Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Physiological handling of dietary fructose-containing sugars: implications for health

Abstract

Fructose has always been present in our diet, but its consumption has increased markedly over the past 200 years. This is mainly due to consumption of sucrose or high-fructose corn syrup in industrial foods and beverages. Unlike glucose, fructose cannot be directly used as an energy source by all cells of the human body and needs first to be converted into glucose, lactate or fatty acids in the liver, intestine and kidney. Because of this specific two-step metabolism, some energy is consumed in splanchnic organs to convert fructose into other substrates, resulting in a lower net energy efficiency of fructose compared with glucose. A high intake of fructose-containing sugars is associated with body weight gain in large cohort studies, and fructose can certainly contribute to energy imbalance leading to obesity. Whether fructose-containing foods promote obesity more than other energy-dense foods remains controversial, however. A short-term (days–weeks) high-fructose intake is not associated with an increased fasting glycemia nor to an impaired insulin-mediated glucose transport in healthy subjects. It, however, increases hepatic glucose production, basal and postprandial blood triglyceride concentrations and intrahepatic fat content. Whether these metabolic alterations are early markers of metabolic dysfunction or merely adaptations to the specific two-step fructose metabolism remain unknown.

Introduction

There is increasing concern that fructose and fructose-containing sugars may have a role in obesity, diabetes, cardiovascular diseases and many other pathological conditions. The proposal that fructose-containing sugars are ‘toxic’ is often supported by reports that fructose is lipogenic, causes hyperlipidemia and alters glucose homeostasis.1, 2, 3 True enough, fructose consumed with flowers’ nectar, wild fruits and berries is instrumental in building up body fat reserves in migratory birds and hibernating animals.4, 5, 6 Yet, understanding the role and consequences of dietary fructose requires that it is placed in a physiological context. For this purpose, it may be useful to have a brief, schematic recall of animal nutritional physiology.

Nutritional physiology in eukaryotes

Energy release is an absolute requirement of living organisms, and metabolic pathways allowing the conversion and use the energy of molecules present in the environment have been instrumental in the development of life. Prokaryotes, the earlier forms of living organisms, developed when energy substrate and oxygen were scarce in the environment and rely on a variety of relatively simple metabolic pathways to use the few energy substrates that were available at the beginning of life on earth. This includes ‘anaerobic’ respiration using H2S as an electron donor, fermentative anaerobic metabolism and finally oxidative metabolism and respiration based on oxygen as an electron donor.7, 8 Eukaryotes, which cover a wide range of organisms (unicellular, plants and animals, including humans) developed later, when organic substrate and oxygen became widely available on earth and rely mainly on aerobic metabolic pathways (aerobic glycolysis, beta-oxidation, tricarboxylic acid cycle and mitochondrial respiratory chain), which remain largely conserved throughout evolution.9, 10

Glucose is certainly the key energy substrate for life. All eukaryote cells can metabolize glucose through glycolysis and the tricarboxylic acid cycle coupled with mitochondrial respiratory chain to synthesize adenosine triphosphate (ATP). Relying on ambient glucose was fine for aquatic unicellular organisms and plants but became a limiting factor for the development of larger animals. More particularly, the development of animals capable of moving themselves over long distances has come along with a need to store energy within their body. Given that storage of important quantities of starch would have resulted in undesirable increases in body weight, evolution has favored the storage of energy-dense fat. As a correlate to this evolutionary choice, all cells of most animals, including humans, can rely either on glucose or fatty acids as source of energy. However, most specialized cells rely on glucose and fat as their sole sources of energy but are not able to directly use the energy present in other nutrients. This limited choice of energy substrate allows them to put emphasis on the synthesis of the specific proteins required for their specialized function while sparing the synthesis of numerous enzymes, which would be required for the metabolism of all individual nutrients (Figure 1a).

Figure 1
figure1

Dietary starch and fat are precursors of the blood ‘primary substrates’ glucose and fatty acids, which can be directly used as an energy source by all cells of the organism (a). Fructose is a ‘subsidiary substrate' (such as galactose, most amino acids or alcohol), which need first to be processed into primary substrates in the splanchnic organs (b). GLU, glucose; LAC, lactate; NEFA, non-esterified fatty aids; TG, triglycerides.

