Soft drink consumption and obesity: it is all about fructose George A. Bray

Soft drink consumption and obesity: it is all about fructose George A. Bray Pennington Center, Louisiana State University, Baton Rouge, Louisiana, USA Correspondence to George A. Bray, MD, 6400 Perkins Road, Baton Rouge, LA 70808, USA Tel: +1 225 763 3176; e-mail: brayga@pbrc.edu Current Opinion in Lipidology 2010, 21:51 57 Purpose of review The purpose of the review is to suggest that fructose, a component of both sucrose (common sugar) and high fructose corn syrup, should be of concern to both healthcare providers and the public. Recent findings Consumption of sugar-sweetened beverages has increased steadily over the past century and with this increase has come more and more reports associating their use with the risk of overweight, diabetes and cardiometabolic disease. In a meta-analysis of the relationship between soft drink consumption and cardiometabolic risk, there was a 24% overall increased risk comparing the top and bottom quantiles of consumption. Several factors might account for this increased risk, including increased carbohydrate load and increased amounts of dietary fructose. Fructose acutely increases thermogenesis, triglycerides and lipogenesis as well as blood pressure, but has a smaller effect on leptin and insulin release than comparable amounts of glucose. In controlled feeding studies, changes in body weight, fat storage and triglycerides are observed as well as an increase in inflammatory markers. Summary The present review concludes on the basis of the data assembled here that in the amounts currently consumed, fructose is hazardous to the cardiometabolic health of many children, adolescents and adults. Keywords beverages, health risk, high fructose corn syrup, obesity, sucrose, weight gain Curr Opin Lipidol 21:51 57 ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins 0957-9672 Introduction Sucrose intake has risen steadily for more than 200 years [1]. With this increase in sucrose has come an increased intake of fructose, as fructose is half the sucrose molecule. Prior to the domestication of the sugar plant, some 1500 years ago, fructose in the human diet came primarily from fruits and vegetables [2]. Following the development of soft drinks a century ago, sugar intake has increased even more as it was the principal sweetener used in these beverages until after World War II. Consumption of sugar-sweetened beverages (SSBs) is still rising around the world and in the USA, it has increased from 11.8% of calories in 1965 to over 20% of calories by 2002 [3]. The most recent estimates of soft drink consumption for US children and adults put the figures at 154 and 142 kcal per day, respectively [4,5]. Fructose is half of the consumed sucrose or high fructose corn syrup (HFCS) and is estimated to be an average of 54.7 g per day (range 38.4 72.8) and accounts for a mean of 10.2% of total caloric intake. Adolescents, in whom consumption is highest (12 18 years), consume an average of 72.8 g per day (12.1% of total calories) of fructose [6 ]. One-quarter of adolescents consume more than 15% of their calories from fructose [6 ]. As HFCS and sucrose have similar metabolic profiles after oral administration [7,8 ], it is reasonable to lump them together as the major sources of dietary fructose the central focus of this review. As the use of caloric sweeteners has continued to rise, more and more reports suggest that they may cause weight gain in some adults [9 14,15,16,17 24,25 ]. Reports also suggest that the increasing intake of soft drinks is associated with an increase in the risk of diabetes [10,14,15,26 28,29 ] and the risk of cardiometabolic disease [14,29 31 ] and gout [32 ]. The intake of fructose is related to lipid disturbances in small dense LDL cholesterol in children [33]. Studies comparing glucose and fructose have suggested that fructose is much more likely to be the culprit for these diseases than glucose. The studies supporting effects of fructose and caloric sweeteners in the obesity epidemic and reports of cardiovascular and metabolic risk will be summarized in five categories: (1) Response to acute exposure to fructose or sucrose. (2) Response to fructose or sucrose in short-term studies lasting up to 12 weeks. (3) Meta-analyses of soft drink consumption. 0957-9672 ß 2010 Wolters Kluwer Health Lippincott Williams & Wilkins DOI:10.1097/MOL.0b013e3283346ca2

