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Letter to the Editor| Volume 90, ISSUE 7, P984-988, July 01, 2015

Fructose as a Driver of Diabetes: An Incomplete View of the Evidence

DOI:https://doi.org/10.1016/j.mayocp.2015.04.017
Fructose as a Driver of Diabetes: An Incomplete View of the Evidence
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      To the Editor:
      We are concerned that the article by DiNicolantonio et al
      • DiNicolantonio J.J.
      • O'Keefe J.H.
      • Lucan S.C.
      Added fructose: a principal driver of type 2 diabetes mellitus and its consequences.
      Mayo Clin Proc. 2015; 90: 372-381
      published in the March 2015 issue of Mayo Clinic Proceedings that implicated added fructose as a driver of type 2 diabetes misrepresented the data by placing undue emphasis on low-quality evidence from ecological observations, animal models of fructose overfeeding, and selected human studies assessed in isolation. It also ignored important biological mechanisms by which fructose may assist in the metabolic handling of glucose. If one considers the totality of the highest-quality evidence from controlled feeding trials and prospective cohorts, then different conclusions are reached.
      A series of carefully conducted systematic reviews and meta-analyses
      • Livesey G.
      • Taylor R.
      Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies.
      Am J Clin Nutr. 2008; 88: 1419-1437
      , 
      • Cozma A.I.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
      Diabetes Care. 2012; 35: 1611-1620
      , 
      • Sievenpiper J.L.
      • de Souza R.J.
      • Mirrahimi A.
      • et al.
      Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.
      Ann Intern Med. 2012; 156: 291-304
      , 
      • 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.
      Diabetes Care. 2009; 32: 1930-1937
      , 
      • Wang D.D.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials.
      Atherosclerosis. 2014; 232: 125-133
      , 
      • Ha V.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials.
      Hypertension. 2012; 59: 787-795
      , 
      • 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.
      J Nutr. 2012; 142: 916-923
      , 
      • Chiu S.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.
      Eur J Clin Nutr. 2014; 68: 416-423
      of more than 50 controlled trials that included over 1000 participants of the effect of fructose across a wide dose range have failed to document a signal for harm of fructose in isocaloric substitution for other carbohydrates likely to replace it (Figure 1). Contrary to the hypothesis put forward by DiNicolantonio et al,
      • DiNicolantonio J.J.
      • O'Keefe J.H.
      • Lucan S.C.
      Added fructose: a principal driver of type 2 diabetes mellitus and its consequences.
      Mayo Clin Proc. 2015; 90: 372-381
      pooled analyses of the totality of the evidence from these trials show that fructose in isocaloric exchange for other sources of carbohydrate leads to clinically meaningful improvements in glycemic control as assessed by glycated blood proteins (equivalent to a 0.57% reduction in hemoglobin A1c, which exceeds the US Food and Drug Administration threshold of 0.3% for the development of new oral antihyperglycemic agents) in individuals with and without diabetes.
      • Livesey G.
      • Taylor R.
      Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies.
      Am J Clin Nutr. 2008; 88: 1419-1437
      , 
      • Cozma A.I.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
      Diabetes Care. 2012; 35: 1611-1620
      Favorable results are also seen in blood pressure, without any adverse effects on other cardiometabolic risk factors including insulin sensitivity, body weight, fasting lipid levels, postprandial lipid levels, uric acid concentration, and markers of nonalcoholic fatty liver disease in individuals with varying metabolic phenotypes.
      • Livesey G.
      • Taylor R.
      Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies.
      Am J Clin Nutr. 2008; 88: 1419-1437
      , 
      • Cozma A.I.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
      Diabetes Care. 2012; 35: 1611-1620
      , 
      • Sievenpiper J.L.
      • de Souza R.J.
      • Mirrahimi A.
      • et al.
      Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.
      Ann Intern Med. 2012; 156: 291-304
      , 
      • 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.
      Diabetes Care. 2009; 32: 1930-1937
      , 
      • Wang D.D.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials.
      Atherosclerosis. 2014; 232: 125-133
      , 
      • Ha V.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials.
      Hypertension. 2012; 59: 787-795
      , 