In this perspective, we may refer to dietary glucose, starch and fat as ‘primary dietary substrates’. Lactic and acetic acids, as direct precursors of pyruvate and acetyl-CoA, can also be used directly by virtually all cell types but are not present to any great extent in animals’ diet. By contrast, other nutrients present in our diet (lets call them ‘subsidiary substrates’) cannot be used directly as energy sources (with the exception of some amino acids) in most cells of the organism. Instead, they are processed by specialized metabolic cells in the liver, gut and kidney, which express a comprehensive set of metabolic enzymes to process amino acids,11 fructose,12 galactose,13 alcohol14 and other rare substrates, and release their carbons as glucose, fatty acids, lactate or acetate in the blood stream (Figure 1b). This two-step metabolism in which subsidiary substrates are converted into primary substrates in splanchnic organs comes at some energy cost, however, and reduces their net energy yield.

Disposal of fructose in specialized metabolic cells

Although the fructose molecule is very similar to glucose, it is not readily phosphorylated by hexokinases. Fructose-metabolizing cells therefore instead convert fructolysis, which involves a ketohexokinase, fructokinase and aldolase B. Trioses-phosphate are the channel toward the synthesis and release of lactate, glucose and triglyceride-rich lipoprotein or toward intrahepatic glycogen and triglycerides. These metabolic pathways are not commonly active in most specialized cells outside the gut, liver, kidney tubules and some cells in the central nervous system. Fructose-metabolizing cells therefore express not only fructolytic enzymes but also other specialized metabolic enzymes and transporters required for lactate and glucose release into the blood, de novo lipogenesis and lipoprotein synthesis and secretion (Figure 2).

Figure 2
figure2

Fructose-metabolizing cells (hepatocytes, enterocytes, kidney tubular cells) express an extensive set of specific enzymes. In addition to enzymes involved in fructose conversion into trioses-phosphate (fructolysis), these cells also express enzymes responsible for fructose conversion into glucose (gluconeogenesis), release of glucose into the blood (glucose-6-phosphatase), de novo lipogenesis and secretion of triglyceride-rich lipid protein and glucose, fructose and lactate transporters. ACC, acetyl-CoA carboxylase; AldoB, aldolase B; DHAP, dihydroxyacetone-hosphate; FAS, fatty acid synthase; FK, fructokinase; GA, glyceraldehyde; GAP, glyceraldehyde-phosphate; GCK, glucokinase; MCT4, monocarboxylate transporter 4; TK, triokinase.

Place of fructose and sugars in the food chain

Glucose, fructose and sucrose are synthesized by photosynthesis in many plants and are direct precursors for complex carbohydrate. As such, they are present very early in the food chain (Figure 3). Most animals consume exclusively (herbivores) or non-exclusively (omnivores) vegetable foods, which may occasionally contain important amounts of fructose. It is therefore not surprising that they synthesize enzymes to metabolize this substrate. Interestingly, fructolytic enzymes show little interspecies differences.15 Furthermore, they are generally only expressed in specialized cells together with gluconeogenic and lipogenic enzymes. Exclusive carnivores rely mainly on dietary protein for their metabolism and can survive without dietary carbohydrate. They nonetheless express fructolytic enzymes and can tolerate small amounts of carbohydrate and sugars in their diet.16 They, however, do not synthesize glucokinase,17, 18 which has a central role in glucose sensing by the liver and pancreatic beta-cells, and therefore display large glycemic excursions when fed carbohydrates. The conservation of fructolysis during evolution attests of the importance of fructose as a subsidiary substrate in wild animals and suggests that it was also important for humans during some periods of human history.

Figure 3
figure3

Fructose and sucrose are present at the earliest step of the food chain. Herbivores and omnivorous animals express both sweet taste receptors (presumably triggering a pleasant feeling to indicate that it is a valuable source of energy) and fructose-metabolizing enzymes. Carnivores have lost sweet taste receptors but still express fructose-metabolizing enzymes and hence can use this substrate as a source of energy. AldoB, aldolase B; FK, fructokinase; GK, glucokinase; TR, taste receptor.

