The potential role of excessive intake of fructose (defined as >50 g·d−1) in the epidemic of obesity, hypertension, and diabetes has been the topic of recent scientific attention (19,25,28). In contrast to the negative health implications of much of the data, fructose is the primary sugar in natural fruits, suggesting there may be healthy benefits associated with its consumption. Fructose also has been used commonly by individuals with diabetes because fructose ingestion does not stimulate insulin release acutely. Finally, fructose is a common component in sports drinks where evidence suggests that fructose in combination with other sugars may be beneficial to the athlete (23,35). In this article, we review the evidence for both the beneficial and negative aspects of fructose in health and disease, with specific reference to athletes.
WHAT ARE THE PRIMARY DIETARY SOURCES OF FRUCTOSE?
Fructose is a monosaccharide that is the principal sugar present in fruits and honey. Table sugar (sucrose) derived from sugar cane and sugar beets is another source of fructose, as this disaccharide is degraded by sucrase in the intestine to equal parts glucose and fructose. The other major source of dietary fructose is high fructose corn syrup (HFCS), which is generated enyzmatically by converting corn starch to a mixture of fructose and glucose, often in a 55:45 mixture. HFCS is a common sweetener because it is liquid and mixes well, does not crystallize with freezing, is relatively inexpensive, and has a long shelf life. Natural fructose also is present in some vegetables (such as the sweet pea and sweet potato), but most fructose ingested today comes from products containing sugar and HFCS. It should be noted that HFCS comes in two commercially used variants: HFCS-55, as described above, and HFCS-42, in which only 42% of the total carbohydrate is fructose. In other words, HFCS-55 delivers slightly more fructose than table sugar (sucrose is composed of 50% glucose and 50% fructose), whereas HFCS-42 delivers slightly less fructose. HFCS-55 is used more often as a sweetener because its higher fructose content confers greater perceived sweetness. Most importantly, from a metabolic perspective, the three sugar sources are indistinguishable.
EPIDEMIOLOGY OF FRUCTOSE INTAKE
Until the availability of table sugar (sucrose), total fructose content of the American diet was relatively low due to variable availability of fruit and honey. Indeed, before 1700, sugar was relatively expensive and was afforded only by the wealthy and royalty. Sugar intake increased dramatically in England beginning around 1700. Based on production data, total per capita sugar intake increased from approximately 4 lb·yr−1 in 1700, to 18 lb·yr−1 in 1800, to 90 lb·yr−1 in 1900, and to 155 lb·yr−1 in 2000 (10,65). Two major accelerations in fructose intake can be observed, with the first occurring in the mid-1800s with the successive reduction and then complete repeal of the English sugar tax by Gladstone and Disraeli in 1874, and the second acceleration following the introduction of HFCS in the early 1970s (28). Today, the average American is ingesting three to four times more fructose than in 1920, with average intake approaching 60-70 g·d−1 (i.e., 48-56 lb·yr−1). Several studies suggest that a significant percentage of preschoolers and adolescents are ingesting more than the recommended upper limit of 25% of total energy intake as added sugar (13,30,39).
BIOLOGY OF FRUCTOSE
Fructose metabolism is unique among sugars. First, fructose is absorbed in the proximal small intestine by the fructose-specific glucose transporter type 5 (GLUT5) membrane transporter. Fructose is absorbed more slowly than glucose, and it lingers in the intestinal lumen long enough to predispose to osmotic diarrhea and gastrointestinal discomfort when large boluses (e.g., >25 g) of fructose are ingested (3). Following uptake in the intestine, fructose is transported to the liver where nearly 70% is metabolized by hepatocytes on first pass. Unlike glucose, which is phosphorylated in a carefully regulated manner, once inside liver cells, fructose is rapidly phosphorylated by fructokinase (KHK) to generate fructose-1-phosphate. The phosphorylation of fructose occurs rapidly such that cellular levels of adenosine triphosphate (ATP) drop precipitously (4,32). Depletion of ATP in a variety of cell types, including in vascular endothelial cells and tubular epithelial cells have been shown with concentrations of fructose as low as 1 μM, which is a concentration achievable in the blood following a meal high in fructose (e.g., > 50 g fructose) (6,18). Studies in humans also have confirmed the ability of small doses of fructose to cause ATP depletion in the liver following intravenous injection (4,37).
A consequence of fructose-induced ATP depletion is a transient arrest in protein synthesis (4,32). In addition, both proinflammatory and prooxidative pathways are activated (6,18), and both lactate and uric acid are generated and rise in the circulation (15,34,58). Finally, the rapid production of downstream metabolites, acetyl-CoA and glycerol-3-phosphate, engages lipogenesis with the production of fatty acids and triglyceride (57,58,60).
The transient reduction in hepatic ATP distinguishes fructose from other sugars and likely plays a major role in its downstream metabolic effects (Fig.).