      • 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.
      J Nutr. 2012; 142: 916-923
      , 
      • Chiu S.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.
      Eur J Clin Nutr. 2014; 68: 416-423
      DiNicolantonio et al implied that bias from industry funding might explain these favorable results among the available controlled trials, but very few of these trials were funded exclusively by industry. The majority were funded by a combination of agency and industry or agency alone, and there was no evidence of publication bias across the end points.
      • Livesey G.
      • Taylor R.
      Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies.
      Am J Clin Nutr. 2008; 88: 1419-1437
      , 
      • Cozma A.I.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
      Diabetes Care. 2012; 35: 1611-1620
      , 
      • Sievenpiper J.L.
      • de Souza R.J.
      • Mirrahimi A.
      • et al.
      Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.
      Ann Intern Med. 2012; 156: 291-304
      , 
      • 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.
      Diabetes Care. 2009; 32: 1930-1937
      , 
      • Wang D.D.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials.
      Atherosclerosis. 2014; 232: 125-133
      , 
      • Ha V.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials.
      Hypertension. 2012; 59: 787-795
      , 
      • 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.
      J Nutr. 2012; 142: 916-923
      , 
      • Chiu S.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.
      Eur J Clin Nutr. 2014; 68: 416-423
      Figure thumbnail gr1
      Figure 1Forest plots of summary estimates from recent meta-analyses of the effect of fructose interventions on cardiometabolic risk factors in controlled dietary trials. The meta-analyses were grouped on the basis of the control of calories in the trial comparisons: A—isocaloric substitution trials, in which fructose was exchanged for other carbohydrate sources under energy-matched conditions; and B—hypercaloric addition trials, in which excess calories from fructose were added to a diet compared with the same diet without the excess calories. Summary estimates (diamonds) were derived from pooled trial-level data. The data for glycemic control and insulin sensitivity in individuals with and without diabetes were derived from an update by Cozma et al.
      • Cozma A.I.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
      Diabetes Care. 2012; 35: 1611-1620
      To allow the summary estimates for each end point to be displayed on the same axis, mean differences were transformed to standardized mean differences (SMDs). Pseudo-95% CIs for each transformed SMD were derived directly from the original mean difference and 95% CI. The scales were also flipped for high-density lipoprotein cholesterol (HDL-C), whole-body insulin sensitivity, and hepatic insulin sensitivity so that the direction of the effect for benefit or harm was in the same direction as that for the other end points. Asterisks indicate significant interstudy heterogeneity as assessed by the Cochran Q statistic and quantified by the I2 statistic at a significance level of P<.10 (the higher significance level was chosen owing to the poor sensitivity of the test). ALT = alanine aminotransferase; Apo-B = apolipoprotein B; DBP = diastolic blood pressure; FBG = fasting blood glucose; FBI = fasting blood insulin; GBP = glycated blood proteins; HOMA-IR = homeostatic model assessment-insulin resistance; IHCL = intrahepatocellular lipid; LDL-C = low-density lipoprotein cholesterol; MAP = mean arterial pressure; SBP = systolic blood pressure; TG = triglycerides.
      Prospective cohort studies, which provide the greatest protection against bias among observational studies because of their long longitudinal follow-up and the ability to adjust for multiple confounding factors, have also failed to document a direct relationship between fructose and diabetes. Although pooled analyses of the available cohorts have revealed that sugar-sweetened beverages (SSBs) as a source of free fructose are associated with an increased risk of diabetes when the highest and lowest levels of exposure are compared,
      • Malik V.S.
      • Popkin B.M.
      • Bray G.A.
      • Després J.P.
      • Willett W.C.
      • Hu F.B.
      Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis.
      Diabetes Care. 2010; 33: 2477-2483
      , 
      • Xi B.
      • Li S.
      • Liu Z.
      • et al.
      Intake of fruit juice and incidence of type 2 diabetes: a systematic review and meta-analysis.
      PLoS One. 2014; 9: e93471
      pooled analyses involving many of the same cohorts have not found the same relationship for total sugars, total sucrose, total fructose,

