S.K.

Thomas W.

et al. Effects of dietary fructose on plasma lipids in healthy subjects. 4 Stanhope K.L.

Schwarz J.M.

Keim N.L.

et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. , 6 Livesey G. More on mice and men: fructose could put brakes on a vicious cycle leading to obesity in humans. 37 Chong M.F.

Fielding B.A.

Frayn K.N. Mechanisms for the acute effect of fructose on postprandial lipemia. Fructose and glucose overfeeding resulted in equal outcomes in terms of TAG in the serum, liver, and muscle; hepatic volume, insulin resistance, andP metabolites; and whole-body substrate oxidation. This was more than just maintenance of the status quo because the hypercaloric period resulted in a clear hepatic challenge. The responses to the challenge were markedly similar in both groups ( Figure 1 ), with similar absolute increases in key parameters including weight (+1.0% ± 1.4% vs +0.6% ± 1.1%); and TAG in liver (+40% ± 47% vs +38% ± 51%) and serum (+35% ± 66% vs +28% ± 30%); and liver biochemistry. Hence, the message appears clear that liver-related parameters do not differ with a 2-week period of glucose or fructose overfeeding, except for the impact from any energy excess. This lack of difference conflicts with the perception of fructose being highly lipogenic. There is, however, considerable debate as to whether any such effect exists.High doses of fructose result in greater fasted serum TAG than matched intakes of starch,but not in comparison with glucose,as has been shown again here. A greater postprandial triglyceride response after fructose than glucose was reported and attributed to increased de-novo lipogenesis and reduced insulin excursion with fructose resulting in a lower activation of adipose tissue lipoprotein lipase.Only 1.5% of the energy from fructose overfeeding is used for de-novo lipogenesisand the magnitude of any difference with glucose is minimal.

4 Stanhope K.L.

Schwarz J.M.

Keim N.L.

et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. 38 Tilg H.

Hotamisligil G.S. Nonalcoholic fatty liver disease: cytokine-adipokine interplay and regulation of insulin resistance. , 39 Schaffler A.

Scholmerich J.

Buchler C. Mechanisms of disease: adipocytokines and visceral adipose tissue–emerging role in nonalcoholic fatty liver disease. , 40 Nielsen S.

Guo Z.

Johnson C.M.

et al. Splanchnic lipolysis in human obesity. , 41 Musso G.

Cassader M.

De Michieli F.

et al. Nonalcoholic steatohepatitis versus steatosis: adipose tissue insulin resistance and dysfunctional response to fat ingestion predict liver injury and altered glucose and lipoprotein metabolism. 4 Stanhope K.L.

Schwarz J.M.

Keim N.L.

et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. The report by Stanhope et algenerated a comprehensive metabolic assessment but only a limited assessment of adipose tissue storage and distribution. There were significant increases in body weight, waist circumference, and total body fat, which did not differ between fructose and glucose. Visceral adiposity, as assessed by a single-slice umbilical computed tomography scan, was greater with fructose. Visceral adiposity has been linked to nonalcoholic steatohepatitis via an increased portal NEFA concentration, a proinflammatory cytokine profile, and hepatic insulin resistance.Stanhope et aldid not present NEFA data. They reported that fructose had a negative impact on the whole body, as opposed to hepatic insulin sensitivity, whereas fructose appeared to result in a favorable adiponectin/TNFα gene expression ratio in gluteal subcutaneous adipose tissue and glucose resulted in a deleterious ratio. As a result, we do not believe that hepatic outcomes can be inferred from this article's visceral adiposity findings. Interestingly, the current TAG changes were not associated with evidence of systemic inflammation as assessed by CRP, TNFα, or IL-6.

42 Sobrecases H.

Le K.A.

Bortolotti M.

et al. Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men. The lack of an alternative nutrient comparator in this study means that we cannot be certain that these changes were solely from the effects of energy overfeeding, or specific to energy overfeeding with monosaccharides. To date, the hepatic outcomes from carbohydrate overfeeding has not been compared with a matched amount of energy from an alternative macronutrient.The current data, however, highlight the impact that a short-term change in lifestyle can have on HTGC.

4 Stanhope K.L.

Schwarz J.M.

Keim N.L.

et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. , 27 Silbernagel G.

