More on Mice and Men: Fructose Could put Brakes on a Vicious Cycle Leading to Obesity in Humans
2011; Elsevier BV; Volume: 111; Issue: 7 Linguagem: Inglês
10.1016/j.jada.2011.05.020
ISSN1878-3570
Autores Tópico(s)Liver Disease Diagnosis and Treatment
ResumoThe role played by dietary fructose in the ‘epidemic’ of obesity has recently been debated in the Journal of the American Dietetic Association (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar, 2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) following the earlier review by Lustig (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar) in which fructose is argued to have a prominent role in the causation and perpetuation of obesity. These warrant comment because the arguments do not represent the literature in humans on this topic and literature is cited inaccurately, particularly in regard to my own work.In addition to these problems, there is a question of whether the review article (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar) meets acceptable evidence-based standards sufficient to affect nutrition policy and practice. Moreover, evidence synthesis needs to focus on practice needs recognizing one policy may not fit all circumstances. Correspondents Sievenpiper and colleagues (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar) appear concerned primarily with the acceptability and potential benefits of moderate intake of pure or crystalline fructose in diabetics. By contrast, correspondents Lustig and Schwarz (2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) appear concerned primarily with the risks of excessive sucrose or high-fructose corn syrup consumption in infants, children, and adolescents. Both camps work on respectable hypotheses, and one ought not to be seen as to exclude the other.The idea that moderate intakes of pure fructose is acceptable and potentially beneficial for the control of dysglycemia and diabetes is not new. However, the idea has been given a boost by recent systematic and meta-analytical evidence of human intervention studies showing moderate doses of pure fructose (up to at least 90 g daily) lower glycated hemoglobin (HbA1c) in a dose-dependent manner (4Livesey 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: 1419-1437Google Scholar) when provided by carbohydrate exchange, with possible implications for diabetes and coronary heart disease (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar). This is contrary to expectations about HbA1c offered in the review article by Lustig (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar). The idea received a further boost when it was shown that moderate and high doses of pure fructose (up to 150 g/d) in human intervention studies leads to improvement in insulin sensitivity (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar). Again this is contrary to the expectations raised in the review article by Lustig (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar).Consistent with Lustig's expectations, nevertheless, a reduction in insulin sensitivity does arise with excessive pure fructose intake in humans, as in mice. However, in humans, this has not been demonstrated unless fructose intake is higher than the published threshold of ∼150 g/d (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar), a value from meta-analysis that holds true after recently doubling the number of intervention studies available for analysis (6Livesey G. Insulin sensitivity—Modification by dietary fructose in human intervention studies?. Independent Nutrition Logic Ltd, Wymondham, UK2010Google Scholar). According to the most recent published information on fructose intakes in a representative sample of the US population, the 150 g/d threshold is much higher than the 95% percentile fructose intake for the highest consumer group (19- to 22-year-olds) and adolescents. It is also three times higher than the published population average intake of 49 g/d (7Marriott B.P. Cole N. Lee E. National estimates of dietary fructose intake increased from 1977 to 2004 in the United States.J Nutr. 2009; 139: 1228S-1235SGoogle Scholar), an intake value falling since the turn of the millennium (8US Department of Agriculture, Economic Research ServiceSugar and sweeteners: Recommended data: U.S. consumption of caloric sweeteners [Tables 49-53].http://www.ers.usda.gov/briefing/sugar/data.htmGoogle Scholar).According to the review article (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar), insulin resistance and hyperinsulinemia are central to the vicious-cycle hypothesis that describes possible events thought to contribute to obesity. The hypothesis is well articulated in earlier reviews (9Isganaitis E. Lustig R.H. Fast food, central nervous system insulin resistance, and obesity.Arterioscler Thromb Vasc Biol. 2005; 25: 2451-2462Google Scholar, 10Mietus-Snyder M.L. Lustig R.H. Childhood obesity: Adrift in the “Limbic Triangle.”