Sucrose, High-Fructose Corn Syrup, and Fructose, Their Metabolism and Potential Health Effects: What Do We Really Know?

Both controversy and confusion exist concerning fructose, sucrose, and high-fructose corn syrup (HFCS) with respect to their metabolism and health effects. These concerns have often been fueled by speculation based on limited data or animal studies. In retrospect, recent controversies arose when a scientific commentary was published suggesting a possible unique link between HFCS consumption and obesity. Since then, a broad scientific consensus has emerged that there are no metabolic or endocrine response differences between HFCS and sucrose related to obesity or any other adverse health outcome. This equivalence is not surprising given that both of these sugars contain approximately equal amounts of fructose and glucose, contain the same number of calories, possess the same level of sweetness, and are absorbed identically through the gastrointestinal tract. Research comparing pure fructose with pure glucose, although interesting from a scientific point of view, has limited application to human nutrition given that neither is consumed to an appreciable degree in isolation in the human diet. Whether there is a link between fructose, HFCS, or sucrose and increased risk of heart disease, metabolic syndrome, or fatty infiltration of the liver or muscle remains in dispute with different studies using different methodologies arriving at different conclusions. Further randomized clinical trials are needed to resolve many of these issues. The purpose of this review is to summarize current knowledge about the metabolism, endocrine responses, and potential health effects of sucrose, HFCS, and fructose. Adv. Nutr. 4: 236–245, 2013. Introduction Over the past decade, considerable scientific debate and controversy have arisen concerning the metabolism, endocrine response, and potential health effects of sucrose, high-fructose corn syrup (HFCS), and fructose (1–17). Although an enormous body of scientific literature has been available on all 3 of these sugars for many years (18– 23), in retrospect, the recent controversy seems to have started with the publication of a commentary in the American Journal of Clinical Nutrition (AJCN) in 2004 (3), suggesting that HFCS in beverages might play a unique role in the epidemic of obesity currently being experienced in the United States and many other countries. Although the authors of this commentary clearly stated that they were only describing a temporal association and not a causeand-effect relationship, a heated debate concerning the metabolism and potential health effects of sucrose, HFCS, and fructose subsequently ensued. This debate has involved not only the scientific community but also major media outlets, the public at large, and policymakers. Controversies concerning these 3 sugars have been fueled by conditions that, in our view, created a “perfect storm” for confusion and mistaken identity. Even though the original authors of the AJCN commentary were clear that they were simply offering a hypothesis, other investigators, food manufacturers, and the public at large have contributed to this controversy, often without distinguishing between an association and cause and effect, while frequently confusing the sugars used in research studies, or exaggerating the implications of animal work. In addition, several other factors appear to have contributed to the ongoing controversy about these 3 sugars. The historic choice of the name “high-fructose” corn syrup certainly 1 Presented at the symposium “Fructose, Sucrose and High-Fructose Corn Syrup. Modern Scientific Findings and Health Implications,” held April 22, 2012, at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2012 in San Diego, CA. The symposium was sponsored by the American Society for Nutrition and supported in part by an educational grant from the Corn Refiners Association. A summary of the symposium “Fructose, Sucrose and High-Fructose Corn Syrup. Modern Scientific Findings and Health Implications” was published in the September 2012 issue of Advances in Nutrition. 2 Author disclosures: J. M. Rippe, consulting fees from ConAgra Foods, PepsiCo International, Kraft Foods, the Corn Refiners Association, and Weight Watchers International. T. J. Angelopoulos, no conflicts of interest. * To whom correspondence should be addressed. E-mail: [email protected]. 