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Supplement: The State of the Science on Dietary Sweeteners Containing Fructose

Misconceptions about High-Fructose Corn Syrup: Is It Uniquely Responsible for Obesity, Reactive Dicarbonyl Compounds, and Advanced Glycation Endproducts?^1,2

White Technical Research, Argenta, IL 62501

^* To whom correspondence should be addressed. E-mail: white.tech.res{at}gmail.com.

	ABSTRACT

TOP ABSTRACT Introduction LITERATURE CITED

 
Misconceptions about high-fructose corn syrup (HFCS) abound in the scientific literature, the advice of health professionals to their patients, media reporting, product advertising, and the irrational behavior of consumers. Foremost among these is the misconception that HFCS has a unique and substantive responsibility for the current obesity crisis. Inaccurate information from ostensibly reliable sources and selective presentation of research data gathered under extreme experimental conditions, representing neither the human diet nor HFCS, have misled the uninformed and created an atmosphere of distrust and avoidance for what, by all rights, should be considered a safe and innocuous sweetener. In the first part of this article, common misconceptions about the composition, functionality, metabolism, and use of HFCS and its purported link to obesity are identified and corrected. In the second part, an emerging misconception, that HFCS in carbonated soft drinks contributes materially to physiological levels of reactive dicarbonyl compounds and advanced glycation endproducts, is addressed in detail, and evidence is presented that HFCS does not pose a unique dietary risk in healthy individuals or diabetics.

	Introduction

TOP ABSTRACT Introduction LITERATURE CITED

The use of a specific fructose-containing sweetener, high-fructose corn syrup (HFCS),³ has been weakly associated with increased risk of obesity and related diseases in the United States (2). Although initially intended as a simple hypothesis, this association has grown in the minds of many in the general public, the media, and health care professions to a belief that HFCS is somehow uniquely responsible for obesity, that is, beyond its fundamental energy contribution to foods. Moreover, suggestions that HFCS be removed from foods and replaced with sucrose and its many variants,⁴ fruit juice concentrate, or agave nectar further imply that these are in some way nutritionally distinct and superior to HFCS.

Supporting data have been misused when applied to HFCS: they have measured metabolic upsets under extreme conditions, pure fructose versus pure glucose at very high concentrations, conditions not at all reflecting the American diet or even the composition of common sweeteners (3). The use of toxicological testing principles, as currently applied to fructose and HFCS, is inappropriate for assessing the safety of these dietary macronutrients. No food would be considered safe under such test conditions; indeed, even pure water triggers adverse health effects at high repeat dose levels. Despite consistent findings by expert scientific panels in each the past 4 decades that fructose-containing sweeteners are not a health risk for Americans (4–10), doubt persists, and scientific study continues.

Common misconceptions about HFCS are addressed in the first part of this article by adding much-needed perspective to the HFCS-obesity debate: defining the true composition and characteristics of added sugars, their metabolism, and practical considerations that must be addressed whenever sweeteners are used with foods and beverages. It concludes with a thorough evaluation of an emerging misconception: whether HFCS in carbonated soft drinks is a substantive contributor of reactive dicarbonyl compounds (RDC) and advanced glycation endproducts (AGE) in comparison to other dietary sources and endogenous physiological production levels. The reader is referred to the recent comprehensive review by the author (11) of dietary sources, manufacture, composition, functionality, and availability of HFCS.

All common nutritive sweeteners have fructose

Near equal amounts of fructose and glucose are found in all common nutritive sweeteners, save those based totally on glucose (pure glucose and regular corn syrup). Crystalline fructose, agave nectar, and fruit juice concentrates from pear and apple contain higher fructose levels but have specialty uses and represent only a small fraction of total nutritive sweetener use in the United States. Fructose and glucose occur principally as monosaccharides in honey, fruits and vegetables, total invert sugar, HFCS, and crystalline fructose; the 2 are joined via an ,β-glycosidic bond in sucrose, a disaccharide (12,13). The fructose source in agave nectar is inulin, a fructose polymer that must be enzyme or acid hydrolyzed to monosaccharide fructose before the product becomes a useful sweetener. Because fructose and glucose are consumed together in the diet, they appear together in digestion, absorption, circulation, and metabolic disposition. Pure fructose is rarely presented to the body as the sole carbohydrate, making dosing studies of this monosaccharide irrelevant to the human diet.