52 Nutrition and metabolism (4) Experimental studies of fructose and fat. (5) Potential mechanisms for responses to fructose. In preparing this review, Medline was searched for papers relating to fructose and beverages and obesity. Two meta-analyses [34,35] were also examined for additional relationships and this topic has been discussed previously by the author [5,35,36]. Dietary fructose comes from two principal sources [6 ], foods such as fruits and vegetables, and from refined products that contain sucrose or HFCS. The growth of fructose in our diet during the past century has come through adding sucrose (sugar) or HFCS to foods. To help distinguish these two sources of fructose, I have labeled those in naturally occurring fruits and vegetables as good fructose and the fructose that comes from sucrose or HFCS as bad fructose. Acute studies Several studies have examined the effects of single doses of fructose versus glucose on energy expenditure [37,38], serum lipids [39 42,43,44,45,46 ], leptin [42,47], insulin [42,47] and blood pressure [48]. From these studies, it is clear that fructose increases thermogenesis, triglycerides and blood pressure. In one study, a 75 g oral load of glucose or fructose was given to 17 volunteers and metabolic changes followed for 4 h. Fructose stimulated oxygen consumption more than glucose but produced a much smaller stimulation of insulin [37]. Fructose increased the respiratory quotient more than glucose, a finding that may imply increased de-novo lipogenesis. Blockade of the sympathetic nervous system with propanolol, a b-adrenergic blocking drug, reduced oxidation of both fructose and glucose by about 40%. Of interest, both obese and diabetic patients had a similar stimulation of oxygen uptake after infusion of glucose that was smaller than the response to fructose [49]. In the most recent study to evaluate the acute effects of fructose on lipids [46 ], 17 healthy obese men (N ¼ 9) and women (N ¼ 8) with a BMI more than 30 kg/m 2 were admitted to the Clinical and Translational Research Center for a cross-over study lasting 24 h, in which mixed meals and beverages with 30% fructose or 30% glucose were given and blood samples drawn periodically. The area under the curve of insulin, leptin and triglyceride was measured. The rise in plasma glucose was smaller after fructose, but the rise in triglycerides and lactate was larger. Insulin and leptin both showed a lower response to fructose than to glucose. These responses in lipids are seen primarily in men with small or no response in women [50,51]. The lipogenic effects of fructose probably lie in its pathways of hepatic metabolism. Fructose is phosphorylated at the 1 position (F-1-P), in contrast to glucose, which is phosphorylated at the 6 position (G-6-P). This F-1-P is a ready substrate for enolase which cleaves it to triose phosphates that serve as the backbone of triglycerides. In contrast, glucose 6-P must be converted to glucose-1,6-diphosphate before it is a substrate for enolase. The acute response of blood pressure to fructose was examined in 15 healthy men who drank, on three occasions, 500 ml volumes of water (placebo) or 60 g of fructose or glucose. Blood pressure, metabolic rate and autonomic nervous system activity were measured for 2 h. Administration of fructose was associated with an increase in both systolic and diastolic blood pressure. Blood pressure did not rise after either glucose or water [48]. This rise in blood pressure acutely is consistent with the rise in blood pressure noted in the 10-week study described below [52]. Intermediate length studies Several intermediate length feeding studies have examined the effects of glucose and fructose [43,44, 50,52,53]. In one of these, 41 overweight men and women entered a 10-week parallel arm study. Twenty-one received 3.4 MJ (813 kcal) of sugar-containing beverages and were compared with 20 others who received beverages sweetened with aspartame, containing about 1 MJ (240 kcal) and no sugar [52]. For their other foods, the participants could select freely from items available at a kiosk run by the study group. After 10 weeks, energy intake had increased by 1.6 MJ per day (581 kcal per day) and sucrose to 28% of calorie intake in the group receiving the sugar-containing beverages. Protein and fat intakes declined [52]. Body weight and fat mass increased by 1.6 and 1.3 kg, respectively in the sugared-beverage group and decreased by 1.0 and 0.3 kg in the aspartamesweetened group. Blood pressure increased by 3.8/ 4.1 mmhg in the sugared-beverage-consuming group but it did not change in the aspartame group. Concentrations of several inflammatory markers were also changed [54]. In the group consuming sucrose, haptoglobin increased by 13%, transferrin by 5% and C-reactive protein by 6%. In the group receiving the aspartamesweetened beverages, haptoglobin decreased by 16%, C-reactive protein decreased by 26% and transferrin was basically unchanged with a small 2% fall [54]. An increase in inflammatory markers also occurs when the quantity of rapidly absorbed carbohydrates, that is, those with a high glycemic load, is increased, and this component of soft drinks may be another reason for its association with cardiometabolic disease [55 59]. In a study of similar length, fructose and glucose were compared by replacing 25% of the calories with either a glucose-containing drink or a fructose-containing drink for 10 weeks, 8 weeks as outpatients and 2 weeks as