236 ã2013 American Society for Nutrition. Adv. Nutr. 4: 236–245, 2013; doi:10.3945/an.112.002824. by gest on M arch 4, 2013 advannutrition.org D ow nladed fom contributed to the confusion, even though HFCS contains virtually the same amount of fructose as sucrose. Furthermore, over the past decade, a number of researchers reported results based on experiments comparing metabolic and health effects of pure fructose with those of pure glucose, which brought other issues into the debate (13,17). Not surprisingly, the public and media have found it difficult to distinguish between studies conducted with pure fructose versus pure glucose, neither of which is commonly consumed in the human diet and the more commonly consumed HFCS and sucrose, which contain both fructose and glucose. Finally, because the United States and many other countries are in the midst of an obesity epidemic, further impetus was added to these discussions because the premise of limiting consumption of added sugars seemed to many an attractive option for potentially affecting the increasing prevalence of obesity. With all of this as background, the purpose of the current review is to discuss the metabolism and the endocrine responses to consumption of sucrose, HFCS, and fructose. We also attempt to elucidate the strengths and weaknesses of the evidence supporting the putative link between the consumption of these sugars and potential adverse health consequences. We then discuss results of recent randomized, controlled trials using various levels of fructose, HFCS, and sucrose. We address these issues by asking and attempting to answer a series of questions related to the metabolism, endocrine responses, and health effects of these 3 sugars. Current status of knowledge Is there a unique link between HFCS and obesity? In their commentary in AJCN in 2004, Bray et al. (3) argued that increased use of HFCS in the United States mirrored the rapid increase in obesity. Data to support this hypothesized connection were presented in graphic form, as illustrated in Figure 1. These authors argued that the digestion, absorption, and metabolism of fructose compared with glucose differed in ways that promoted the likelihood of increased energy consumption, resulting in an increased likelihood of obesity and diabetes, metabolic syndrome, and cardiovascular disease (3,24–29). In retrospect, the argument that HFCS is uniquely linked to obesity failed to take into consideration a number of important issues. Although consumption of HFCS in the United States dramatically increased from the early 1970s when it first came into use until about 1999, over the past decade the consumption of HFCS has decreased (30), whereas obesity has increased or remained at the same levels in most population groups (31). Moreover, as HFCS consumption increased in the United States, there was a commensurate, dramatic decrease in the amount of sucrose consumed (30). Although total caloric sweetener consumption in the United States has increased since 1970, sucrose remains the leading added sugar consumed in the American diet and the leading source of fructose (32). According to the USDA’s Economic Research Service, between 1970 and 2005, sugars and sweeteners available for consumption increased 76 kcal/d per person from 400 kcal to 476 kcal (33). Furthermore, worldwide consumption of sucrose is 9 times as much as HFCS, and there are epidemics of obesity and diabetes in areas where little or no HFCS is available (e.g., Mexico, Australia, and Europe). Research studies since the 2004 AJCN article have also refuted the idea that HFCS is metabolically different from sucrose (15,34–36). Studies published from our research group demonstrated that acute responses to HFCS and sucrose are virtually identical with regard to glucose, insulin, leptin, ghrelin, and appetite in both normal weight (34) and obese (37) women. Studies by Stanhope et al. (36) showed findings similar to those that we reported in both men and women and also demonstrated no difference in postprandial triglycerides after consumption of either HFCS or sucrose at 25% of energy (36). Studies by Soenen and Westerterp-Plantenga (35) showed no differences in satiety or energy intake after HFCS, sucrose, or milk preloads. These studies and other scientific literature persuaded the American Medical Association (8) and the Academy of Figure 1 Temporal association between increased consumption of high-fructose corn syrup (HFCS) and prevalence of obesity. Adapted from (3) with permission. Figure 2 Metabolism of fructose and glucose in the liver. Reproduced from (41) with permission. Sucrose, HFCS, fructose: what do we really know? 237 by gest on M arch 4, 2013 advannutrition.org D ow nladed fom Nutrition and Dietetics (9) to issue statements indicating that there were no differences between HFCS and sucrose in their likelihood of causing obesity. In addition, the ASN recently released a consensus statement on energy balance noting its complexity and arguing specifically against isolation of 1 component of the diet as uniquely responsible for weight gain and obesity (38). Perhaps the prevailing scientific consensus relating to the metabolic equivalence of HFCS and sucrose was best summarized by G. Harvey Anderson (39) when he wrote: The hypothesis that the replacement of sucrose by HFCS in beverages plays a positive role in obesity is not supported on the basis of its composition, biologic actions, or short-term effects on food intake. Had the hypothesis been phrased in the converse, namely that replacing HFCS with sucrose in beverages would be seen as a solution to the obesity epidemic, its merit would have been seen more clearly. Put simply, a proposal that a return to sucrose containing beverages would be a credible solution to the obesity