Fructose:glucose ratios in HFCS are common in nature

Although fruits are widely recognized for their "fruit sugar," vegetables and nuts are surprisingly rich sources of fructose. Most of these natural sources also contain appreciable glucose as free sugar, oligomers, or polymers (starch); some have disaccharide sucrose as well. These carbohydrates are efficiently hydrolyzed to their component monosaccharides during human digestion before absorption. It is important, therefore, when comparing dietary contributors of fructose, to analyze their total sugars as the free, hydrolyzed monosaccharides because it is this free sugars composition that reaches the bloodstream and enters metabolism.

More than 50 fruits, vegetables, and nuts fall within the fructose composition range of HFCS, sucrose, invert sugar, and honey, i.e., 42–55% of the total sweetener being composed of fructose, refuting the widely held misconception that HFCS has an atypically high ratio of fructose (11). Apples and pears have the highest percentage fructose of any fruit, a major reason apple and pear juice concentrates are so widely used to sweeten juice beverages.

Fructose:glucose ratios in HFCS are common in nutritive sweeteners

Most of the fructose-containing sweeteners have fructose:glucose ratios from 0.7 to 1.2, the range bounded by HFCS-42 and HFCS-55: sucrose, medium and total invert sugar, honey, and grape juice concentrate (11). The human body is well adapted to handling sugars ratios in this range. Apple and pear juice concentrates, agave nectar, and crystalline fructose all have ratios considerably higher. There are reports in the literature of malabsorption (gastric upset and osmotic diarrhea) in sensitive individuals with excessive fructose intake when insufficient glucose sugars or polymers are present (14–18). However, Riby et al. (19) demonstrated in fructose-versus-glucose titration experiments that absorption of fructose markedly improves when the fructose:glucose ratio falls below 2:1 and that malabsorption essentially disappears below a ratio of 1.3:1, a value well above the 1:1 ratio of most fructose-containing sweeteners.

Concern that the introduction of HFCS in the 1970s changed the balance of fructose and glucose in the diet is unfounded. Forshee et al. (6) calculated a fructose:glucose ratio of 0.72 in the typical diet using the USDA disappearance data series and reported that the ratio in the U.S. food supply has not changed since the 1960s.

HFCS and sucrose are equally sweet

A common misconception is that HFCS has twice the sweetness of sucrose, exploiting the American sweet tooth and encouraging overeating. In fact, only crystalline fructose in dry applications has this sweetness (20). Fructose exists as 1 of 4 tautomeric (easily interconverted) isomers in nature. It crystallizes in the sweetest, β-D-fructopyranose, form but in solution is free to mutarotate among 3 less-sweet tautomers: -D-fructopyranose, β-D-fructofuranose, and β-D-fructofuranose (21). Expert taste panels report that the sweetness intensity of pure fructose in solution (10% solids) falls to 1.2 times that of sucrose (22). HFCS-55 was purposefully formulated to the same sweetness intensity as sucrose (isosweet) to facilitate its substitution in beverages (11), sweetness parity that has subsequently been verified by Schiffman et al. (23).

HFCS adds functionality beyond sweetness

HFCS fulfills nontraditional roles in food systems aside from its expected role as a sweetener. Consumers express surprise at finding it unexpectedly on product labels without realizing that this occurs largely because of the unique functionality of the free fructose molecule. HFCS replaces an earlier generation of less desirable food ingredients (e.g., propylene glycol for moisture retention) by providing the following functional benefits (24–26): flavor enhancement with fruit and spice flavors; colligative properties such as freezing point depression and osmotic pressure, useful in ice cream and frozen fruit; fermentable solids, necessary in yogurt and yeast-raised baked goods; reducing sugars, responsible for the pleasing brown colors, appetizing flavors, and aromas of baked goods and cooked meats; resistance to crystallization, enabling soft-moist cookies and eliminating "sticky caps" in pharmaceutical elixirs; and for moisture retention, improving palatability in low-moisture granola bars.