Soft drink consumption and obesity Bray 53 inpatients at the end of the study. Thirty-two men and women ate a 15% protein, 30% fat and 55% carbohydrate diet. Fifteen received 25% of calories as the glucosesweetened beverages and 17 received 25% of kcal as the fructose-sweetened beverage. Visceral fat increased by 14% in the fructose-consuming group compared with about 5% in the control group with no significant change in body weight or subcutaneous fat. De-novo lipogenesis increased and postprandial triglycerides increased, particularly at night [7 ]. Meta-analyses of beverage consumption Several meta-analyses relating soft drink consumption to changes in energy intake, changes in body weight or risk of cardiometabolic diseases have been published [34,60 ]. In the study by Vartanian et al. [34], the magnitude of the relationship between the beverage intake and body weight was expressed as the effect size or r value. An effect size of 0.1 was small, an effect size of 0.25 was moderate and an effect size of 0.4 as large (Table 1). In the studies examining the relationship between soft drink consumption and body weight, Vartanian et al. [34] found that outcomes from the crosssectional studies varied depending on how body weight was expressed. When the focus was on the association between soft drink consumption and BMI, two studies reported a significant positive association, whereas nine did not. Two studies revealed a positive association between soft drink consumption and body fat percentage, but one study did not. In addition, four studies showed that people s risk of being overweight or obese was positively associated with their soft drink consumption (Table 1). Other studies reported a positive association between soft drink consumption and body weight and ponderal index but not skinfold thickness. In 11 cross-sectional studies, they found a significant positive relationship in two, but not in nine others, and there were no studies in which drinking beverage was associated with a significant reduction in BMI. Among longitudinal studies that have examined the association between soft drink consumption and change in body weight or BMI, one was positive, two were mixed and four showed no association. Of seven experimental studies, five reported a positive association with weight. Effect sizes, which represent the magnitude of the relationship between the beverage intake and body weight, were moderate (0.24; Table 1). The effect sizes for change in body weight were, in general, smaller than the effects on energy intake as soft drinks are only one source of calories. In cross-sectional studies, the effect size was only 0.06, in longitudinal studies it was 0.03 and in short experimental studies, it was 0.24. A second meta-analysis of soft drink intake and weight gain reported by Olsen and Heitmann [60 ] included some additional studies. A total of 14 prospective and five experimental studies were identified. The majority of the prospective studies found positive associations between intake of calorically sweetened beverages and obesity. Three experimental studies found positive effects of calorically sweetened beverages and subsequent changes in body fat, but two experimental studies did not. Eight prospective studies adjusted for energy intake. Seven of these studies reported associations that were essentially similar before and after energy adjustment. The authors concluded that a high intake of calorically sweetened beverages is a determinant for obesity. There are a number of other studies suggesting that soft drinks may be related to cardiometabolic diseases. There are six studies that have shown relationships between soft drink consumption and the risk of developing diabetes [11,15,26 28,29 ]. Most of the studies use a contrast between lowest and highest intake. Three studies show a relationship of soft drink consumption to the risk of developing the metabolic syndrome [14,29,30 ]. One study shows that soft drink consumption is related to risk of developing coronary heart disease and one that fructose intake is related to the risk of developing gout in men [32 ]. Experimental studies of fructose and fat In two animal experiments, there is a clear interaction between fructose intake and the response to a high fat diet. In one experiment [61], groups of C57Bl mice were fed one of four diets: a trans-fat diet with mouse chow at 30% of calories and fat at 45% of calories (28% saturated, 57% monounsaturated, 13% polyunsaturated fatty acids (PUFAs) and 3% trans fats with access water); the transfat diet with access to 55/45 HFCS solution in water/gel at 42 g/l placed in petri dishes in the bottom of the cage; a Table 1 Average effect size of soft drink consumption by type of research design Cross-sectional studies Longitudinal studies Short experimental studies Overall effect size Research design r (95% CI) No. r (95% CI) No. r (95% CI) No. r (95% CI) No. Energy intake 0.13 (0.12 0.14) 12 0.24 (0.23 0.26) 5 0.24 (0.16 0.31) 9 0.16 (0.15 0.16) 22 Body weight 0.06 (0.03 0.08) 12 0.03 (0.00 0.06) 6 0.24 (0.18 0.28) 7 0.06 (0.05 0.08) 25 Adapted from Tables 1, 2 and 3 with permission [34]; r, average effect size calculated using version 2 of the comprehensive meta-analysis software program. The authors of this paper considered an effect size of 0.1 as a small effect, an effect size of 0.25 as medium and an effect size of 0.4 as large. CI, confidence interval; No., number of studies in meta-analysis.