      Tsilas CS, de Souza RJ, Tawfik R, et al. No relation between total sugars intake and incident diabetes: a systematic review and meta-analysis of cohorts. In: Proceedings of the 32nd International Symposium on Diabetes and Nutrition; June 25-27, 2014; Reykjavik, Iceland.

      or other sources of free fructose such as 100% fruit juice
      • Xi B.
      • Li S.
      • Liu Z.
      • et al.
      Intake of fruit juice and incidence of type 2 diabetes: a systematic review and meta-analysis.
      PLoS One. 2014; 9: e93471
      and cakes and cookies
      • Buijsse B.
      • Boeing H.
      • Drogan D.
      • et al.
      Consumption of fatty foods and incident type 2 diabetes in populations from eight European countries.
      Eur J Clin Nutr. 2015; 69: 455-461
      (Figure 2). The opposite relationship (benefit) has also been reported for fruit as a source of bound fructose.
      • Li M.
      • Fan Y.
      • Zhang X.
      • Hou W.
      • Tang Z.
      Fruit and vegetable intake and risk of type 2 diabetes mellitus: meta-analysis of prospective cohort studies.
      BMJ Open. 2014; 4: e005497
      Figure thumbnail gr2
      Figure 2Forest plots of summary estimates from recent meta-analyses of the relationship between different sources of sugars and incident type 2 diabetes in adults. Summary estimates (diamonds) were derived from pooled risk ratios for comparison of extreme quantiles (the highest level of exposure compared with the lowest level of exposure). The one exception was for cakes and cookies, which compared the highest level of exposure with the middle level of exposure, the reference exposure that was associated with the lowest risk. Data are expressed as risk ratios with 95% CIs. Asterisks indicate significant interstudy heterogeneity as assessed by the Cochran Q statistic and quantified by the I2 statistic at a significance level of P<.10 (the higher significance level was chosen owing to the poor sensitivity of the test). SSBs = sugar-sweetened beverages.
      Setting aside these discrepant findings, if one wants to invoke the evidence for SSBs as a proxy for all added fructose-containing sugars, then one has to ask how important a risk factor is the intake of SSBs. A recent comparative risk assessment revealed that the burden of disease and mortality attributable to SSBs (that is, population-attributable fraction) is still much less than that of other established risk factors measured among the cohort studies, ranking 32nd among 57 risk factors globally.
      • Lim S.S.
      • Vos T.
      • Flaxman A.D.
      • et al.
      A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.
      Lancet. 2012; 380 ([published correction appears in Lancet. 2013;381(9874):1276]): 2224-2260
      Even among the dietary and physical inactivity risk factors, SSBs ranked 12th of 15 for both burden of disease and mortality, and no other sources of added fructose-containing sugars were identified as risk factors.
      • Lim S.S.
      • Vos T.
      • Flaxman A.D.
      • et al.
      A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.
      Lancet. 2012; 380 ([published correction appears in Lancet. 2013;381(9874):1276]): 2224-2260
      The question becomes why the higher-level evidence disagrees with the current hypothesis from DiNicolantonio et al.
      • DiNicolantonio J.J.
      • O'Keefe J.H.
      • Lucan S.C.
      Added fructose: a principal driver of type 2 diabetes mellitus and its consequences.
      Mayo Clin Proc. 2015; 90: 372-381
      One reason may be that the mechanisms being invoked are not as relevant in humans as in the animal models used to support them. For example, although de novo lipogenesis is extremely high (estimated at ≥50%) with excessive fructose feeding (typically 60% of total energy intake) in rodents, a careful review of stable isotope tracer studies reveals that de novo lipogenesis from fructose (as indeed from all carbohydrate) is a minor pathway for fructose disposal in humans (estimated to range from 0%-1% at moderate intake to up to 5% with overfeeding in humans).
      • van Buul V.J.
      • Tappy L.
      • Brouns F.J.
      Misconceptions about fructose-containing sugars and their role in the obesity epidemic.
      Nutr Res Rev. 2014; 27: 119-130
      Another reason for the differences may lie in biologically plausible pathways that offset any harm and even explain some benefits. Fructose has a very low glycemic index (15), a factor that led to an early interest in fructose in diabetes management. Emerging evidence also shows that low-dose fructose (≤10 g per meal) may benefit glycemic control through its metabolite fructose-1-phosphate by inducing glucokinase activity. This catalytic effect of fructose on hepatic glucose metabolism has been reported to coincide with (1) a decrease in hepatic glucose production under hyperglycemic clamp conditions in patients with type 2 diabetes and (2) an increase in glycogen synthesis by carbon 13 nuclear magnetic resonance spectroscopy under euglycemic clamp conditions in participants without diabetes.