HFCS and sucrose are equally used in the United States

The common misconception that HFCS is in everything implies that it must be the dominant sweetener in the United States. However, sucrose and HFCS are used today in roughly the same amounts. Per capita availability data for sucrose and HFCS between 1970 and 2005 (27) reveal that HFCS use grew rapidly in the years 1975–1985. The product availability curve for sucrose is the mirror image, because sucrose was replaced on a 1-for-1 basis by HFCS. This was a period in which the sugar industry lost 40% of its market share.

Major technological breakthroughs in enzyme and refining technology improved quality to the point that HFCS could successfully compete with sucrose in the important carbonated beverage industry (28), and 1984 was the year that large cola companies completed the switch from sucrose to HFCS after several years of incremental changes. This decision was based on the following considerations: finished product quality—sucrose inverts (hydrolyzes) over time in acidic soft drinks, changing both the sweetness character and the product flavor profile; stable domestic production and supply—sugar cane was grown in unstable geographic and political regions, whereas corn is a stable domestic grain; lower cost and freedom from wild sugar price fluctuations (resulting from weather and politics); and ease of handling—beverage production with dry, bulk sugar was labor and energy intensive. HFCS could be pumped from the delivery vehicle directly into a holding tank and from there to the mixing tank. Dilution to desired solids was a simple matter of adding water and agitation.

Growth in annual usage slowed dramatically between 1985 and 1998 as HFCS became a mature product with fewer markets left to penetrate. HFCS lost aggregate sales volume starting in 1999, largely as a result of greater consumer awareness of diet and nutrition; the development of high-intensity noncaloric sweeteners with improved sweetness profiles, stability, and functionality; and the increasing popularity of bottled water.

Honey and crystalline fructose are fructose-containing sweeteners that serve specialized markets; they are produced in volumes on the order of 1–2% of sucrose and HFCS and are, therefore, not viable mainstream sweeteners. Although agave nectar and fruit juice concentrates are finding increasing applications, statistics on their use as sweeteners are difficult to find. Foreign imports of honey, fruit juices and concentrates, and agave constitute an appreciable proportion of that used in U.S. products.

It must be noted that glucose-based sweeteners (regular corn syrup and glucose) are not suitable substitutes for HFCS because they lack sufficient sweetness and functionality.

Sucrose is the dominant sweetener worldwide

In many regions of the world, local sugar production is protected by formidable trade restrictions. For example, there is a quota system in place within the European Union that limits HFCS production by country; and until recently, the special tax levied by Mexico on HFCS-sweetened carbonated soft drinks was very effective in protecting its domestic sugar industry. Consequently, we live in a sucrose-sweetened world, and HFCS remains a distinctly U.S. sweetener. Indeed, Fereday et al. estimated HFCS worldwide production versus sucrose at 8% of the combined total (29).

HFCS correlates poorly with U.S. and global obesity

Despite the considerable attention paid to the hypothesis of Bray et al. (2), there does not appear to be a strong U.S. or global correlation between obesity (BMI > 30 kg/m²) and HFCS availability (11,29–32): in the United States, HFCS availability peaked in 1999 and is now dropping, but obesity rates have remained elevated at 33% of the population for those over 20 y; HFCS has been widely available in South Korea since the 1980s, where it currently has a 26% share of added sugars; however, obesity rates are low to moderate by global standards (5% for men and 14% for women); although Argentina has some domestic HFCS production, sucrose is clearly dominant with 84% of the sweetener market, and obesity rates are among the highest in the world (41% for both men and women); in Mexico, HFCS availability amounted to only 5% of total sugars in 2005, but obesity rates among men and women were higher than those in the United States (46% for women and 30% for men).