54 Nutrition and metabolism 30% chow diet with Lard replacing the fat mixture above; and a standard mouse chow diet with ad lib access to water. Over the 16 weeks, mice fed the trans-fat diet with HFCS to drink gained the most, with the Lard þ HFCS not significantly less. When HFCS was omitted from the trans-fat diet, the weight gain was greater than chow alone, but significantly less than with the combination of the HFCS and trans-fat diet. Fatty accumulation and inflammatory changes were observed most in the trans-fat and HFCS diet group. In another experiment [62], rats were begun on a 64% starch or 65% fructose diet for 6 months and then tested for their response of food intake in intraperitoneal leptin. The weight gain was identical in these two groups, but the animals eating the high fructose diet had markedly impaired response to leptin and an increase in one of the suppressors of cytokine signaling (SOCS-3) in the hypothalamus, which reduces the response to leptin. For the final 2 weeks, half the rats in each group were provided a diet with 60% Lard and 7% sucrose and the others continued on their previous diets. The rats exposed to fructose for 6 months had a significantly greater gain in body fat on the high fat diet (14.1 g) than those previously eating the starch diet (9.1 g). Potential mechanisms for the detrimental effects of fructose Several mechanisms have been suggested for the effects of fructose that come from drinking either HFCS or sucrose-sweetened beverages. The inadequate reduction in caloric intake of solid foods when calorie-sweetened beverages are ingested is one of these mechanisms [63 66,52,67,68,69,70,71,72 ]. In acute feeding studies, SSBs failed to reduce energy intake, in contrast to water [73]. A second mechanism is that fructose is metabolized primarily in the liver where it is converted to fructose-1-phosphate from which it can readily become a substrate for the backbone of the triglyceride molecule [74]. Third, the metabolism of fructose in the liver generates adenosine 5 phosphate that is a substrate for conversion to uric acid through a process that alters nitric oxide generation. The enhanced production of uric acid by the liver may contribute to the relation of uric acid to cardiovascular disease [75 ]. Another mechanism is the increase in blood pressure that is observed with acute administration of fructose that is not seen with glucose [48] and the increase in blood pressure over 10 weeks when individuals drank SSBs as contrasted with aspartame-sweetened beverages [52]. A final potential mechanism is the differences in gene expression following fructose administration [53]. Soft drinks are clearly a part of our culture and their consumption has risen steadily for more than 50 years. A 20-ounce soft drink made with HFCS has about 250 kcal. Thus, an extra 20-ounce soft drink each day is probably enough to account for the increased body weight over the last quarter of a century [76 ]. Soft drinks are a prominent part of the fast food culture. When individuals eat at a fast food restaurant, compared to a day when they do not, the fast food day has a larger intake of soft drinks and French fries and a smaller intake of cereal, vegetables and milk [77]. Soft drink consumption and milk consumption are inversely related [34,36]. As soft drink consumption has increased, the consumption of milk, a major source of calcium, has decreased. In the meta-analysis of crosssectional studies by Vartanian et al. [34], the effect size was small, but in the longitudinal studies, it was moderate. Milk, particularly low-fat milk, is a valuable source of calcium for bone growth during the time of maximal bone accretion, and, as part of the Dietary Approach to Stop Hypertension (DASH) diet, may be helpful in lowering blood pressure [78]. Reducing consumption of beverages containing HFCS or glucose fructose (sucrose) might reverse this pattern of decreased milk consumption. The rising consumption of calorie-sweetened beverages provides a rising intake of fructose with all of its potential negative biological effects. Based on this review of the literature, this reviewer concludes that in the amounts currently consumed, fructose is hazardous to the cardiometabolic health of many children, adolescents and adults. An increase in the risk of diabetes mellitus, metabolic syndrome, coronary heart disease and gout has been reported with higher consumption of soft drinks. This increase is opposite in direction to the highly significant reduction of about one-quarter in the first event rate for nonfatal myocardial infarction or coronary death in patients treated with simvastatin in the Heart Protection Study [79]. Replacing fructose-containing beverages with healthier alternatives [80] such as water would be an important strategy in the battle of the bulge and its cardiometabolic consequences [81 ]. Conclusion In summary, it seems clear that fructose, a component of both sucrose (common sugar) and HFCS, in the amounts now consumed should be of concern to both healthcare providers and the public. The growing evidence of its association with the risk of overweight, diabetes and cardiometabolic disease is highlighted in meta-analyses of the relationship between soft drink consumption and cardiometabolic risk. Several factors might account for this increased risk, including increased carbohydrate load and the increased amounts of fructose that are components of both sucrose (table sugar) and HFCS. Fructose acutely increases thermogenesis, triglycerides and lipogenesis as well as blood pressure, but has a