.Annul Rev Med. 2008; 59: 147-162Google Scholar), but elsewhere is promoted by Lustig with a focus on fructose (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar, 11Lustig R.H. The trouble with fructosePowerPoint slides presented at: Children's Environmental Health Research: Past, Present & FutureResearch Triangle Park, NC: January 2007.http://www.niehs.nih.gov/news/events/pastmtg/2007/cehr/docs/metabolicsyndromelustig.pdfGoogle Scholar, 12Lustig R.H. The Fructose Epidemic.The Bariatrician. 2009; 12: 10-18Google Scholar, 13Lustig R.H. Sugar: The Bitter Truth [video] YouTube Web site.http://www.youtube.com/watch?v=dBnniua6-oMGoogle Scholar, 14Lustig R.H. The ‘skinny’ on childhood obesity: How our Western environment starves kids' brains.Pediatr Ann. 2006; 35 (905-7): 898-902Google Scholar). All those reviews focusing on fructose are narrative—none has followed the principles of systematic review and meta-analysis that are essential to the establishment of evidence-based practice and, later, practice-based evidence. Now we have some insight from such information (4Livesey 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: 1419-1437Google Scholar, 5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar, 6Livesey G. Insulin sensitivity—Modification by dietary fructose in human intervention studies?. Independent Nutrition Logic Ltd, Wymondham, UK2010Google Scholar) the vicious cycle hypothesis might be elaborated further.Abbreviating the hypothesised vicious cycle to its most basic (Figure), excessive carbohydrate food intake promotes an insulin response that can facilitate the retention or storage of energy in adipose tissue as fat. Excess fat accumulation leads to insulin resistance and hyperinsulinemia. Subsequent leptin resistance and ghrelin hyposecretion promote greater food intake, so advancing the obese state. Excessive glucose intake from high-glycemic sugars or starchy foods helps to turn the cycle by promoting an insulin response and increasing fat storage. By contrast, firstly, pure fructose could put a brake on the vicious cycle owing to its poor ability to stimulate an insulin response and storage of fat in adipose tissue. This of course might be somewhat balanced by a lower ghrelin response to fructose than glucose in some (15Teff K.L. Elliott S.S. Tschöp M. Kieffer T.J. Rader D. Heiman M. Townsend R.R. Keim N.L. D'Alessio D. Havel P.J. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women.J Clin Endocrinol Metab. 2004; 89: 2963-2972Google Scholar), but not all, studies (16Teff K.L. Grudziak J. Townsend R.R. Dunn T.N. Grant R.W. Adams S.H. Keim N.L. Cummings B.P. Stanhope K.L. Havel P.J. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: Influence of insulin resistance on plasma triglyceride responses.J Clin Endocrinol Metab. 2009; 94: 1562-1569Google Scholar, 17Akhavan T. Anderson G.H. Effects of glucose-to-fructose ratios in solutions on subjective satiety, food intake, and satiety hormones in young men.Am J Clin Nutr. 2007; 86: 1354-1363Google Scholar). Second, fructose would put a further brake on the cycle by promoting insulin sensitivity at doses 150 g/d do the opposite and override the first brake on the cycle posed by the low insulin response to fructose. According to this perspective, fructose at doses 95% caloric compensation to fructose (and other sugars) in sweetened beverages as the duration of chronic studies approaches 1 year (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar).So what about the role of de novo lipogensis (DNL) debated by the correspondents—might this add fat to obesity? Excessive dietary fats add directly to fat accumulation in adipose tissue, so an excess would favor insulin resistance and obesity. A contribution to fat accumulation is made by dietary carbohydrate via hepatic DNL, but does this add a significant amount? It is argued by one group of correspondents that fructose adds little to DNL as assessed by appearance of plasma lipids using stable isotope techniques (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar). Meanwhile the other correspondents (2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) argue it is important to be aware of the time course of DNL rather than assume fasting rates are representative. This is well illustrated by the work of Stanhope and colleagues (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar) in overweight/obese patients (mean body mass index 29), who estimated the time-course of fractional DNL over a 24-hour period, and which peaked highest after the third meal of the day.However, from their data (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar) estimates of 24-hour average rates expressed as the fraction of triglyceride exported by liver due to DNL (fDNL) are still low, and only ∼3% more for their diet—excessive with 25% of energy requirement as fructose— compared with a similar glucose loaded diet. This corresponds to 100 g fructose is consumed daily (ie, approximately >33 g/meal), among studies of longest duration (Table 3 and Figure 7 in reference [4Livesey 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: 1419-1437Google Scholar]). DNL in adipose tissue can be expected to be less still (23Diraison F. Yankah V. Letexier D. Dusserre E. Jones P. Beylot M. Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans.J Lipid Res. 2003; 44: 846-853Google Scholar).It might be argued that a high proportion of DNL triglyceride stays in the liver rather than being exported, but such accumulation is thought for the present to be no greater than the amount exported (24Diraison F. Moulin P. Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease.Diabetes Metab. 2003; 29: 478-485Google Scholar) and, of course, may reside in the liver only temporarily. Moreover, fat accumulation in the liver after excessive fructose intake has, so far, been observed to be no more than occurs after a similar glucose intake in sound and well-controlled studies of both men (25Ngo Sock E.T. Lê K.A. Ith M. Kreis R. Boesch C. Tappy L. Effects of a short-term overfeeding with fructose or glucose in healthy young males.Br J Nutr. 2009; 103: 939-943Google Scholar) and women (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar). Another study in men also indicates similarity of glucose and fructose (26Silbernagel G. Machann J. Unmuth S. Schick F. Stefan N. Haring H.U. Fritsche A. Effects of 4-week very-high-fructose/glucose diets on insulin sensitivity, visceral fat and intrahepatic lipids: An exploratory trial [e-pub ahead of print].Br J Nutr. 2011; (Published March 14, 2011. Accessed May 4, 2011): 1-8http://journals.cambridge.org/download.php?file=%2FBJN%2FS000711451000574Xa.pdf&code=37d0bba32b6c7cd33e3ad43a422129d3https://doi.org/10.1017/S000711451000574XGoogle Scholar). Data for men in a further study (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar) suggests a different outcome, but consideration has to be given to marked inequality between treatment groups at baseline.Correspondents Lustig and Schwarz (2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) suggest a visit to the Sick Children's Hospital in Toronto, Canada, to convince others about the relationship of sick children to fructose. More easily we might consult publication from that hospital (27Mager D.R. Patterson C. So S. Rogenstein C.D. Wykes L.J. Roberts E.A. Dietary and physical activity patterns in children with fatty liver.Eur J Clin Nutr. 2010; 64: 628-635Google Scholar) informing us that lifestyle factors are important, and that a sample of obese children (average age 14 years) with fatty liver consume on average 33 g/d of fructose from sugars (7% of energy intake). The study had no case-control; however, the fructose intake was less than the US average for this age group at 48 g/d (10% of energy intake) (7Marriott B.P. Cole N. Lee E. National estimates of dietary fructose intake increased from 1977 to 2004 in the United States.J Nutr. 2009; 139: 1228S-1235SGoogle Scholar). Other factors, but not fructose or sugars, were reported to associate with insulin resistance (27Mager D.R. Patterson C. So S. Rogenstein C.D. Wykes L.J. Roberts E.A. Dietary and physical activity patterns in children with fatty liver.Eur J Clin Nutr. 2010; 64: 628-635Google Scholar). Lifestyle including dietary factors also differ by much more than can be accounted for by simple caloric dilution with sugars (or ‘fructose’), as noted elsewhere for adults (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar) and likely so for sugar-sweetened beverages in adolescents, too (28Ranjit N. Evans M.H. Byrd-Williams C. Evans A.E. Hoelscher D.M. Dietary and activity correlates of sugar-sweetened beverage consumption among adolescents.Pediatrics. 