      • Petersen K.F.
      • Laurent D.
      • Yu C.
      • Cline G.W.
      • Shulman G.I.
      Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans.
      Diabetes. 2001; 50: 1263-1268
      , 
      • Hawkins M.
      • Gabriely I.
      • Wozniak R.
      • Vilcu C.
      • Shamoon H.
      • Rossetti L.
      Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes.
      Diabetes. 2002; 51: 606-614
      These mechanisms appear to be sustainable over the long term. A systematic review and meta-analysis of controlled trials of the effect of small “catalytic” fructose doses (≤36 g/d) in exchange for starch reproduced the favorable glycemic effects seen at higher doses, without any adverse effects on metabolic control over 1 to 52 weeks of follow-up.
      • Sievenpiper J.L.
      • Chiavaroli L.
      • de Souza R.J.
      • et al.
      ‘Catalytic’ doses of fructose may benefit glycaemic control without harming cardiometabolic risk factors: a small meta-analysis of randomised controlled feeding trials.
      Br J Nutr. 2012; 108: 418-423
      Harm from fructose, however, is seen under certain conditions. Dose thresholds for harm have been previously identified for the effect of fructose on fasting and postprandial lipid levels,
      • Livesey G.
      • Taylor R.
      Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies.
      Am J Clin Nutr. 2008; 88: 1419-1437
      , 
      • 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.
      Diabetes Care. 2009; 32: 1930-1937
      Although these thresholds have not been reproduced in updated meta-analyses,
      • Wang D.D.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials.
      Atherosclerosis. 2014; 232: 125-133
      individual trials of fructose feeding at very high doses (>100 g/d) have found increases in fasting and postprandial triglyceride levels in energy-matched comparisons with glucose.
      • Egli L.
      • Lecoultre V.
      • Theytaz F.
      • et al.
      Exercise prevents fructose-induced hypertriglyceridemia in healthy young subjects.
      Diabetes. 2013; 62: 2259-2265
      The most consistent signal for harm remains restricted to hypercaloric addition trials, in which excess calories from pure fructose are added to a diet, compared with the same diet without these excess calories. Systematic reviews and meta-analyses of the available trials have found that fructose under these conditions leads to weight gain and increases in fasting and postprandial triglyceride levels, fasting glucose levels, whole-body and hepatic insulin resistance, uric acid concentrations, and markers of nonalcoholic fatty liver disease
      • Cozma A.I.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
      Diabetes Care. 2012; 35: 1611-1620
      , 
      • Sievenpiper J.L.
      • de Souza R.J.
      • Mirrahimi A.
      • et al.
      Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.
      Ann Intern Med. 2012; 156: 291-304
      , 
      • 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.
      Diabetes Care. 2009; 32: 1930-1937
      , 
      • Wang D.D.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials.
      Atherosclerosis. 2014; 232: 125-133
      , 
      • Ha V.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials.
      Hypertension. 2012; 59: 787-795
      , 
      • 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.
      J Nutr. 2012; 142: 916-923
      , 
      • Chiu S.
      • Sievenpiper J.L.
      • de Souza R.J.
      • et al.
      Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.
      Eur J Clin Nutr. 2014; 68: 416-423
      (Figure 1). The inability of fructose to induce the same adverse effects in isocaloric substitution for other carbohydrates suggests that the main determinant of this observed harm is excess calories rather than any special metabolic or endocrine responses to the fructose. Any adverse effects observed under conditions of overfeeding appear to be no more mediated by fructose than by other sources of carbohydrate used to replace it. That these adverse effects appear to be reversible by exercise also suggests that they may not be generalizable to all individuals.
      • Egli L.
      • Lecoultre V.
      • Theytaz F.
      • et al.
      Exercise prevents fructose-induced hypertriglyceridemia in healthy young subjects.
      Diabetes. 2013; 62: 2259-2265
      In conclusion, efforts to identify the factors that contribute to the development of type 2 diabetes remain an important goal. These efforts, however, must be conducted using systematic evidence-based approaches that protect against important sources of bias that include confounding from energy. In the case of fructose, the totality of the highest-level evidence from the systematic reviews and meta-analyses of controlled trials and prospective cohort studies fails to implicate fructose as an independent driver of type 2 diabetes.