Soft drink consumption and obesity Bray 55 smaller effect on leptin and insulin release than comparable amounts of glucose. In controlled feeding studies, changes in body weight, fat storage and triglycerides are observed as well as an increase in inflammatory markers. This reviewer concludes on the basis of the data assembled here that in the amounts currently consumed, fructose is hazardous to the cardiometabolic health of many children, adolescents and adults. Although we need more evidence about whether there is a threshold effect for fructose, we also need more work on how to help consumers switch to healthy beverages and sweeteners. References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 87). 1 Yudkin J. Pure, white and deadly. London: Penguin Books; 1986. 2 Mintz S. Sweetness and power. The Place of Sugar in Modern History; 1986. 3 Duffey KJ, Popkin BM. Consumption of calorie sweetened beverages between 1995 and 2002. Obesity 2007; 15:2839 2847. 4 Nielsen SJ, Popkin BM. Changes in beverage intake between 1977 and 2001. Am J Prev Med 2004; 27:205 210. 5 Bray GA, Nielsen SJ, Popkin BM. High fructose corn syrup and the epidemic of obesity. Am J Clin Nutr 2004; 79:537 544. 6 Vos MB, Kimmons JE, Gillespie C, et al. Dietary fructose consumption among US children and adults: the Third National Health and Nutrition Examination Survey. Medscape J Med 2008; 10:160; PubMed PMID: 18769702; PubMed Central PMCID: PMC2525476.. This paper provides detailed estimates of fructose intake by various demographic groups of the American population showing that over 10% of daily calories come from this source. 7 Stanhope KL, Griffen SC, Bair BR, et al. Twenty-four-hour endocrine and metabolic profiles following consumption of high-fructose corn syrup-, sucrose-, fructose-, and glucose-sweetened beverages with meals. Am J Clin Nutr 2008; 87:1194 1203. This paper shows that HFCS and sucrose have metabolic patterns similar to each other and more like fructose than glucose. 8 Melanson KJ, Angelopoulos TJ, Nguyen V, et al. High-fructose corn syrup, energy intake, and appetite regulation. Am J Clin Nutr 2008; 88:1738S 1744S; Review. PubMed PMID: 19064539. This paper shows that HFCS and sucrose have metabolic patterns similar to each other and more like fructose than glucose. 9 French SA, Jeffery RW, Forster JL, et al. Predictors of weight change over two years among a population of working adults: the Healthy Worker Project. Int J Obes Relat Metab Disord 1994; 18:145 154. 10 Schulz M, Kroke A, Liese AD, et al. Food groups as predictors for short-term weight changes in men and women of the EPIC-Potsdam cohort. J Nutr 2002; 132:1335 1340. 11 Schulze MB, Liu S, Rimm EB, et al. Glycemic index, glycemic load, and dietary fiber intake and incidence of type 2 diabetes in younger and middle-aged women. Am J Clin Nutr 2004; 80:348 356. 12 Kvaavik E, Meyer HE, Tverdal A. Food habits, physical activity and body mass index in relation to smoking status in 40 42 year old Norwegian women and men. Prev Med 2004; 38:1 5. 13 Bes-Rastrollo M, Sanchez-Villegas A, Gómez-Gracia E, et al. Predictors of weight gain in a Mediterranean cohort: the Seguimiento Universidad de Navarra Study 1. Am J Clin Nutr 2006; 83:362 370; quiz 394 395. 14 Dhingra R, Sullivan L, Jacques PF, et al. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation 2007; 116:480 488. 15 Palmer JR, Boggs DA, Krishnan S, et al. Sugar-sweetened beverages and incidence of type 2 diabetes mellitus in African American women. Arch Intern Med 2008; 168:1487 1492; PubMed PMID: 18663160. This paper shows that the regular consumption of calorically sweetened soft drinks and fruit drinks is associated in African American women with an increased risk of type 2 diabetes. 16 Chen L, Appel LJ, Loria C, et al. Reduction in consumption of sugar-sweetened beverages is associated with weight loss: the PREMIER trial. Am J Clin Nutr 2009; 89:1299 1306. In this population, baseline intake of liquid calories represented 19% of total daily intake. A reduction of 100 kcal per day of liquid calorie intake was associated with a 0.25 kg loss of weight at 6 months and a 0.24 kg loss at 18 months. 17 Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet 2001; 357:505 508. 18 Berkey CS, Rockett HR, Field AE, et al. Sugar-added beverages and adolescent weight change. Obes Res 2004; 12:778 788. 19 James J, Thomas P, Cavan D, Kerr D. Preventing childhood obesity by reducing consumption of carbonated drinks: cluster randomised controlled trial. BMJ 2004; 328:1237. 20 Phillips SM, Bandini LG, Naumova EN, et al. Energy-dense snack food intake in adolescence: longitudinal relationship to weight and fatness. Obes Res 2004; 12:461 472. 