Fructose sweeteners have not driven disproportionate energy intake

Another widely repeated misconception is that increased availability of HFCS has fueled a disproportionate increase in added sugars intake and, consequently, an increase in total energy. The line graph in Figure 1 illustrates how total per capita energy intake increased 24% in the United States between 1970 and 2005 (30). The bar graph demonstrates that over the same period, flour/cereal products and fats increased as a percentage of total energy intake (3% and 5%, respectively), while that from added sugars, vegetables, fruit, dairy and meat/eggs/nuts declined. In actuality, energy from added sugars, although higher in 2005 than in 1970, increased at a slower rate than total energy and energy from fats and flour/cereals. And availability of HFCS has been in decline since peaking in 1999. Thus, the increase in total energy in the U.S. diet was not caused specifically by increased consumption of HFCS or even aggregate added sugars; rather, Americans are eating more of everything.

View larger version (22K): [in this window] [in a new window]   FIGURE 1  Total per capita daily energy (line) (1 kcal = 4.184 kJ) and change in percentage of total energy by nutrient food category (bars): 1970 to 2005.

Pure fructose is a poor model for HFCS in studies intended to explore effects of dietary HFCS on human metabolism because HFCS is also half glucose. Nor is an experimental challenge of pure fructose versus pure glucose a valid comparison: the incidence of either dietary extreme must surely be so low as to be inconsequential.

Because HFCS largely displaced use of sucrose in specific food categories over the past 35 y, the most appropriate test to measure the metabolic effects of HFCS is against the sucrose it replaced. In the relatively few studies in which the 2 have been compared, no differences in metabolic markers of obesity or measures of satiety were observed (33–38): serum glucose and insulin, the obesity hormones ghrelin and leptin, triacylglycerols and uric acid, and hunger, satiety, and short-term energy intake are all comparable for both sweeteners. These results are not surprising, given the similar fructose:glucose ratio of the 2 sweeteners and that both HFCS and sucrose are absorbed into the bloodstream as the constituent monosaccharides.

Fructose-containing sweeteners use common refining methods

A popular misconception is that the corn wet milling process for HFCS is more "complex" than the perceived "simpler" or "more natural" processes for sugar, fruit juice concentrate, or agave nectar production. However, the manufacturing processes for all fructose-containing sweeteners must include production methods that can accommodate raw materials carrying a formidable hodgepodge of agricultural dirt and residue, botanical structure and nonessential chemical compounds, and unwanted colors, flavors, and odors. The production methods in each case must refine the raw material into a robust and versatile sweetener that can be formulated into a wide range of foods and beverages. Common unit operations are relied on by all sweetener producers to accomplish this task: pulping, clarification, evaporation, carbon treatment, ion exchange, centrifugation, filtration, and enzyme treatment. For example, fruit juice concentrates must be "stripped" of their color, flavor, and aroma unless there is no concern that these natural characteristics will overwhelm the product they are sweetening (39). And agave nectar is a poor sweetener unless the native inulin fructose polymers are first hydrolyzed via acid or enzyme to sweet fructose monomers.

It is not strictly accurate, then, to call 1 process simpler or more natural than another because many of the same processing steps are common to all. In fact, the U.S. FDA recently verified that HFCS can be labeled "natural" because it contains no artificial or synthetic ingredients or color additives, and its manufacturing process satisfies FDA requirements (40).

Several food companies recently reformulated products away from HFCS, accompanied by high-profile public relations and advertising campaigns, to capitalize on the poor image of HFCS and promote a "healthier" label: Juicy Juice replaced HFCS with fruit juice concentrates (41), LIV sports drink is now sweetened with agave nectar (42), Driftwood Dairy's flavored milks for school lunches use evaporated cane juice (43), and Jones Soda reverted to sucrose (44). In light of similarities in composition, sweetness, energy content, processing, and metabolism, claims that such sweetener substitutions bring nutritional benefit to children and their families appear disingenuous and misleading.