Complementary roles of sweet receptors and fructolytic enzymes in nutrition

Sensing of tastes, informing on foods’ properties, is present in most animals and involves receptors activated by specific nutrients. Humans detect five tastes through specific identified taste receptors expressed at the surface of taste buds’ cells on the tongue and on various cells throughout the body. There is increasing evidence for a ‘fat taste’, detected through activation of CD36 receptors.19 In a somewhat simplistic view, one may suppose that sweet, umami (responding to protein-rich foods) and fat tastes facilitate the consumption of energy-rich foods, while bitter (and possibly acid) taste prevents the consumption of toxic foods.20 Sugars, almost by definition, are substances that activate sweet taste receptors when in solution. There are large differences regarding the potency with which various sugars elicit a sweet taste sensation. Fructose and sucrose are characterized by a high sweetening power, whereas maltose, lactose and galactose are much weaker. Pure glucose’s sweetening power stands between fructose and lactose. Other disaccharides and small hexoses polymers such as maltodextrins elicit only a weak sweet sensation. Intense sweeteners are natural or synthetic compounds of various chemical structures, which all activate the same sweet receptors as natural sugars.21 Sweet taste receptors are present in many animal species and activate neural pathways associated with pleasant, (rewarding) feelings, thus reinforcing the liking of sugar-containing foods. They may also be involved in the fine tuning of metabolism by regulating gut hormone secretion or signaling the brain on food intake.22 Interestingly, sweet receptors are expressed in most animals with the exception of exclusive carnivores.23

Evolution of fructose consumption from prehistory to present times

Most human and animal diets have therefore always contained fructose and fructose-containing sugars consumed as a component of fruits, berries, vegetables and honey (with possible rare exceptions in places of the world where such products are not naturally available). In many areas, these foods are only available in relatively small quantities in the wild and at some specific times of the year. With the exception of honey, these foods degrade rapidly, and their consumption is likely to have shown important seasonal variations.

Fructose-containing sugars became really part of our every-day diet when it was recognized that sugar cane (and later sugar beets) contained exceptionally high amounts of sucrose, which could be extracted and stored as crystallized sugar. Sugar was initially available mainly in Asia and the Middle-East, but its consumption increased rapidly worldwide during the colonial period.24 Nowadays, production of fructose–glucose syrups from cereal starch (high-fructose corn syrup in North America, ‘isoglucose’ in the European Union) has also become a substantial source of fructose-containing sugars, mainly in North America.25 Sugar consumption per capita has progressively increased from a few percentage of total energy intake at the turn of the nineteenth century to 15–20% in the United States of America nowadays. Sugar-sweetened beverages, industrial breakfast cereals and sweets (chocolate bars, candies, ice cream and so on) account for a large portion of this high sugar consumption.26, 27, 28

Regulation of fructose metabolism in hepatocytes

Digestion of foods containing sucrose first necessitates the presence of a disaccharidase (sucrose-isomaltase, an alpha 1-4-glucosidase also able to hydrolyze the beta 1-2 glycosidic bond of sucrose) to release free glucose and fructose. Sodium-glucose-cotransporter 1 mediates the secondary active transport of glucose and GLUT5 the passive facilitated diffusion of fructose at the apical pole of enterocytes. Both glucose and fructose are then released into the portal vein by facilitated diffusion through GLUT2 located at the basolateral pole of enterocytes and enter liver cells through the same GLUT2 transporters expressed on hepatocytes. Once glucose and fructose have been transported inside the cell, fructolysis and glycolysis reactions bear much similarity. However, glycolysis is tightly regulated at several levels. First, hexokinases enzymes (with the exception of the hexokinase IV, or glucokinase, expressed in the liver and kidney tubular cells, enterocytes and pancreatic alpha- and beta-cells) are inhibited by increased concentrations of their product, glucose-6-phosphate. Second, phosphofructokinase is strongly inhibited by high cytosolic ATP and citrate concentrations, and therefore glucose utilization slows down when cells reach an energy level sufficient to meet their needs.29