21 Ebbeling CB, Feldman HA, Osganian SK, et al. Effects of decreasing sugarsweetened beverage consumption on body weight in adolescents: a randomized, controlled pilot study. Pediatrics 2006; 117:673 680. 22 Viner RM, Cole TJ. Who changes body mass between adolescence and adulthood? Factors predicting change in BMI between 16 year and 30 years in the 1970 British Birth Cohort. Int J Obes (Lond) 2006; 30:1368 1374. 23 Dubois L, Farmer A, Girard M, Peterson K. Regular sugar-sweetened beverage consumption between meals increases risk of overweight among preschool-aged children. J Am Diet Assoc 2007; 107:924 934; discussion 934 925. 24 Striegel-Moore RH, Thompson D, Affenito SG, et al. Correlates of beverage intake in adolescent girls: the National Heart, Lung, and Blood Institute Growth and Health Study. J Pediatr 2006; 148:183 187. 25 Nissinen K, Mikkila V, Mannisto S, et al. Sweets and sugar-sweetened soft drink intake in childhood in relation to adult BMI and overweight. The Cardiovascular Risk in Young Finns Study. Public Health Nutr 2009; 28:1 9. This paper identified an important differential response to calorically sweetened beverages between young men and women. The increase in consumption of sugar-sweetened soft drinks from childhood to adulthood was directly associated with BMI in adulthood in women but not in men. In women, BMI increased by 0.45 kg/m 2 for every 10-unit increase per month. 26 Paynter NP, Yeh HC, Voutilainen S, et al. Coffee and sweetened beverage consumption and the risk of type 2 diabetes mellitus: the atherosclerosis risk in communities study. Am J Epidemiol 2006; 164:1075 1084. 27 Montonen J, Jarvinen R, Knekt P, et al. Consumption of sweetened beverages and intakes of fructose and glucose predict type 2 diabetes occurrence. J Nutr 2007; 137:1447 1454. 28 Bazzano LA, Li TY, Joshipura KJ, Hu FB. Intake of fruit, vegetables, and fruit juices and risk of diabetes in women. Diabetes Care 2008; 31:1311 1317. 29 Nettleton JA, Lutsey PL, Wang Y, et al. Diet soda intake and risk of incident metabolic syndrome and type 2 diabetes in the Multi-Ethnic Study of Atherosclerosis (MESA). Diabetes Care 2009; 32:688 694. This is an observational study that implicates diet soda in the cardiometabolic syndromes. It shows that the consumption of diet soda at least daily was associated with significantly greater risks of select incident metabolic syndrome components and type 2 diabetes. However, observational data cannot establish causality and must be interpreted that way. 30 Lutsey PL, Steffen LM, Stevens J, et al. Dietary intake and the development of the metabolic syndrome: the Atherosclerosis Risk in Communities Study. Circulation 2008; 117:754 761. This study again implicates diet soda in the potential risks of the cardiometabolic syndrome in addition to the negative effects of the western style diet. Dairy consumption may provide some protection. 31 Fung TT, Malik V, Rexrode KM, et al. Sweetened beverage consumption and risk of coronary heart disease in women. Am J Clin Nutr 2009; 89:1037 1042. This study of women enrolled in the Nurses Health Study showed that regular consumption of calorically sweetened beverages is associated with a higher risk of cardiovascular disease in women, even after other unhealthful lifestyle or dietary factors are accounted for. 32 Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ 2008; 336:309 312. Prospective data from the Health Professionals Follow-up Study suggest that consumption of sugar-sweetened soft drinks and fructose is strongly associated with an increased risk of gout in men. Fructose whether from beverages or foods may be implicated. Dietary fructose, however, comes mainly from refined foods with sugar (sucrose) or HFCS. Diet soft drinks were not associated with the risk of gout.

56 Nutrition and metabolism 33 Aeberli I, Zimmermann MB, Molinari L, et al. Fructose intake is a predictor of LDL particle size in overweight schoolchildren. Am J Clin Nutr 2007; 86:1174 1178. 34 Vartanian LR, Schwartz MB, Brownell KD. Effects of soft drink consumption on nutrition and health: a systematic review and meta-analysis. Am J Public Health 2007; 97:667 675. 35 Bray GA. Fructose: should we worry? Intern J Obes 2008; 32:S127 S131. 36 Bray GA. Fructose: is it bad for our health? A commentary prepared for a joint ILSI North America/USDA Workshop: State-of-the-Science on Dietary Sweeteners Containing Fructose; March 2008b. www.pbrc.edu/pdf/brayfinal-paper-080508.pdf. 37 Tappy L, Randin JP, Felber JP, et al. Comparison of thermogenic effect of fructose and glucose in normal humans. Am J Physiol 1986; 250:E718 E724. 38 Schwarz J-M, Acheson KJ, Tappy L, et al. Thermogenesis and fructose metabolism in humans. Am J Physiol 1992; 262:E591 E598. 39 Faeh D, Minchira K, Schwarz J-M, et al. Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes 2005; 54:1907 1913. 40 Le K-A, Faeh D, Rodrigue S, et al. A 4-wk high-fructose diet alters lipid metabolism without affecting insulin sensitivity or ectopic lipids in healthy humans. Am J Clin Nutr 2006; 84:1374 1379. 41 Abdel-Sayed A, Binnert C, Le K-A, et al. A high-fructose diet impairs basal and stress-mediated lipid metabolism in healthy male subjects. Br J Nutr 2008; 100:393 399. 