2011; 126: e754-e761Google Scholar).In their correspondence, Sievenpiper and colleagues (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar) incorrectly cite our revival work on fructose (4Livesey 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: 1419-1437Google Scholar)—inadvertently, one trusts, citing another of our papers from the same journal published shortly afterwards but related to fiber and glycemia (29Livesey G. Tagami H. Interventions to lower the glycemic response to carbohydrate foods with a low-viscosity fiber (resistant maltodextrin): Meta-analysis of randomized controlled trials.Am J Clin Nutr. 2009; 89: 114-125Google Scholar). This revival and subsequent work (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar) indicated a need for researchers to take account of dose response and thresholds of effect in humans. There also is a need to take a balanced view of health markers, with the examples of HbA1c responding beneficially at regular fructose intakes and fasting triglycerides responding adversely at very high or excessive dose of fructose. It further used fasting triglycerides as an example of a potentially unwelcome response to excessive fructose for which studies of longest duration show least effect. These concerns are added to elsewhere (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar), noting that fructose is not sucrose or high-fructose corn syrup, for which the same fructose dose would be accompanied by more energy, more carbohydrate, and greater glycemic load. These additional attributes confound interpretation of observational studies making appropriate intervention studies essential (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar). Even interventional studies on fructose can inadvertently use confounding designs in which researchers seem to forget that fructose is also a source of carbohydrate and energy, thus appropriate systematic reviews including meta-analyses are essential as well (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar). With exceptions from a limited number of research centers, knowledge of these problems seems to be gathering pace elsewhere, too, with more circumspect reviews about fructose (4Livesey 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: 1419-1437Google Scholar, 5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar, 18Dolan L.C. Potter S.M. Burdock G.A. Evidence-based review on the effect of normal dietary consumption of fructose on development of hyperlipidemia and obesity in healthy, normal weight individuals.Crit Rev Food Sci Nutr. 2010; 50: 53-84Google Scholar, 19Dolan L.C. Potter S.M. Burdock G.A. Evidence-based review on the effect of normal dietary consumption of fructose on blood lipids and body weight of overweight and obese individuals.Crit Rev Food Sci Nutr. 2010; 50: 889-918Google Scholar, 30Rizkalla S.W. Health implications of fructose consumption: A review of recent data.Nutr Metab (Lond). 2010; 7: 82Google Scholar, 31Tappy L. Le K.A. Tran C. Paquot N. Fructose and metabolic diseases: New findings, new questions.Nutrition. 2010; 26: 1044-1049Google Scholar, 32Tappy L. Le K.A. Metabolic effects of fructose and the worldwide increase in obesity.Physiol Rev. 2010; 90: 23-46Google Scholar, 33Sievenpiper J.L. Carleton A.J. Chatha S. Jiang H.Y. de Souza R.J. Beyene J. Kendall C.W. Jenkins D.J. 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: 1930-1937Google Scholar, 34Murphy S.P. The state of the science on dietary sweeteners containing fructose: Summary and issues to be resolved.J Nutr. 2009; 139: 1269S-1270SGoogle Scholar). The role played by dietary fructose in the ‘epidemic’ of obesity has recently been debated in the Journal of the American Dietetic Association (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar, 2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) following the earlier review by Lustig (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar) in which fructose is argued to have a prominent role in the causation and perpetuation of obesity. These warrant comment because the arguments do not represent the literature in humans on this topic and literature is cited inaccurately, particularly in regard to my own work. In addition to these problems, there is a question of whether the review article (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar) meets acceptable evidence-based standards sufficient to affect nutrition policy and practice. Moreover, evidence synthesis needs to focus on practice needs recognizing one policy may not fit all circumstances. Correspondents Sievenpiper and colleagues (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar) appear concerned primarily with the acceptability and potential benefits of moderate intake of pure or crystalline fructose in diabetics. By contrast, correspondents Lustig and Schwarz (2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) appear concerned primarily with the risks of excessive sucrose or high-fructose corn syrup consumption in infants, children, and adolescents. Both camps work on respectable hypotheses, and one ought not to be seen as to exclude the other. The idea that moderate intakes of pure fructose is acceptable and potentially beneficial for the control of dysglycemia and diabetes is not new. However, the idea has been given a boost by recent systematic and meta-analytical evidence of human intervention