In contrast, fructolytic enzymes are not regulated by ATP, citrate or other cytosolic markers of cells' energy status and are not inhibited by their products. As a consequence, nearly all of the dietary fructose absorbed into the portal circulation is taken up by hepatocytes and converted into trioses-phosphate. Hepatocytes are therefore ‘flooded’ by large amounts of trioses-phosphate and answer by activating trioses-phosphate disposal pathways, that is, lactic acid production; gluconeogenesis, glucose production and synthesis of hepatic glycogen; and de novo synthesis and secretion of triglycerides.29 In addition, the rapid phosphorylation of fructose to fructose-1- phosphate, if not matched by downstream ATP production from fructose-1-phosphate catabolism, can lead to a drop in hepatic ATP stores and a rise in hepatic inorganic phosphorus concentration; this may cause acute hepatic dysfunctions owing to hepatocytes’ energy deprivation, eventually resulting in hypoglycemia and increased uric acid production.30 In addition, fructose-1-phosphate indirectly stimulates glucokinase through the activation of a glucokinase-regulating protein, and this effect may contribute to the development of hypoglycemia by decreasing hepatic glucose production.31, 32 These effects are observed already with minute amounts of dietary fructose in patients with hereditary fructose intolerance (owing to a lack of functional aldolase B). They can also be elicited in healthy subjects with intravenous administrations of fructose and with very large oral fructose loads. There is, however, little evidence that this occurs with administration of physiological oral fructose loads.

It is generally considered that the major part of an ingested pure fructose load is metabolized in the liver and is mainly converted into glucose (ca 50% of ingested fructose), hepatic glycogen (ca 15–20%), lactic acid (15–25%) and triglycerides secreted with very low-density lipoproteins or temporarily stored as intrahepatic fat.33 The relative importance of these metabolic pathways cannot be accurately measured by isotopic methods and is therefore somewhat approximate. They have been mainly assessed after administration of pure fructose loads, and recent studies suggest that release of fructose carbons as glucose may be somewhat lower when fructose is co-ingested with glucose. The effect of glucose co-ingestion with fructose on hepatic de novo lipogenesis has not been accurately quantified, but qualitative estimates suggest that it is not drastically different than with pure fructose.34

Fructose metabolism in specialized cells outside the liver

Small bowel enterocytes and proximal renal tubule cells also express fructose-metabolizing enzymes, together with gluconeogenic and lipogenic enzymes and glucose and lactate transporters. Their relative contribution to fructose metabolism remains, however, speculative. Enterocytes metabolize an unspecified portion of absorbed fructose and contributes to the release of fructose carbons as glucose, lactate and chylomicrons-associated triglycerides in the blood. One may speculate that this may lower the intraenterocytic concentrations of fructose and therefore facilitate the GLUT5-mediated diffusion of fructose from the dietary lumen.35, 36, 37

Fructosemia increases considerably more after intravenous than oral fructose administration. In such conditions, the kidney accounts for 20–25% of total fructose uptake and converts it mainly into glucose and lactate.38 The contribution of renal tubule cells to the metabolism of an oral fructose load remains unknown. One may, however, speculate that the kidneys may be involved in the clearance of the small amount of fructose escaping first-pass splanchnic extraction.

Effects of short-term fructose overfeeding in healthy and overweight

Several clinical trials have assessed the metabolic effects associated with high-fructose consumption in humans. The duration of fructose administration varied from a few days to several months, and trials showed important differences in their experimental protocols. Some interventions consisted of adding pure fructose or fructose-containing sugars to an isocaloric, weight-maintenance diet, thus resulting in a positive energy balance; others substituted fructose or fructose-containing sugars for a portion of dietary starch and thus resulted in isocaloric, high-fructose intakes. Noteworthy, most of these studies have assessed the effects of pure fructose and thus provided useful information regarding specific fructose metabolism; however, as fructose is always consumed together with glucose in our foods (whether as sucrose or as free hexoses in fruits and high-fructose corn syrup), these studies may provide limited evidence regarding how dietary fructose is actually handled. Many metabolic or hemodynamic end points have been reported in the literature (for review, see Tappy and Le29), but we will focus here only on blood glucose and lipid homeostasis and on intrahepatic fat concentrations.

Effects on glucose homeostasis

It has been known for a long time that acute fructose administration increases less blood glucose and insulin responses than isocaloric amounts of glucose. This is particularly striking in patients with type 2 diabetes, in whom the average daily glycemia and glycated hemoglobin concentrations decrease when fructose replaces sucrose or starch.39

The effects of supplementing the diet of non-diabetic subjects with pure fructose on insulin sensitivity have led to somewhat contradictory results, possibly more related to differences in data interpretation rather than to divergent data. Most studies report that a high-fructose diet consumed for 4 days to 12 weeks does not significantly increase fasting blood glucose or insulin concentration. Some studies have documented that fasting hepatic glucose production was slightly, but significantly, increased by a high-fructose diet and that suppression of hepatic glucose production by insulin was significantly impaired.40, 41, 42 This is consistent with a decreased hepatic insulin sensitivity in subjects consuming fructose. Alterations of glucose production did not come close to those observed in subjects with type 2 diabetes mellitus, however. Several studies measured whole-body glucose utilization during high insulin infusion, and all but one failed to detect any significant decrease in insulin-mediated glucose disposal.43 This strongly supports the conclusion that a high-fructose diet does not cause significant resistance to insulin-mediated glucose transport even when consumed over several weeks.