      References

        • DiNicolantonio J.J.
        • O'Keefe J.H.
        • Lucan S.C.
        Added fructose: a principal driver of type 2 diabetes mellitus and its consequences.
        Mayo Clin Proc. 2015; 90: 372-381
        View in Article
        • Livesey G.
        • Taylor R.
        Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies.
        Am J Clin Nutr. 2008; 88: 1419-1437
        View in Article
        • Cozma A.I.
        • Sievenpiper J.L.
        • de Souza R.J.
        • et al.
        Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials.
        Diabetes Care. 2012; 35: 1611-1620
        View in Article
        • Sievenpiper J.L.
        • de Souza R.J.
        • Mirrahimi A.
        • et al.
        Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis.
        Ann Intern Med. 2012; 156: 291-304
        View in Article
        • 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.
        Diabetes Care. 2009; 32: 1930-1937
        View in Article
        • Wang D.D.
        • Sievenpiper J.L.
        • de Souza R.J.
        • et al.
        Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials.
        Atherosclerosis. 2014; 232: 125-133
        View in Article
        • Ha V.
        • Sievenpiper J.L.
        • de Souza R.J.
        • et al.
        Effect of fructose on blood pressure: a systematic review and meta-analysis of controlled feeding trials.
        Hypertension. 2012; 59: 787-795
        View in Article
        • 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.
        J Nutr. 2012; 142: 916-923
        View in Article
        • Chiu S.
        • Sievenpiper J.L.
        • de Souza R.J.
        • et al.
        Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of controlled feeding trials.
        Eur J Clin Nutr. 2014; 68: 416-423
        View in Article
        • Malik V.S.
        • Popkin B.M.
        • Bray G.A.
        • Després J.P.
        • Willett W.C.
        • Hu F.B.
        Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: a meta-analysis.
        Diabetes Care. 2010; 33: 2477-2483
        View in Article
        • Xi B.
        • Li S.
        • Liu Z.
        • et al.
        Intake of fruit juice and incidence of type 2 diabetes: a systematic review and meta-analysis.
        PLoS One. 2014; 9: e93471
        View in Article

      12. Tsilas CS, de Souza RJ, Tawfik R, et al. No relation between total sugars intake and incident diabetes: a systematic review and meta-analysis of cohorts. In: Proceedings of the 32nd International Symposium on Diabetes and Nutrition; June 25-27, 2014; Reykjavik, Iceland.