epidemic would have been met with outright dismissal. Although this debate has largely been resolved within the scientific community, multiple articles in the lay press and Internet postings still maintain that HFCS is somehow uniquely linked to obesity. Furthermore, a number of food and beverage manufacturers have touted removal of HFCS from their products as though it somehow makes these products “healthier.” These examples serve as a reminder that scientific debate on issues that the public cares about does not take place in a vacuum and that misperceptions may linger long after the scientific debate has largely been resolved. Is research comparing fructose with glucose relevant to human nutrition? Several studies have compared the metabolism, endocrine response, and health effects of pure fructose with those of pure glucose. Often these studies have compared amounts of either fructose or glucose delivered as 25% of energy as components of mixed nutrient diets (13,17,40). The theoretical justification for such research trials rests on the well-established difference in hepatic metabolism of fructose and glucose in the liver. The routes of hepatic metabolism of fructose and glucose are depicted in Figure 2 (41). Fructose metabolism differs from that of glucose in 2 major ways (41,42). First, there is nearly complete hepatic extraction of fructose. Second, as illustrated in Figure 2, there are different enzymatic reactions in the initial steps of the metabolism of fructose and glucose. These differences in hepatic metabolism could theoretically lead to a variety of different shortand long-term effects of fructose compared with glucose. Teff et al. (17) reported that when either fructose or glucose were consumed as 25% of energy, glucose caused higher spikes in blood glucose and insulin as well as greater increases in leptin and more suppression of ghrelin levels than did fructose. However, when these conditions were repeated in our research laboratory comparing 30% of energy from HFCS versus sucrose, all of these differences disappeared (Fig. 3) (15). Our findings were subsequently confirmed by Stanhope et al. (36) and extended to men (Fig. 4). Stanhope et al. (36) reported that consuming fructosesweetened, .but not glucose-sweetened beverages at the same levels of energy consumption (25% of energy), increased visceral adiposity and lipids, and decreased insulin sensitivity in overweight or obese individuals. Initial research in our laboratory did not support these findings (43). Subsequent research in our laboratory involving 352 overweight or obese individuals who consumed either HFCS or sucrose at levels up to the 90th percentile population consumption level for fructose (30% of energy from either HFCS or sucrose) did not show any changes in either systolic or diastolic blood pressure or glucose. HDL cholesterol decreased by <1 mg/dL and triglycerides increased 10% (104.1 6 51.8 mg/dL to 114.1 6 67.4 mg/dL) (P < 0.05) (unpublished observations). Recent research reviews by Dolan et al. (44,45) reported that no adverse effect on triglycerides or weight was observed in multiple trials using fructose at up to the 95th percentile population consumption level. Meta-analyses by Ha et al. (46) also documented that no increases in blood pressure or propensity toward obesity occurred at up to the 90th percentile population consumption levels of fructose (47). It should be emphasized that these meta-analyses included only studies exploring consumption of fructose in isolation. Stanhope et al. (36) also did not find increases in blood pressure when obese individuals consumed as much as 25% of energy as either fructose or glucose. It should be noted that fructose and glucose are rarely consumed in isolation in the human diet. Thus, studies comparing pure fructose with pure glucose, particularly at high levels, should be treated with caution, particularly because studies comparing the more commonly consumed sucrose and HFCS have yielded different results. Does fructose, HFCS, or sucrose consumption increase the risk of heart disease? With the recognition that fructose versus glucose experiments do not reflect typical human nutrition, increased scrutiny has been focused on the fructose moiety of both HFCS and sucrose. Sucrose is composed of 50% glucose and 50% fructose, whereas the forms of HFCS used in most foods and beverages are typically composed of 55% fructose and 45% glucose (this is the common form used in beverages) or 42% fructose and 58% glucose (the form commonly used in baked goods and other food applications) (48). Because soft drinks are a major source of added sugar consumption in the American diet, a number of studies have explored soft-drink consumption and its potential association with a variety of metabolic and health issues. Cross-sectional studies in humans have linked soft-drink consumption with less optimum nutrition, greater body weight, and higher energy intake (49,50). It has also been suggested that excessive fructose consumption from added 238 Rippe and Angelopoulos by gest on M arch 4, 2013 advannutrition.org D ow nladed fom