RDC and AGE are formed in common foods and beverages

The French scientist Louis Camille Maillard showed nearly a century ago that sugars, particularly the monosaccharides, react spontaneously with amines to undergo a cascade of chemical reactions. Food scientists have shown that similar reactions between dietary sugars and proteins produce the pleasing aromas and golden crusts of baked goods; the savory cooked, roasted, and fried flavor of meats; the rich, creamy flavor of caramels; and the complex flavors of fermented and aged cheeses, sauces, and beverages. Many of the Maillard reaction products that are formed during cooking of foods are also produced during heat sterilization of milk and infant formula and by microorganisms during fermentation reactions, including those involved in the preparation of bread, buttermilk, and alcoholic beverages. There is now evidence that some of these compounds have biological activity when consumed in foods (exogenous sources) and that they are also produced in appreciable amounts by the body itself (endogenous sources). One group of compounds, the RDC, which are intermediates in the Maillard reaction, has been variously described as cytotoxic, mutagenic, carcinogenic, and prooxidant. Paradoxically, researchers have also demonstrated bactericidal, antiviral, antiparasitic, and antitumorigenic activities for RDC. RDC are produced by the reaction of Maillard products with protein.

A second group of compounds, AGE, are formed by reaction of RDC with protein. These also have seemingly contradictory properties: pro- and antioxidant, pro- and antimutagenic, toxic and protective. AGE modify and crosslink most proteins in the body and affect their structure and function, a process that is countered through continuous turnover of body proteins. However, some long-lived proteins accumulate AGE, such as collagen in the vascular wall, crystallins in the lens of the eye, and in blood proteins. Similar modifications also occur on membrane phospholipids and in DNA. AGE have been proposed as activators of proinflammatory pathways through the binding of cell surface receptors, such as RAGE, the receptor for AGE (45). It must be noted, however, that the RAGE hypothesis of AGE-induced inflammation is not uniformly accepted (46,47). Increases in AGE formation are considered important in the development of pathology in diabetes, cardiovascular and renal disease, and in inflammatory, prooxidant, and aging processes.

RDC and AGE are produced from many simple sugars

Glyoxal and methylglyoxal are 2 of the most important RDC. They are formed via glucose degradation and early glycation reactions (48) and exogenenously in food products through fragmentation of sugars via retro-aldol condensation and autooxidation, and from lipid peroxidation (49). Methylglyoxal is readily formed during the heating of glucose, fructose, maltose, and lactose. RDC also appear to be ubiquitous in the environment. WHO (50) reported measurable quantities of glyoxal in the atmosphere, river sediments, swimming pools, ozonated drinking water, groundwater, and household cleaners. Taken together, however, these environmental sources are but a small fraction of the total exposure to RDC; our primary exposures are by endogenous production and through food intake.

Exogenous RDC and AGE are produced by Maillard reactions during cooking. Baking, roasting, frying, braising, broiling, grilling, flaming, scalding, microwaving, pasteurizing, evaporating, and thermal processing all provide sufficient heat to generate RDC and AGE. High temperatures and longer cooking times cause degradation, dehydration, and rearrangement reactions between carbohydrates and proteins. There is a direct relation among time, temperature and AGE formation. Other factors that influence the extent of AGE formation include reactant concentrations, pH, moisture content, water activity, and trace metals (45,51).

RDC and AGE are continually produced in human metabolism

The endogenous production of reactive carbonyls has been studied since the early 1900s, when Neuberg and then Szent-Gyorgyi began examining the glyoxalase system and the metabolism of methylglyoxal. Although RDC are formed endogenously from a variety of enzymatic and nonenzymatic reactions, the most important of these is the fragmentation of triosephosphate intermediates during glycolysis (52–54), a mainstream enzymatic pathway found in all cells. Nonenzymatic formation of RDC occurs by a number of other pathways, including (50) the spontaneous reaction of reducing sugars with proteins (Maillard reaction); sugar autooxidation; DNA oxidation; peroxidation of polyunsaturated fatty acids; UV photo damage; oxidative stress; and metabolism and microsomal oxidation of glycoaldehyde, ethylene glycol, and β-hydroxy-substituted N-nitrosamines.