        View in Article
        • Buijsse B.
        • Boeing H.
        • Drogan D.
        • et al.
        Consumption of fatty foods and incident type 2 diabetes in populations from eight European countries.
        Eur J Clin Nutr. 2015; 69: 455-461
        View in Article
        • Li M.
        • Fan Y.
        • Zhang X.
        • Hou W.
        • Tang Z.
        Fruit and vegetable intake and risk of type 2 diabetes mellitus: meta-analysis of prospective cohort studies.
        BMJ Open. 2014; 4: e005497
        View in Article
        • Lim S.S.
        • Vos T.
        • Flaxman A.D.
        • et al.
        A comparative risk assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010.
        Lancet. 2012; 380 ([published correction appears in Lancet. 2013;381(9874):1276]): 2224-2260
        View in Article
        • van Buul V.J.
        • Tappy L.
        • Brouns F.J.
        Misconceptions about fructose-containing sugars and their role in the obesity epidemic.
        Nutr Res Rev. 2014; 27: 119-130
        View in Article
        • Petersen K.F.
        • Laurent D.
        • Yu C.
        • Cline G.W.
        • Shulman G.I.
        Stimulating effects of low-dose fructose on insulin-stimulated hepatic glycogen synthesis in humans.
        Diabetes. 2001; 50: 1263-1268
        View in Article
        • Hawkins M.
        • Gabriely I.
        • Wozniak R.
        • Vilcu C.
        • Shamoon H.
        • Rossetti L.
        Fructose improves the ability of hyperglycemia per se to regulate glucose production in type 2 diabetes.
        Diabetes. 2002; 51: 606-614
        View in Article
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      Article Info

      Footnotes

      Grant Support: This work was supported in part by a PSI Foundation Graham Farquharson Knowledge Translation Fellowship (J.L.S.), the Canadian Institutes of Health Research Knowledge Synthesis Program (funding reference number 102078) and Programmatic Grants in Food and Health (funding reference number 129920) through the Canada-wide Human Nutrition Trialists’ Network, and grant 32003B_156167 from the Swiss National Foundation for Science (L.T.). The sponsors did not have any role in the study design; collection, analysis, and interpretation of data; writing of the manuscript; and decision to submit for publication.

      Potential Competing Interests: Dr Sievenpiper has received research support from the Canadian Institutes of Health Research, Calorie Control Council, American Society of Nutrition (ASN), Coca-Cola Company (investigator initiated, unrestricted), Dr Pepper Snapple Group (investigator initiated, unrestricted), Pulse Canada, and International Tree Nut Council Nutrition Research & Education Foundation; has received reimbursement of travel expenses, speaker’s fees, and/or honoraria from the American Heart Association, American College of Physicians, ASN, National Institute of Diabetes and Digestive and Kidney Diseases, Canadian Diabetes Association (CDA), Canadian Nutrition Society, University of South Carolina, University of Alabama at Birmingham, Oldways Preservation Trust, Nutrition Foundation of Italy, Calorie Control Council, Diabetes and Nutrition Study Group (DNSG) of the European Association for the Study of Diabetes (EASD), International Life Sciences Institute (ILSI) North America, ILSI Brazil, Abbott Laboratories, Pulse Canada, Canadian Sugar Institute, Dr Pepper Snapple Group, Coca-Cola Company, Corn Refiners Association, World Sugar Research Organisation, Dairy Farmers of Canada, Società Italiana di Nutrizione Umana, C3 Collaborating for Health White Wave Foods, Rippe Lifestyle, and mdBriefcase; has ad hoc consulting arrangements with Winston & Strawn LLP, Perkins Coie LLP, and Tate & Lyle; is on the Clinical Practice Guidelines Expert Committee for Nutrition Therapy of the CDA, Canadian Cardiovascular Society, and EASD and on an ASN writing panel for a scientific statement on sugars; is a member of the International Carbohydrate Quality Consortium and board member of the DNSG of the EASD; serves as an unpaid scientific advisor for ILSI North America Food, Nutrition, and Safety Program and Committee on Carbohydrates; and is married to an employee of Unilever Canada.

      Dr Tappy has received research support from the Swiss National Science Foundation, Swiss Federal Office of Sport, Nestlé SA, Ajinomoto Co, Inc, and C3 Collaborating for Health.