Blood lipid concentrations

There is one point on which most studies agree, that is, that high intakes of fructose lead to significant increases in blood triglyceride concentrations, often associated with decreased high-density lipoprotein-cholesterol concentrations and/or increased total cholesterol concentrations.44, 45, 46 Many studies have assessed the effects of supplementing a fructose-free, weight-maintenance diet with extra energy as fructose and have reported either significant increases in fasting plasma triglyceride concentrations or significant increases in postprandial triglyceride concentrations or both. The mechanisms remain hypothetical but most likely involve both a stimulation of hepatic de novo lipogenesis and very low-density lipoprotein secretion and a lower postprandial activation of adipose tissue lipoprotein lipase secondary to low blood insulin concentration. Two recent studies have also assessed the effect of fructose incorporated in a weight-maintenance diet and reported that fasting and postprandial blood triglyceride were significantly increased and that hepatic fractional de novo lipogenesis was enhanced by fructose even in the absence of an excess energy intake.47, 48 Similar observations have been reported in subjects consuming weight-maintenance diets with various amounts of sucrose or high-fructose corn syrup.49

Intrahepatic fat concentrations

Several intervention studies reported that dietary fructose can increase intrahepatic fat concentrations.47, 50 In healthy, normal weight subjects, this effect was observed within 6–7 days of exposure to dietary fructose supplementations corresponding to ca 30% energy requirements. In contrast, no effects was observed with fructose supplementation corresponding to 15% energy requirements, even when fructose administration was pursued for 4 weeks.41 This effect could not be unequivocally attributed to fructose, however, as it was also observed with glucose or fat overfeeding.51 Furthermore, one study reported that consumption of a hyperenergetic diet containing 30% excess energy as either fructose or glucose significantly increased intrahepatic fat in normal subjects, while consumption of weight-maintenance diets in which 30% fructose or glucose were substituted for starch had no effect.52 These observations raise the possibility that intrahepatic fat accumulation may be due to excess energy intake rather than to specific effects of fructose.

What are the effects of dietary fructose on the human health?

Several cohort studies have assessed the relationship between consumption of added sugars, dietary fructose or sweetened beverages on various health outcomes. They generally reported that fructose-containing sugar consumption was strongly associated with body weight gain.53 It was also associated with the incidence of high blood pressure, dyslipidemia, gout and cardiovascular diseases,54, 55, 56, 57, 58, 59 but these associations became much weaker or disappeared when data were adjusted for body weight.60 In some studies, even the association with body weight gain was markedly decreased when sugar intake was adjusted for total energy.60, 61, 62 This suggests that fructose-containing sugars have a role in the development of obesity mainly by contributing to increased total energy intake. Of note, mere common sense may lead us to the same conclusion: given that added sugar makes up to 15–20% of total energy intake in populations with high prevalence of obesity, there is no doubt that sugar calories contribute to excess energy intake. Sugar is just one of several contributors, however, and epidemiological studies analyzing more globally the relationship between diet and obesity indeed reported that many other foods contributed to weight gain as well.

As mentioned earlier, a high-fructose intake decreases hepatic insulin sensitivity and increases fasting and postprandial blood triglycerides. It is tempting to speculate that fructose-induced decreased hepatic insulin sensitivity and hypertriglyceridemia may be early markers of metabolic and cardiovascular diseases. There is, however, no direct evidence that these effects of fructose increase with time. In fact, one study documented that hypertriglyceridemia and insulin resistance developed within 1 week of exposure to a hypercaloric high-fructose diet but did not further increase when exposure was extended to 4 weeks.41 In the same study, there was no evidence for a decrease in insulin-mediated glucose disposal, and no significant accumulation of intrahepatic fat between 1 week and 4 weeks of exposure to fructose. In addition, the reported effects of dietary fructose on blood triglycerides and hepatic insulin sensitivity were certainly significant in many studies but remain quantitatively modest: in healthy normal-weight subjects, blood triglyceride concentrations may almost double with a diet containing 30% energy as fructose, yet still remain within the normal physiological range.47, 48 One may therefore wonder whether the alterations of blood triglyceride and of hepatic glucose production may be physiological adaptations to a dietary nutrient that needs to be preprocessed into glucose and fat in the liver, rather than early markers of adverse metabolic effects.