AGE are also formed endogenously via several mechanisms: directly from reversible reactions of glucose or other carbohydrates or metabolic intermediates with amines, followed by release of RDC and formation of AGE; oxidative stress that converts glucose to dicarbonyls, which further bind to proteins to form AGE; lipid peroxidation; and metabolically, through fragmentation and elimination of phosphate from glycolytic intermediates (55).

Concentration estimates for methylglyoxal and glyoxal in human blood plasma are 100–120 nmol/L (56,57), whereas cellular concentration estimates for methylglyoxal and glyoxal are 1–5 µmol/L and 0.1–1 µmol/L, respectively (58). Thornalley calculated the whole-body rate of formation of methylglyoxal at 125 µmol·L^–1·d^–1 (59).

Carbonated soft drinks are not a unique food source of RDC and AGE

Lo et al. (60) raised the concern recently that carbonated soft drinks may be an important source of RDC, especially to diabetics, who typically present elevated RDC and AGE levels in blood and tissues. The RDC were presumed by Lo to originate with the HFCS used to sweeten the carbonated soft drinks. The authors reported methylglyoxal in the range of 235–1395 µg/L. Lo's report (60) received wide media attention and prompted the introduction of legislation to the Florida House of Representatives that would ban HFCS-sweetened products from the state's school lunch program (61).

Before commencing legislative action, it would be prudent to consider 3 questions left unresolved in the Lo paper (60): 1) Is HFCS a unique and important contributor of RDC and AGE to foods and beverages? 2) Are reported levels for RDC reliable and accurate (i.e., based on sound analytical methodology)? 3) Does HFCS in carbonated soft drinks contribute appreciably to endogenous RDC and AGE levels?

    HFCS is not a unique and important contributor of RDC and AGE to foods and beverages. RDC and AGE have been measured in a limited number of foods, and amounts appear to vary widely. Available data for glyoxal, methylglyoxal, and 3-deoxyglucosone are presented in Table 1. Methylglyoxal levels in carbonated soft drinks are comparable to those reported for bread, instant coffee, and alcoholic beverages. Considerably higher levels are found in fermented or thermally processed foods such as toast, brewed coffee, soybean paste and sauce, and cheeses. There also appears to be less glyoxal in carbonated soft drinks than in baked breadcrumbs and fermented foods such as soybean derivatives, brewer's grains, and cheese.

Table 2 was adapted from Goldberg et al. (51), who used the ELISA immunoreactivity assay to measure AGE in selected foods. Although the reliability of the method is unproven, particularly in comparison to the new UPLC-MS/MS method by Assar et al. (62), the data may be useful for comparing relative amounts of AGE. Low levels of AGE were found in all foods tested. With the exception of infant milk, beverages have exceedingly low levels of AGE, and colas were among the lowest of all foods tested. Meats, baked goods, and fermented, cooked, and heated foods have up to 1400 times the AGE of carbonated soft drinks.

A comparison of the RDC values reported by Lo et al. (60) (Table 1) for HFCS-55 and carbonated soft drinks affords an internal check on the consistency of the method. Many carbonated soft drinks are sweetened by diluting HFCS-55 (solids content of 77%) to a solids content of 11%, a 7-fold dilution factor. If the Lo analytical method is sound, multiplying the concentrations reported for the 3 RDC in the carbonated soft drink from Table 1 by the 7-fold dilution factor should yield concentrations approximating those reported for HFCS-55. The following ranges would be expected (mg/kg): glyoxal, 0.77–7.4; methylglyoxal, 1.82–9.8; and 3-deoxyglucosone, 68.6–244.3. It will be observed that the RDC concentrations thus calculated from the carbonated soft drink data exaggerate the amount actually measured for HFCS-55 by as much as 14-fold. Some difference between reported and calculated values is to be expected because it is highly unlikely the carbonated beverages measured by Lo, which were not identified in the article, were formulated from the HFCS-55 he tested. That the difference between reported and calculated was not consistent, however, suggests either inherent variability in RDC levels in HFCS or an inconsistency in the analytical method that was not addressed by the authors.