studies showing moderate doses of pure fructose (up to at least 90 g daily) lower glycated hemoglobin (HbA1c) in a dose-dependent manner (4Livesey 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: 1419-1437Google Scholar) when provided by carbohydrate exchange, with possible implications for diabetes and coronary heart disease (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar). This is contrary to expectations about HbA1c offered in the review article by Lustig (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar). The idea received a further boost when it was shown that moderate and high doses of pure fructose (up to 150 g/d) in human intervention studies leads to improvement in insulin sensitivity (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar). Again this is contrary to the expectations raised in the review article by Lustig (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar). Consistent with Lustig's expectations, nevertheless, a reduction in insulin sensitivity does arise with excessive pure fructose intake in humans, as in mice. However, in humans, this has not been demonstrated unless fructose intake is higher than the published threshold of ∼150 g/d (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar), a value from meta-analysis that holds true after recently doubling the number of intervention studies available for analysis (6Livesey G. Insulin sensitivity—Modification by dietary fructose in human intervention studies?. Independent Nutrition Logic Ltd, Wymondham, UK2010Google Scholar). According to the most recent published information on fructose intakes in a representative sample of the US population, the 150 g/d threshold is much higher than the 95% percentile fructose intake for the highest consumer group (19- to 22-year-olds) and adolescents. It is also three times higher than the published population average intake of 49 g/d (7Marriott B.P. Cole N. Lee E. National estimates of dietary fructose intake increased from 1977 to 2004 in the United States.J Nutr. 2009; 139: 1228S-1235SGoogle Scholar), an intake value falling since the turn of the millennium (8US Department of Agriculture, Economic Research ServiceSugar and sweeteners: Recommended data: U.S. consumption of caloric sweeteners [Tables 49-53].http://www.ers.usda.gov/briefing/sugar/data.htmGoogle Scholar). According to the review article (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar), insulin resistance and hyperinsulinemia are central to the vicious-cycle hypothesis that describes possible events thought to contribute to obesity. The hypothesis is well articulated in earlier reviews (9Isganaitis E. Lustig R.H. Fast food, central nervous system insulin resistance, and obesity.Arterioscler Thromb Vasc Biol. 2005; 25: 2451-2462Google Scholar, 10Mietus-Snyder M.L. Lustig R.H. Childhood obesity: Adrift in the “Limbic Triangle.”.Annul Rev Med. 2008; 59: 147-162Google Scholar), but elsewhere is promoted by Lustig with a focus on fructose (3Lustig R.H. Fructose: Metabolic, hedonic, and societal parallels with ethanol.J Am Diet Assoc. 2010; 110: 1307-1321Google Scholar, 11Lustig R.H. The trouble with fructosePowerPoint slides presented at: Children's Environmental Health Research: Past, Present & FutureResearch Triangle Park, NC: January 2007.http://www.niehs.nih.gov/news/events/pastmtg/2007/cehr/docs/metabolicsyndromelustig.pdfGoogle Scholar, 12Lustig R.H. The Fructose Epidemic.The Bariatrician. 2009; 12: 10-18Google Scholar, 13Lustig R.H. Sugar: The Bitter Truth [video] YouTube Web site.http://www.youtube.com/watch?v=dBnniua6-oMGoogle Scholar, 14Lustig R.H. The ‘skinny’ on childhood obesity: How our Western environment starves kids' brains.Pediatr Ann. 2006; 35 (905-7): 898-902Google Scholar). All those reviews focusing on fructose are narrative—none has followed the principles of systematic review and meta-analysis that are essential to the establishment of evidence-based practice and, later, practice-based evidence. Now we have some insight from such information (4Livesey 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: 1419-1437Google Scholar, 5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar, 6Livesey G. Insulin sensitivity—Modification by dietary fructose in human intervention studies?. Independent Nutrition Logic Ltd, Wymondham, UK2010Google Scholar) the vicious cycle hypothesis might be elaborated further. Abbreviating the hypothesised vicious cycle to its most basic (Figure), excessive carbohydrate food intake promotes an insulin response that can facilitate the retention or storage of energy in adipose tissue as fat. Excess fat accumulation leads to insulin resistance and hyperinsulinemia. Subsequent leptin resistance and ghrelin hyposecretion promote greater food intake, so advancing the obese state. Excessive glucose intake from high-glycemic sugars or starchy foods helps to turn the cycle by promoting an insulin response and increasing fat storage. By contrast, firstly, pure fructose could put a brake on the vicious cycle owing to its poor ability to stimulate an insulin response and storage of fat in adipose tissue. This of course might be somewhat balanced by a lower ghrelin response to fructose than glucose in some (15Teff K.L. Elliott S.S. Tschöp M. Kieffer T.J. Rader D. Heiman M. Townsend R.R. Keim N.L. D'Alessio D. Havel P.J. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women.J Clin Endocrinol Metab. 2004; 89: 2963-2972Google Scholar), but not all, studies (16Teff K.L. Grudziak J. Townsend R.R. Dunn T.N. Grant R.W. Adams S.H. Keim N.L. Cummings B.P. Stanhope K.L. Havel P.J. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: Influence of insulin resistance on plasma triglyceride responses.J Clin Endocrinol Metab. 2009; 94: 1562-1569Google Scholar, 17Akhavan T. Anderson G.H. Effects of glucose-to-fructose ratios in solutions on subjective satiety, food intake, and satiety hormones in young men.Am J Clin Nutr. 2007; 86: 1354-1363Google Scholar). Second, fructose would put a further brake on the cycle by promoting insulin sensitivity at doses 150 g/d do the opposite and override the first brake on the cycle posed by the low insulin response to fructose. According to this perspective, fructose at doses 95% caloric compensation to fructose (and other sugars) in sweetened beverages as the duration of chronic studies approaches 1 year (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar). So what about the role of de novo lipogensis (DNL) debated by the correspondents—might this add fat to obesity? Excessive dietary fats add directly to fat accumulation in adipose tissue, so an excess would favor insulin resistance and obesity. A contribution to fat accumulation is made by dietary carbohydrate via hepatic DNL, but does this add a significant amount? It is argued by one group of correspondents that fructose adds little to DNL as assessed by appearance of plasma lipids using stable isotope techniques (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar). Meanwhile the other correspondents (2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) argue it is important to be aware of the time course of DNL rather than assume fasting rates are representative. This is well illustrated by the work of Stanhope and colleagues (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar) in overweight/obese patients (mean body mass index 29), who estimated the time-course of fractional DNL over a 24-hour period, and which peaked highest after the third meal of the day. However, from their data (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar) estimates of 24-hour average rates expressed as the fraction of triglyceride exported by liver due to DNL (fDNL) are still low, and only ∼3% more for their diet—excessive with 25% of energy requirement as fructose— compared with a similar glucose loaded diet. This corresponds to 100 g fructose is consumed daily (ie, approximately >33 g/meal), among studies of longest duration (Table 3 and Figure 7 in reference [4Livesey 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: 1419-1437Google Scholar]). DNL in adipose tissue can be expected to be less still (23Diraison F. Yankah V. Letexier D. Dusserre E. Jones P. Beylot M. Differences in the regulation of adipose tissue and liver lipogenesis by carbohydrates in humans.J Lipid Res. 2003; 44: 846-853Google Scholar). It might be argued that a high proportion of DNL triglyceride stays in the liver rather than being exported, but such accumulation is thought for the present to be no greater than the amount exported (24Diraison F. Moulin P. Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease.Diabetes Metab. 2003; 29: 478-485Google Scholar) and, of course, may reside in the liver only temporarily. Moreover, fat accumulation in the liver after excessive fructose intake has, so far, been observed to be no more than occurs after a similar glucose intake in sound and well-controlled studies of both men (25Ngo Sock E.T. Lê K.A. Ith M. Kreis R. Boesch C. Tappy L. Effects of a short-term overfeeding with fructose or glucose in healthy young males.Br J Nutr. 2009; 103: 939-943Google Scholar) and women (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar). Another study in men also indicates similarity of glucose and fructose (26Silbernagel G. Machann J. Unmuth S. Schick F. Stefan N. Haring H.U. Fritsche A. Effects of 4-week very-high-fructose/glucose diets on insulin sensitivity, visceral fat and intrahepatic lipids: An exploratory trial [e-pub ahead of print].Br J Nutr. 2011; (Published March 14, 2011. Accessed May 4, 2011): 1-8http://journals.cambridge.org/download.php?file=%2FBJN%2FS000711451000574Xa.pdf&code=37d0bba32b6c7cd33e3ad43a422129d3https://doi.org/10.1017/S000711451000574XGoogle Scholar). Data for men in a further study (21Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. McGahan J.P. Seibert A. Krauss R.M. Chiu S. Schaefer E.J. Ai M. Otokozawa S. Nakajima K. Nakano T. Beysen C. Hellerstein M.K. Berglund L. Havel P.J. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans.J Clin Invest. 2009; 119: 1322-1334Google Scholar) suggests a different outcome, but consideration has to be given to marked inequality between treatment groups at baseline. Correspondents Lustig and Schwarz (2Lustig R.H. Schwarz J.M. Is fructose a story of mice but not men [authors' response]?.J Am Diet Assoc. 2011; 111: 220-222Google Scholar) suggest a visit to the Sick Children's Hospital in Toronto, Canada, to convince others about the relationship of sick children to fructose. More easily we might consult publication from that hospital (27Mager D.R. Patterson C. So S. Rogenstein C.D. Wykes L.J. Roberts E.A. Dietary and physical activity patterns in children with fatty liver.Eur J Clin Nutr. 2010; 64: 628-635Google Scholar) informing us that lifestyle factors are important, and that a sample of obese children (average age 14 years) with fatty liver consume on average 33 g/d of fructose from sugars (7% of energy intake). The study had no case-control; however, the fructose intake was less than the US average for this age group at 48 g/d (10% of energy intake) (7Marriott B.P. Cole N. Lee E. National estimates of dietary fructose intake increased from 1977 to 2004 in the United States.J Nutr. 2009; 139: 1228S-1235SGoogle Scholar). Other factors, but not fructose or sugars, were reported to associate with insulin resistance (27Mager D.R. Patterson C. So S. Rogenstein C.D. Wykes L.J. Roberts E.A. Dietary and physical activity patterns in children with fatty liver.Eur J Clin Nutr. 2010; 64: 628-635Google Scholar). Lifestyle including dietary factors also differ by much more than can be accounted for by simple caloric dilution with sugars (or ‘fructose’), as noted elsewhere for adults (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar) and likely so for sugar-sweetened beverages in adolescents, too (28Ranjit N. Evans M.H. Byrd-Williams C. Evans A.E. Hoelscher D.M. Dietary and activity correlates of sugar-sweetened beverage consumption among adolescents.Pediatrics. 2011; 126: e754-e761Google Scholar). In their correspondence, Sievenpiper and colleagues (1Sievenpiper J.L. de Souza R.J. Kendall C.W.C. Jenkins D.J.A. Is fructose a story of mice but not men?.J Am Diet Assoc. 2011; 111: 219-220Google Scholar) incorrectly cite our revival work on fructose (4Livesey 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: 1419-1437Google Scholar)—inadvertently, one trusts, citing another of our papers from the same journal published shortly afterwards but related to fiber and glycemia (29Livesey G. Tagami H. Interventions to lower the glycemic response to carbohydrate foods with a low-viscosity fiber (resistant maltodextrin): Meta-analysis of randomized controlled trials.Am J Clin Nutr. 2009; 89: 114-125Google Scholar). This revival and subsequent work (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar) indicated a need for researchers to take account of dose response and thresholds of effect in humans. There also is a need to take a balanced view of health markers, with the examples of HbA1c responding beneficially at regular fructose intakes and fasting triglycerides responding adversely at very high or excessive dose of fructose. It further used fasting triglycerides as an example of a potentially unwelcome response to excessive fructose for which studies of longest duration show least effect. These concerns are added to elsewhere (5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar), noting that fructose is not sucrose or high-fructose corn syrup, for which the same fructose dose would be accompanied by more energy, more carbohydrate, and greater glycemic load. These additional attributes confound interpretation of observational studies making appropriate intervention studies essential (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar). Even interventional studies on fructose can inadvertently use confounding designs in which researchers seem to forget that fructose is also a source of carbohydrate and energy, thus appropriate systematic reviews including meta-analyses are essential as well (20Livesey G. Fructose, obesity and related epidemiology.Critl Rev Food Sci Nutr. 2010; 50: 26-28Google Scholar). With exceptions from a limited number of research centers, knowledge