THE DARK SIDE OF FRUCTOSE: RELATIONSHIP WITH THE OBESITY AND METABOLIC SYNDROME
Several lines of evidence suggest that excessive fructose intake may play a role in the development of obesity and metabolic syndrome. For example, epidemiological studies have linked total fructose intake with the rise in obesity, hypertension, metabolic syndrome, and chronic kidney disease (25,28,42,51,55). Indeed, the relationship of fructose intake with cardiovascular disease can be traced back to the mid-1800s and correlates with the epidemic in both developed and developing nations and with the appearance of these conditions in indigenous populations (25,28). Studies also have linked soft drink ingestion (which is the largest source of dietary fructose) with obesity, diabetes, fatty liver, and hypertension within the U.S. population (5,12,31,42,51). It should be kept in mind that correlation does not necessarily mean causation, but in this case, a strong correlation is cause for further investigating the potential role that excessive dietary fructose might play in obesity and metabolic syndrome.
Experimental data also suggest that fructose may have a contributory role in the development of the metabolic syndrome (abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance with or without glucose intolerance, proinflammatory state, and prothrombotic state). Laboratory animals fed fructose develop all features of the metabolic syndrome; this is not observed in rats fed equivalent calories as glucose starch or dextrose (38,44). Fructose ingestion also has been associated with the development of fatty liver and renal injury in laboratory animals (17,47-49). Clinical studies also have documented that diets high in fructose content can induce features of the metabolic syndrome in humans. For example, Stanhope et al. reported that a 10-wk diet in which 25% of the daily energy intake came from fructose induced postprandial hypertriglyceridemia, insulin resistance, and increased intraabdominal fat in overweight adults; this was significantly greater than observed in subjects fed a 25% dextrose-based diet (56). Similarly, in collaborations with Enrique Perez-Pozo, M.D., and Julian Lopez-Lillo, M.D., we found that supplementation of the diet with 200 g fructose daily for 2 wk could induce blood pressure elevation, dyslipidemia, and insulin resistance in healthy adult men (43).
The mechanism by which fructose contributes to metabolic syndrome is under intensive study. Some studies suggest the link is mediated by endothelial dysfunction (66), possibly driven by an increase in uric acid (38). Other studies suggest that fructose and or uric acid may have direct effects on the adipocytes (50). Most recently, our group has focused on the role of ATP depletion and mitochondrial dysfunction as a key underlying mechanism (Sanchez-Lozada LG et al., unpublished manuscript/observations, 2009).
WHAT ABOUT FRUIT?
Interestingly, fruits can be high in fructose (Table) but do not appear to increase the risk for metabolic syndrome, possibly due to their rich content of other nutrients. Most epidemiological studies suggest that the ingestion of fruit is associated with less cardiovascular disease outcomes, and as such, fruit is often recommended in many dietary plans, including the DASH (dietary approaches to stop hypertension) diet. In this regard, studies have shown that fruit contains many nutrients that can improve endothelial function, such as ascorbate (vitamin C), resveratrol and other polyphenols, a variety of antioxidants, and potassium. Ascorbate might be particularly beneficial as it has been shown to help prevent the development of metabolic syndrome in fructose-fed rats (64).
Ascorbate content is highest when a fruit is immature and decreases as it ripens in association with increasing fructose content (36). Not all fruits may be equal in their protective benefits; certain fruits such as apples, pears, and watermelon are relatively low in vitamin C content compared with other fruits. However, since the content of fructose in a fruit is generally small (4-8 g per serving), it is likely that the fructose in fruit is not of major concern. However, ingesting large volumes of fruit juices or fruit drinks (the latter of which often contain HFCS or sugar) might provide significant fructose exposure in addition to excess energy (calorie) intake. Indeed, studies in children have shown a marked increase for obesity in those who drink more than 12 oz·d−1 of juice (11), leading to recommendations by the American Academy of Pediatrics to limit juice intake (and sweetened beverages) in children under age 18 to no more than 12 oz·d−1 (1). The content of fructose in various fruits is shown in the Table, with most fruits having between 4 and 10 g per serving of fructose (27). In comparison, the average 16-oz soft drink contains about 26 g of fructose, and some restaurant desserts can have as much as 60 g of fructose in one serving (27).