Finally, heating the samples during the assay was inadvisable: because of the ease with which RDC are generated from the decomposition of most organic compounds, heating would generate artifacts not only from the samples but from the derivatizing agent as well. Additional studies are needed to verify whether Lo's reported values (60) for RDC in carbonated soft drinks and HFCS are accurate and not overstated.

    Carbonated soft drinks do not contribute appreciably to endogenous RDC and AGE production. By applying approximations to Thornalley's (23,63) estimate of endogenous methylglyoxal production in packed red blood cells (125 µmol·L^–1·d^–1), it is possible to estimate whole-body endogenous RDC production (Paul J. Thornalley, University of Warwick, UK, personal communication). Using a body density of 1.0 L/kg (64) and body cell mass (BCM) of 25 kg (65) yields 225 mg/d endogenous production of methylglyoxal. A second calculation using 2.4 L packed RBC per 70-kg adult and RBC glucose consumption (and methylglyoxal production) at 10% of whole body potential yields a similar value: 216 mg/d.

Dividing methylglyoxal in selected foods from Table 1 into 220 mg/d (averaged from the 2 approximations) and then applying FDA reference serving values (66) yields the intake amounts and calculated number of servings of each that would have to be consumed within a 24-h period to equal daily endogenous production of methylglyoxal (Table 3). For example, 1129 servings/d of carbonated soft drink or 1800 servings/d of toast would need to be consumed to equal amounts produced by natural physiological processes. Such exaggerated quantities are clearly beyond the capacity of even the heartiest appetites. From this perspective, it is clear that food sources of methylglyoxal are inconsequential in comparison with endogenous production.

Baynes suggests that the impact of dietary AGE is further limited by additional considerations (John W. Baynes, University of South Carolina; personal communication): because of their reactivity with proteins and amines, RDC and AGE would likely bind food and gastrointestinal substrates, trapping them within the gastrointestinal tract, and intestinal proteases would have limited ability to digest AGE-modified protein substrates. For these reasons, intact AGE proteins or their degradation products are poorly absorbed, and RDC and AGE proteins are detoxified both in the intestinal epithelia and in the liver.

Indeed, Koschinsky et al. (67) found that only 10% of dietary AGE is absorbed from the intestines and that the kidneys subsequently excrete 30% of those that were absorbed. Clearly, HFCS in carbonated soft drinks does not contribute appreciably to physiological levels of RDC or AGE.

Conclusion: replacing HFCS in foods with other fructose-containing sweeteners will provide neither improved nutrition nor a meaningful solution to the obesity crisis

This article has attempted to bring perspective to the discussion about potential health risks associated with consumption of fructose-containing sweeteners. Their sources, compositions, manufacturing processes, applications, and availability have been presented. Misconceptions have been identified and clarified. And an issue of current interest, the potential contribution of exogenous fructose-containing sweeteners to endogenous RDC and AGE, has been analyzed.

It must be clearly understood that the fructose-containing sweeteners—sucrose, invert sugar, honey, fruit juice concentrates, and HFCS—are essentially interchangeable from a compositional/nutritional/metabolic standpoint. They are all equal in energy content and, once hydrolyzed to monosaccharides and absorbed, present the same sugars at the same ratios to the same tissues within the same timeframe to the same metabolic pathways.