42 Teff KL, Elliott SS, Tschöp M, et al. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 2004; 89:2963 2972. 43 Swarbrick MM, Stanhope KL, Elliott SS, et al. Consumption of fructosesweetened beverages for 10 weeks increases postprandial triacylglycerol and apolipoprotein-b concentrations in overweight and obese women. Br J Nutr 2008; 100:947 952. This paper was a study of metabolic responses to dietary fructose in overweight or obese postmenopausal women. Consumption of fructose-sweetened beverages increased postprandial triglycerides and fasting apob protein concentrations, findings that suggest the potential for an increased risk of cardiovascular disease. 44 Stanhope KL, Schwarz JM, Keim NL, et al. Effects of consuming fructose- or glucose-sweetened beverages for 10 weeks on lipids, insulin sensitivity and adiposity. J Clin Invest 2009; 119:1322 1334. This large and detailed study of the metabolic response to fructose compared beverages with glucose or fructose during a 10-week feeding trial. Fasting plasma triglycerides increased by 10% during 10-week period, but it was the postprandial triglyceride response that increased specifically during fructose consumption. Hepatic de-novo lipogenesis (DNL) and markers of altered lipid metabolism and lipoprotein remodeling, including fasting apob, LDL, small dense LDL, oxidized LDL and postprandial concentrations of remnant-like particle-triglyceride and cholesterol significantly increased during fructose but not glucose consumption. 45 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. Am J Clin Nutr 2009; 89:1760 1765. In this 7-day trial of a high-fructose diet, lipid deposition in liver and muscle was increased as did fasting VLDL triglycerides. The hypertriglyceridemia and ectopic fat deposition in response to fructose in participants with and without a family history of diabetes. 46 Teff KL, Grudziak J, Tonsend RR, et al. 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 Endo Metabolism 2009; 94:1562 1569; e-pub Feb 10, 2009. This study showed that consumption of fructose-sweetened beverages with meals was associated with less secretion of insulin, a blunted diurnal leptin profile and increased postprandial triglyceride concentrations compared with glucose consumption. Increases in triglycerides were augmented in obese patients with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese patients. 47 Adams SH, Stanhope KL, Grant RW, et al. Metabolic and endocrine profiles in response to systemic infusion of fructose and glucose in rhesus macaques. Endocrinology 2008; 149:3002 3008. 48 Brown CM, Dulloo AG, Yepuri G, Montani JP. Fructose ingestion acutely elevates blood pressure in healthy young humans. Am J Physiol 2008; 294:R730 R737. 49 Tappy L, Jéquier E. Fructose and dietary thermogenesis. Am J Clin Nutr 1993; 58 (5 Suppl):766S 770S; Review. 50 Bantle JP, Raatz SK, Thomas W, Georgopoulos A. Effects of dietary fructose on plasma lipids in healthy subjects. Am J Clin Nutr 2000; 72:1128 1134. 51 Couchepin C, Le KA, Bortolotti M, et al. Markedly blunted metabolic effects of fructose in healthy young female subjects compared with male subjects. Diab Care 2008; 31:1254 1256. 52 Raben A, Vasilaras TH, Møller AC, Astrup AA. Sucrose compared with artificial sweeteners: different effects on ad libitum food intake and body weight after 10 wk of supplementation in overweight subjects. Am J Clin Nutr 2002; 76:721 729. 53 Le K-A, Faeh D, Stettler R, et al. Effects of four-week high-fructose diet on gene expression in skeletal muscle of healthy men. Diab Metab 2008; 34:82 85. 54 Sorensen LB, Raben A, Stender S, Astrup A. Effect of sucrose on inflammatory markers in overweight humans. Am J Clin Nutr 2005; 82:421 427. 55 McMillan DE. Increased levels of acute-phase serum proteins in diabetes. Metabolism 1989; 38:1042 1046. 56 Pradhan AD, Manson JE, Rifai N, et al. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 2001; 286:327 334. 57 Liu S, Manson JE, Buring JE, et al. Relation between a diet with a high glycemic load and plasma concentrations of high-sensitivity C-reactive protein in middle-aged women. Am J Clin Nutr 2002; 75:492 498. 58 Engstrom G, Hedblad B, Stavenow L, et al. Inflammation-sensitive plasma proteins are associated with future weight gain. Diabetes 2003; 52:2097 2101. 59 Liu S, Willett WC, Stampfer MJ, et al. A prospective study of dietary glycemic load, carbohydrate intake, and risk of coronary heart disease in US women. Am J Clin Nutr 2000; 71:1455 1461. 60 Olsen NJ, Heitmann BL. Intake of calorically sweetened beverages and obesity. Obes Rev 2009; 10:68 75; e-pub Sep 1. This meta-analysis identified 14 prospective and five experimental studies. The majority of the prospective studies found positive associations between intake of calorically sweetened beverages and obesity. Three experimental studies also found a positive effect of calorically sweetened beverages and subsequent changes in body fat, but two experimental studies did not. Eight prospective studies adjusted for energy intake and seven of them reported associations that were essentially similar before and after energy adjustment. 