      Dr Brouns has received research support, reimbursement of travel expenses, speaker’s fees, conference registration wavers, and/or honoraria from Top Institute Food and Nutrition, European Commission Framework Programme research programs, Netherlands Organisation for Scientific Research, DNSG of the EASD, Dutch Academy of Nutritional Sciences, ILSI North America, ILSI Europe, ILSI Southeast Asia Region, German Institute of Human Nutrition, IDACE, International Fruit Juice Union, New York Academy of Sciences, Vahouny Fiber Conference Organization, Laval University, American College of Sports Medicine, European College of Sport Science, International Olympic Committee, Spanish Olympic Committee, British Olympic Committee, Netherlands Olympic Committee/Netherlands Sports Confederations, French National Institute for Agricultural Research, NutrEvent, Health Information Exchange, Foundation for International Education, Institute of Food Technologists, Cargill, Inc, Cerestar Ltd, Novartis Medical Nutrition, Sandoz Nutrition, Wander Dietetics, FrieslandCampina, Nestlé SA, Institute of Sport Sciences Magglingen, Institute for Cereal Research, International Association for Cereal Science and Technology, Whole Grain Council, Coca-Cola Company, European Fruit Juice Association, Stern-Wywiol Gruppe GmbH & Co KG, PURAC Biochem BV, FEVIA, Kellogg Company, Arla Foods, Unilever, Masterfoods, Sensus BV, General Mills, Jumbo Supermarkten, Puratos Group, Koopmans, DSM Food Specialties, Dutch Bakery Centre, International Association of Plant Bakers, Tate & Lyle, Dutch Sugar Foundation, Kraft Foods Group, Inc, Central Soya Co, Inc, TNO Nutrition and Food Research Institute, NIZO Food Research BV, University of Applied Sciences at Groningen, Amsterdam, Rotterdam, Leiden, Delft, Leeuwarden, den Bosch, Den Haag, Delft, and Nijmegen, University of Leuven, Health Grain Europe, HEALTHGRAIN FORUM, Netherlands Ministry of Health, Welfare and Sport, Bridge2Food, Danone SA, Nutricia, Scelta Institute, Kokkerelli Kids University for Cooking, Syntens, LIOF, European Technology Platform, and European Food Information Council; has organized a number of national and international conferences and workshops cofunded by numerous industries and nongovernmental organizations; has served on various expert panels and boards of research organizations, nongovernmental organizations, and industries; and established a consultancy firm, Brouns Health Food Consulting, in January 2015.

      Identification

      DOI: https://doi.org/10.1016/j.mayocp.2015.04.017

      Copyright

      © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

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      Linked Article

      • Added Fructose: A Principal Driver of Type 2 Diabetes Mellitus and Its Consequences
        Mayo Clinic ProceedingsVol. 90Issue 3
        • Preview
          Data from animal experiments and human studies implicate added sugars (eg, sucrose and high-fructose corn syrup) in the development of diabetes mellitus and related metabolic derangements that raise cardiovascular (CV) risk. Added fructose in particular (eg, as a constituent of added sucrose or as the main component of high-fructose sweeteners) may pose the greatest problem for incident diabetes, diabetes-related metabolic abnormalities, and CV risk. Conversely, whole foods that contain fructose (eg, fruits and vegetables) pose no problem for health and are likely protective against diabetes and adverse CV outcomes.
        • Full-Text
        • PDF
      • In reply—Fructose as a Driver of Diabetes: An Incomplete View of the Evidence
        Mayo Clinic ProceedingsVol. 90Issue 7
        • Preview
          We appreciate the response to our article from Dr Sievenpiper and colleagues, who argue that the highest-level evidence fails to implicate fructose as an independent driver of type 2 diabetes. We respectfully counter that the meta-analyses and systematic reviews the authors present may be misleading and that the totality of data supports our original contention.
        • Full-Text
        • PDF
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