of these problems seems to be gathering pace elsewhere, too, with more circumspect reviews about fructose (4Livesey 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: 1419-1437Google Scholar, 5Livesey G. Fructose ingestion: Dose-dependent responses in health research.J Nutr. 2009; 139: 1246S-1252SGoogle Scholar, 18Dolan L.C. Potter S.M. Burdock G.A. Evidence-based review on the effect of normal dietary consumption of fructose on development of hyperlipidemia and obesity in healthy, normal weight individuals.Crit Rev Food Sci Nutr. 2010; 50: 53-84Google Scholar, 19Dolan L.C. Potter S.M. Burdock G.A. Evidence-based review on the effect of normal dietary consumption of fructose on blood lipids and body weight of overweight and obese individuals.Crit Rev Food Sci Nutr. 2010; 50: 889-918Google Scholar, 30Rizkalla S.W. Health implications of fructose consumption: A review of recent data.Nutr Metab (Lond). 2010; 7: 82Google Scholar, 31Tappy L. Le K.A. Tran C. Paquot N. Fructose and metabolic diseases: New findings, new questions.Nutrition. 2010; 26: 1044-1049Google Scholar, 32Tappy L. Le K.A. Metabolic effects of fructose and the worldwide increase in obesity.Physiol Rev. 2010; 90: 23-46Google Scholar, 33Sievenpiper J.L. Carleton A.J. Chatha S. Jiang H.Y. de Souza R.J. Beyene J. Kendall C.W. Jenkins D.J. 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: 1930-1937Google Scholar, 34Murphy S.P. The state of the science on dietary sweeteners containing fructose: Summary and issues to be resolved.J Nutr. 2009; 139: 1269S-1270SGoogle Scholar). STATEMENT OF POTENTIAL CONFLICT OF INTEREST: The author holds shares in Independent Nutrition Logic Ltd. Independent Nutrition Logic Ltd is an independent consultancy with commissions from many organizations, a full list of which may be found at www.inlogic.co.uk. Among these now are The Calorie Control Council Fructose Committee, its members having a commercial interest in fructose and sugars containing fructose. Fructose: Metabolic, Hedonic, and Societal Parallels with EthanolJournal of the American Dietetic AssociationVol. 110Issue 9PreviewRates of fructose consumption continue to rise nationwide and have been linked to rising rates of obesity, type 2 diabetes, and metabolic syndrome. Because obesity has been equated with addiction, and because of their evolutionary commonalities, we chose to examine the metabolic, hedonic, and societal similarities between fructose and its fermentation byproduct ethanol. Elucidation of fructose metabolism in liver and fructose action in brain demonstrate three parallelisms with ethanol. First, hepatic fructose metabolism is similar to ethanol, as they both serve as substrates for de novo lipogenesis, and in the process both promote hepatic insulin resistance, dyslipidemia, and hepatic steatosis. Full-Text PDF Authors' ResponseJournal of the American Dietetic AssociationVol. 111Issue 2PreviewWe thank Sievenpiper and colleagues for their letter, which allows us to address several commonly held misconceptions about the role of fructose in human obesity and metabolic syndrome. We agree that the results of animal studies assessing the effect of chronic fructose feeding can't be generalized without valid human studies. However, those data are in, and do not paint a pretty picture. Full-Text PDF Is Fructose a Story of Mice but Not Men?Journal of the American Dietetic AssociationVol. 111Issue 2PreviewWe read with interest the hypothesis by Lustig (1) paralleling the metabolic effects of fructose with those of ethanol. We were concerned, however, that the conclusions drew heavily on animal data and that confounding from excess energy was not addressed. Full-Text PDF Author's ResponseJournal of the American Dietetic AssociationVol. 111Issue 7PreviewLivesey disputes several points in my original Journal of the American Dietetic Association article (1), in which I elaborate the parallels between fructose and ethanol. Livesey advances his argument that fructose when ingested alone is a safe, nontoxic foodstuff based on the following points: 1) measurement of de novo lipogenesis (DNL) in response to fructose ingestion alone is low; 2) the potential value of fructose for glucose exchange as a sweetener for type 2 diabetes because it does not raise blood glucose (and, therefore, hemoglobin A1c); 3) the assertion that studies of fructose do not show decompensation of insulin sensitivity until oral doses reach 150 g; 4) according to the proposed model, insulin resistance occurs in response to cytokine production from adipocytes, not from fructose per se; and 5) the Journal article is not a systematic review because it does not discuss fructose for glucose exchange studies. Full-Text PDF
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