FRUCTOSE IN THE INDIVIDUAL WITH DIABETES
Fructose was once considered a better sweetener option for the individual with diabetes. Since fructose does not acutely stimulate insulin release, the ingestion of fructose generally does not require alterations in insulin dosing, and hence fructose has been considered an energy source that people with diabetes could ingest without concern. Acutely, fructose ingestion also may lower blood glucose by stimulating glucose uptake in the liver (33,53,54). Several studies report that fructose administration is well tolerated in the individual with diabetes (29,41). However, as it has become more evident that fructose can cause postprandial hypertriglyceridemia and insulin resistance, the American Diabetes Association no longer recommends the consumption of pure fructose by people with diabetes (16). In addition, several studies suggest that fructose can induce advanced glycation end products (AGE; e.g., glycalated proteins associated with endothelial dysfunction) more effectively than glucose (61,62), and fructose has been reported to accelerate cataract formation in diabetic animals (2,20). Finally, fructose also is associated with the development of renal hypertrophy, glomerular hypertension, and glomerulosclerosis in laboratory animals (48,49). Given these concerns, it seems prudent to minimize fructose intake in the individual with diabetes.
THE BRIGHT SIDE OF FRUCTOSE: A FUNCTIONAL INGREDIENT IN SPORTS DRINKS
Oral rehydration fluids such as sports drinks play a critical role in improving exercise performance and are formulated to help prevent or treat water and sodium loss, hypoglycemia, and metabolic acidosis. Ingestion of appropriately formulated carbohydrate solutions stimulate salt and water absorption, in part because glucose and sodium uptake are linked via the sodium-glucose transporter (SGLT-1) in the intestinal epithelium, but also because carbohydrate absorption may improve paracellular fluid and solute flux (14,40). While glucose and sucrose solutions result in better water and sodium absorption compared with equivalent fructose-based solutions (14), the combination of fructose and glucose appear to be superior in stimulating fluid absorption than either substrate alone at the same osmolality (52).
As strenuous exercise can reduce muscle and liver glycogen stores, it is important to ingest and absorb sufficient carbohydrate during exercise to help maintain energy production. Studies have shown that oral rehydration solutions containing glucose increase exogenous carbohydrate oxidation rates and improve exercise performance and endurance capacity (8,9). However, if fructose is administered with glucose, exogenous carbohydrate oxidation rates can increase by 50% or more even if the total calories ingested are the same (23,45). Similar findings have been reported when sucrose is provided with glucose (21,24). The increase in oxidation may be due to the fact that fructose and glucose are transported via different carriers, and therefore the combination may allow for more total carbohydrate to be absorbed in a given period of time (23). In addition, studies suggest that the absorption of fructose is enhanced in the presence of glucose absorption (46,63). In contrast, studies in which fructose is used as the sole carbohydrate report worsening of exercise performance, a larger loss of plasma volume, and greater side effects (such as bloating and diarrhea) (35), responses due in part to the relatively slow absorption characteristics of fructose.
While the addition of fructose to glucose-based solutions appears to be beneficial during strenuous exercise, it is important to recognize that the fructose content of a typical sports drink is generally in the range of 4-8 g·12 oz−1, similar to the fructose content in one serving of natural fruits and significantly less than that observed in nondiet soft drinks. The ideal fructose level for sports drinks has not been pinpointed, but most available evidence indicates that fructose content should not exceed the glucose content (22,23,45,52) and that total sugar content should not exceed 70 g·L−1 (i.e., a 7% solution) (35). Furthermore, while fructose- (or sucrose-) containing sports drinks may increase plasma lactate slightly, especially in sedentary individuals, in exercising subjects the administration of oral rehydrating solutions containing low amounts of fructose actually may prevent or reverse increases in lactate and uric acid by preventing dehydration and tissue ischemia.
Fructose also may have other benefits. For example, there are increasing data that fructose intake may be beneficial under conditions of stress or starvation due to its ability to increase fat stores in the liver and circulation (26). Fructose, by virtue of inducing mild inflammation, theoretically could be beneficial in subjects with acute infections, whereas chronic inflammation induced by long-term high levels of fructose could have a contributing role in cardiovascular disease (7). These and other anomalies of fructose metabolism indicate the need for additional studies on the role of fructose in health and disease.
There is increasing evidence that excessive intake of fructose, primarily in the form of sugar or HFCS, may play a role in the current epidemic of obesity and diabetes. Chronically sedentary individuals are at greatest risk of obesity and metabolic syndrome, a risk that growing research indicates may be exacerbated by excessive fructose intake (e.g., >50 g·d−1). The relevance of this evidence to athletes and others with high daily energy expenditures and energy intakes (e.g., workers and soldiers) is not well understood. Obesity and metabolic syndrome are rare among athletes, even though dietary fructose intake is often high, underscoring the robust protective role of regular exercise. Athletes should be advised to consume a nutrient-rich diet, high in total carbohydrate (e.g., 6-10 g·kg body weight·d−1 when total energy intake exceeds 2000 kcal·d−1). There is not yet enough athlete-specific research to recommend a limit on daily fructose intake, but the combination of existing data and common sense suggests that athletes should minimize their intake of foods and beverages high in simple sugars, relying instead on nutrient-rich whole foods to meet their daily energy needs.
This study was supported by funds from U.S. Public Health Service Grant HL-68607.
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