At this stage, one may conclude that there are indeed reasons to suspect that fructose-containing sugars exert adverse health effects. The major risk associated with fructose is certainly due to its hedonic effects, which may contribute to excess energy intake. In contrast, there is little direct evidence that fructose-containing sugars would cause metabolic and cardiovascular diseases independently of obesity. A direct pathogenic role of fructose would be supported if fructose withdrawal fully corrected the metabolic alterations observed in obese, high-fructose consumers. Several intervention studies actually showed that a reduction of sweetened beverages consumption significantly decreased body weight gain and reduced blood markers of insulin resistance53, 63, 64 and intrahepatic fat concentrations.65 Its effects remained, however, modest, indicating that sugar reduction should be only one component of a multimodal lifestyle intervention.

Conclusions

Fructose is an energy substrate that has always been present in the human diet but the consumption of which has increased very drastically over the past two centuries. It may have a role in the development of obesity by contributing, together with other nutrients, to an overall excessive energy intake. A high-fructose intake also increases hepatic glucose production, very low-density lipoprotein triglyceride secretion,and intrahepatic fat concentrations, but whether this represents a long-term risk to health remains unknown.

References

  1. 1

    Lustig RH, Schmidt LA, Brindis CD . Public health: the toxic truth about sugar. Nature 2012; 482: 27–29.

    CAS  Article  Google Scholar 

  2. 2

    Taubes G . Treat obesity as physiology, not physics. Nature 2012; 492: 155.

    CAS  Article  Google Scholar 

  3. 3

    Stanhope KL . Sugar consumption, metabolic disease and obesity: the state of the controversy. Crit Rev Clin Lab Sci 2016; 53: 52–57.

    CAS  Article  Google Scholar 

  4. 4

    Hargrove JL . Adipose energy stores, physical work, and the metabolic syndrome: lessons from hummingbirds. Nutr J 2005; 4: 36.

    Article  Google Scholar 

  5. 5

    Suarez RK, Gass CL . Hummingbird foraging and the relation between bioenergetics and behaviour. Comp Biochem Physiol A Mol Integr Physiol 2002; 133: 335–343.

    Article  Google Scholar 

  6. 6

    Shimozuru M, Kamine A, Tsubota T . Changes in expression of hepatic genes involved in energy metabolism during hibernation in captive, adult, female Japanese black bears (Ursus thibetanus japonicus. Comp Biochem Physiol B Biochem Mol Biol 2012; 163: 254–261.

    CAS  Article  Google Scholar 

  7. 7

    Verkhovtseva NV, Filina N, Pukhov DE . [Evolutionary role of iron in metabolism of prokaryotes and biogeochemical processes]. Zh Evol Biokhim Fiziol 2001; 37: 338–343.

    CAS  PubMed  Google Scholar 

  8. 8

    Hansen TA . Metabolism of sulfate-reducing prokaryotes. Antonie Van Leeuwenhoek 1994; 66: 165–185.

    CAS  Article  Google Scholar 

  9. 9

    Hochachka PW . Cross-species studies of glycolytic function. Adv Exp Med Biol 1999; 474: 219–229.

    CAS  Article  Google Scholar 

  10. 10

    Hochachka PW, Rupert JL, Monge C . Adaptation and conservation of physiological systems in the evolution of human hypoxia tolerance. Comp Biochem Physiol A Mol Integr Physiol 1999; 124: 1–17.

    CAS  Article  Google Scholar 

  11. 11

    Jungas RL, Halperin ML, Brosnan JT . Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans. Physiol Rev 1992; 72: 419–448.

    CAS  Article  Google Scholar 

  12. 12

    Mayes PA . Intermediary metabolism of fructose. Am J Clin Nutr 1993; 58: 754S–765S.

    CAS  Article  Google Scholar 

  13. 13

    Williams CA, Macdonald I . Metabolic effects of dietary galactose. World Rev Nutr Diet 1982; 39: 23–52.