Machann J.

Unmuth S.

et al. Effects of 4-week very-high-fructose/glucose diets on insulin sensitivity, visceral fat and intrahepatic lipids: an exploratory trial. , 36 Ngo Sock E.T.

Le K.A.

Ith M.

et al. Effects of a short-term overfeeding with fructose or glucose in healthy young males. 36 Ngo Sock E.T.

Le K.A.

Ith M.

et al. Effects of a short-term overfeeding with fructose or glucose in healthy young males. , 43 Aeberli I.

Hochuli M.

Gerber P.A.

et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. 43 Aeberli I.

Hochuli M.

Gerber P.A.

et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. The 2 groups did differ in terms of their HOMA-IR and uric acid outcomes, findings that appear unrelated, isolated, and hence whose interpretation is uncertain. Increases in fasted glucose and insulin concentrations previously have been reported with both fructose and glucose overfeeding.The current study found such changes only during the isocaloric period with fructose. There is no clear explanation for the difference with the glucose group during this period. The trend for a greater pre-existing HOMA-IR value in the fructose group may have impacted this result. We caution against overinterpretation of this finding, especially in light of the current matched rates of glucose disposal and EGP. The effects of glucose and fructose overfeeding on systemic insulin resistance and EGP have been compared previously, twice by a Swiss group using the clamp method.A greater EGP with fructose has been the only difference reported; although this was in a subgroup analysis of a larger study with no baseline data to fully quantify the impact of both arms.

31P MRS metabolite changes during this period may be because only fasted assessments were performed. 44 Abdelmalek M.F.

Lazo M.

Horska A.

et al. Higher dietary fructose is associated with impaired hepatic adenosine triphosphate homeostasis in obese individuals with type 2 diabetes. 45 Israel K.D.

Michaelis O.E.

Reiser S.

et al. Serum uric acid, inorganic phosphorus, and glutamic-oxalacetic transaminase and blood pressure in carbohydrate-sensitive adults consuming three different levels of sucrose. 46 Wang D.D.

Sievenpiper J.L.

de Souza R.J.

et al. The effects of fructose intake on serum uric acid vary among controlled dietary trials. Uric acid concentrations increased with fructose during both periods and reduced with glucose. This was only significant during the isocaloric period. The lack of associated hepaticP MRS metabolite changes during this period may be because only fasted assessments were performed.In accordance with the increase in hepatic Pi during the hypercaloric period with fructose, an increase in serum Pi has been reported with sucrose overfeeding,with no prior controlled fructose data to our knowledge. The increase in uricemia with fructose has been attributed to its lack of pre-pyruvate feedback inhibition, although this outcome has not been shown consistently.The mechanism behind the current reduction with glucose is unclear. It may reflect a lower purine content in the supplied than the habitual foods (analyses were not possible).

The strengths of this study were the provision of all foodstuffs in the isocaloric phase, repeated baseline assessments, differing energy periods, 31P MRS assessments, and the use of a hyperinsulinemic euglycemic clamp within a subset. The selection of glucose as the comparator maintained energy and macronutrient balance between the groups. Assessments of liver lipid, volume, biochemistry, and inflammatory markers formed a global hepatic profile. A wider metabolic picture was formed with data on nonhepatic lipids, whole-body metabolism, and insulin resistance. The repeat baseline confirmed that parameters had returned to baseline during the washout period.

21 Le K.A.

Ith M.

Kreis R.

et al. Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. 2 and 33%) reported similar fat-free mass glucose disposal rates of 8.2 mg/kg fat-free mass/min to the current 7.2 mg/kg fat-free mass/min. 47 Ferrannini E.

Natali A.

Bell P.

et al. Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR). The cohort was recruited on the basis of being centrally overweight with no evidence of liver or metabolic disease. Central (visceral) obesity drives systemic and hepatic insulin resistance, which appears to result in an increased metabolic response to fructose.The current baseline insulin resistance can be attributed to body composition. A cohort of 376 men with a similar BMI and body fat percentage to this cohort (28.8 ± 3.9 kg/mand 33%) reported similar fat-free mass glucose disposal rates of 8.2 mg/kg fat-free mass/min to the current 7.2 mg/kg fat-free mass/min.