61 Tetri LH, Basaranoglu M, Brunt EM, et al. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high fructose corn syrup equivalent. Am J Physiol 2008; 295:G987 G995. 62 Shapiro A, Mu W, Roncal C, et al. Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Am J Physiol 2008; 295:R1370 1375. 63 Tordoff MG, Alleva AM. Effect of drinking soda sweetened with aspartame or high-fructose corn syrup on food intake and body weight. Am J Clin Nutr 1990; 51:963 969. 64 De Castro J. The effects of the spontaneous ingestion of particular foods or beverages on the meal pattern and overall nutrient intake of humans. Physiol Behav 1993; 53:1133 1144. 65 Mattes RD. Dietary compensation by humans for supplemental energy provided as ethanol or carbohydrate in fluids. Physiol Behav 1996; 59:179 187. 66 DiMeglio DP, Mattes RD. Liquid versus solid carbohydrate: effects on food intake and body weight. Int J Obes Relat Metab Disord 2000; 24:794 800. 67 Reid M, Hammersley R, Hill AJ, Skidmore P. Long-term dietary compensation for added sugar: effects of supplementary sucrose drinks over a 4-week period. Br J Nutr 2007; 97:193 203. 68 DellaValle DM, Roe LS, Rolls BJ. Does the consumption of caloric and noncaloric beverages with a meal affect energy intake? Appetite 2005; 44:187 193. 69 Beridot-Therond ME, Arts I, Fantino M, De La Gueronniere V. Short-term effects of the flavour of drinks on ingestive behaviours in man. Appetite 1998; 31:67 81. 70 Van Wymelbeke V, Beridot-Therond ME, De La Gueronniere V, Fantino M. Influence of repeated consumption of beverages containing sucrose or intense sweeteners on food intake. Eur J Clin Nutr 2004; 58:154 161. 71 Mattes RD. Fluid energy where s the problem? J Am Diet Assoc 2006; 106:1956 1961. 72 Mattes RD, Campbell WW. Effects of food form and timing of ingestion on appetite and energy intake in lean young adults and in young adults with obesity. J Am Diet Assoc 2009; 109:430 437; PubMed PMID: 19248858. This study of 10 men and 10 women explored the form (liquid, semisolid or solid) on six occasions in the laboratory. Whether the food was consumed with a meal or alone asa snack, thebeverageelicitedtheweakest appetitive response, thesolidfood form elicited the strongest appetitive response and the semisolid response was intermediate. The appetite shift was greatest for the solid food when consumed as a snack. Based on theappetitive findings, consumption of an energy-yielding beverage either witha meal orasasnackposesa greaterriskforpromotingpositiveenergy than macronutrient-matched semisolid or solid foods consumed at these times.

Soft drink consumption and obesity Bray 57 73 Rolls BJ, Kim S, Gedoroff IC. Effects of drinks sweetened with sucrose or aspartame on hunger, third and food intake in men. Physiol Behav 1990; 48:1926. 74 Havel PJ. Dietary fructose: implications for dysregulation of energy homeostasis and lipid/carbohydrate metabolism. Nutr Rev 2005; 63:133 157. 75 Johnson RJ, Perez-Pozo SE, Sautin YY, et al. Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endo Rev 2009; 30:96 116. This hypothesis-driven paper examines evidence that fructose intake could be an important contributor to the risk of diabetes through its effects on hepatic metabolism of which uric acid is a marker. 76 Swinburn BA, Sacks G, Lo SK, et al. Estimating the changes in energy flux that characterize the rise in obesity prevalence. Am J Clin Nutr 2009; 89:1723 1728. This study provides the highest estimate to date of the amount of energy needed to produce and maintain the current epidemic of obesity. This figure is about 500 kcal per day. 77 Paeratakul S, York-Crowe EE, Williamson DA, et al. Americans on diets: results from the 1994 1996 Continuing Survey of Food Intakes by Individuals (CSFII 1994 1996). J Am Dietetic Assoc 2002; 102:1247 1251. 78 Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. New Engl J Med 1997; 338:1117 1124. 79 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002; 360:7 22. 80 Popkin BM, Armstrong LE, Bray GA, et al. A new proposed guidance system for beverage consumption in the United States. Am J Clin Nutr 2006; 83:529 542. 81 Muckelbauer R, Libuda L, Clausen K, et al. Promotion and provision of drinking water in schools for overweight prevention: randomized, controlled cluster trial. Pediatrics 2009; 123:e661 e667. This randomized clinical trial with over 2900 children using strategies to increase water intake showed that the risk of overweight could be reduced by 31% in the intervention group, compared with the control group, with adjustment for baseline prevalence of overweight and clustering according to school. Changes in BMI SD scores did not differ between the intervention group and the control group. Water consumption after the intervention was 1.1 glasses per day greater in the intervention group. No intervention effect on juice and soft drink consumption was found. Daily water flow of the fountains indicated lasting use during the entire intervention period, but to varying extent. This environmental and educational, school-based intervention showed that it is possible to prevent overweight among children in elementary school, even in a population from socially deprived areas.