Insufficient care has been exercised in interpreting experimental data purporting to demonstrate untoward metabolic effects for fructose-containing sweeteners, especially HFCS. It has been shown in this article that HFCS, sucrose, invert sugar, and fruit juice concentrates, the primary fructose-containing sweeteners, all share a fructose:glucose ratio between 0.7 and 1.2. It is inappropriate, then, to extrapolate experimental outcomes derived from pure fructose, with a fructose:glucose ratio that is far different, to these sweeteners. It is equally inappropriate to compare experimental outcomes to a pure glucose control. A diet formulated with either single sugar as the sole carbohydrate is so rarely encountered that it must surely be considered insignificant from a public health perspective. And glucose lacks the functionality and sweetness to be considered a viable replacement for either HFCS or sucrose in sweetened foods and beverages.

Care is also called for when interpreting experiments in which the fructose component far exceeds 10% of total energy, the mean population intake recently estimated by Vos et al. (68). One current study measured the effect of a 6-mo, 60% energy fructose diet on the promotion of leptin resistance in rats subsequently fed a high-fat diet for 2 wk (69). The study predictably demonstrated an effect under this glut of fructose and fat; however, it has no relevance to real life human diets. The misinterpretation of such studies as cautions against moderate dietary fructose and HFCS use is simply not justified.

Although much has been made of the RDC levels in HFCS recently reported by Lo et al., the data in Tables 2 and 3 reveal that many foods have comparable or higher levels of RDC and AGE. When amounts in foods are compared for perspective with estimates of endogenously produced RDC, and when poor absorption rates and natural detoxification mechanisms are considered, it must be concluded that exogenous food sources in general, and fructose-containing sweeteners in particular, do not contribute materially to physiological levels of RDC and AGE, either in healthy individuals or in diabetics.

Other articles in this supplement include references (73–82).

	ACKNOWLEDGMENTS

 
The author gratefully acknowledges helpful discussions with Drs. John Baynes, Mark Empie, Dirk Reif, and Paul Thornalley.

	FOOTNOTES

 
¹ Published in a supplement to The Journal of Nutrition. Presented at the conference "The State-of-the-Science on Dietary Sweeteners Containing Fructose," held in Beltsville, MD, March 18–19, 2008. The conference was cosponsored by the Technical Committee on Carbohydrates of the International Life Sciences Institute North America (ILSI North America) and the USDA, Agricultural Research Service. The views expressed in these papers are not necessarily those of the USDA, the Agricultural Research Service, or the Supplement Coordinators. Supplement Coordinators for this supplement were David M. Klurfeld, USDA, Agricultural Research Service, and Molly Kretsch, USDA, Agricultural Research Service. Supplement Coordinator Disclosure: D. Klurfeld and M. Kretsch: no relationships to disclose.

² Author disclosure: J. S. White is a consultant to the food and beverage industry in the area of nutritive sweeteners. His clients include research institutes, food industry councils, trade organizations, and individual companies. Support for preparation of this article was provided by the International Life Sciences Institute (ILSI) and the U.S. Department of Agriculture Economic Research Service (USDA-ERS). Funding to support travel to the 18–19 March 2008 workshop "The State-of-the-Science on Dietary Sweeteners Containing Fructose" and the writing of this resulting manuscript was provided by the International Life Sciences Institute, North American Branch.

³ Abbreviations used: AGE, advanced glycation endproducts; HFCS, high-fructose corn syrup; RAGE, receptor for AGE; RDC, reactive dicarbonyl compounds.

⁴ Contemporary variants of sucrose include cane juice crystals, dehydrated cane juice crystals, unrefined cane juice crystals, raw cane crystals, washed cane juice crystals, Florida Crystals, unbleached evaporated sugar cane juice crystals, crystallized cane juice, unbleached crystallized evaporated cane juice, organic dehydrated cane juice, unbleached sugar cane, evaporated cane juice and evaporated cane juice sugar, raw sugar, turbinado, and sucanat.

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TOP ABSTRACT Introduction LITERATURE CITED

 

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