    CAS  Article  Google Scholar 

  14. 14

    Mascord D, Smith J, Starmer GA, Whitfield JB . Effects of increasing the rate of alcohol metabolism on plasma acetate concentration. Alcohol Alcohol 1992; 27: 25–28.

    CAS  PubMed  Google Scholar 

  15. 15

    Heinz F, Weiner F . Enzymes of fructose metabolism in the liver of some vertebrates. Comp Biochem Physiol 1969; 31: 283–296.

    CAS  Article  Google Scholar 

  16. 16

    Springer N, Lindbloom-Hawley S, Schermerhorn T . Tissue expression of ketohexokinase in cats. Res Vet Sci 2009; 87: 115–117.

    CAS  Article  Google Scholar 

  17. 17

    Schermerhorn T . Normal glucose metabolism in carnivores overlaps with diabetes pathology in non-carnivores. Front Endocrinol (Lausanne) 2013; 4: 188.

    Article  Google Scholar 

  18. 18

    Tanaka A, Inoue A, Takeguchi A, Washizu T, Bonkobara M, Arai T . Comparison of expression of glucokinase gene and activities of enzymes related to glucose metabolism in livers between dog and cat. Vet Res Commun 2005; 29: 477–485.

    CAS  Article  Google Scholar 

  19. 19

    Gilbertson TA, Khan NA . Cell signaling mechanisms of oro-gustatory detection of dietary fat: advances and challenges. Prog Lipid Res 2014; 53: 82–92.

    CAS  Article  Google Scholar 

  20. 20

    Reed DR, Knaapila A . Genetics of taste and smell: poisons and pleasures. Prog Mol Biol Transl Sci 2010; 94: 213–240.

    CAS  Article  Google Scholar 

  21. 21

    Bellisle F, Drewnowski A, Anderson GH, Westerterp-Plantenga M, Martin CK . Sweetness, satiation, and satiety. J Nutr 2012; 142: 1149S–1154S.

    CAS  Article  Google Scholar 

  22. 22

    Laffitte A, Neiers F, Briand L . Functional roles of the sweet taste receptor in oral and extraoral tissues. Curr Opin Clin Nutr Metab Care 2014; 17: 379–385.

    CAS  Article  Google Scholar 

  23. 23

    Jiang P, Josue J, Li X, Glaser D, Li W, Brand JG et al. Major taste loss in carnivorous mammals. Proc Natl Acad Sci USA 2012; 109: 4956–4961.

    CAS  Article  Google Scholar 

  24. 24

    Mintz SN Sweetness and Power: The Place of Sugar in Modern History. Penguin Books: London, UK, 1985.

  25. 25

    White JS . Straight talk about high-fructose corn syrup: what it is and what it ain't. Am J Clin Nutr 2008; 88: 1716S–1721S.

    CAS  Article  Google Scholar 

  26. 26

    Marriott BP, Cole N, Lee E . National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr 2009; 139: 1228S–1235S.

    CAS  Article  Google Scholar 

  27. 27

    Langlois K, Garriguet D. Sugar Consumption Among Canadians of all Ages. Health Reports/Statistics Canada, Canadian Centre for Health Information=Rapports sur la Sante/Statistique Canada, vol. 22. Centre Canadien d'Information sur la Sante. Health Reports, 2011, pp 23–27.

  28. 28

    Sun SZ, Anderson GH, Flickinger BD, Williamson-Hughes PS, Empie MW . Fructose and non-fructose sugar intakes in the US population and their associations with indicators of metabolic syndrome. Food Chem Toxicol 2011; 49: 2875–2882.

    CAS  Article  Google Scholar 

  29. 29

    Tappy L, Le KA . Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 2010; 90: 23–46.

    CAS  Article  Google Scholar 

  30. 30

    Van den Berghe G . Metabolic effects of fructose in the liver. Curr Top Cell Regul 1978; 13: 97–135.

    CAS  Article  Google Scholar 

  31. 31

    Malaisse WJ, Malaisse-Lagae F, Davies DR, Vandercammen A, Van Schaftingen E . Regulation of glucokinase by a fructose-1-phosphate-sensitive protein in pancreatic islets. Eur J Biochem 1990; 190: 539–545.

    CAS  Article  Google Scholar 

  32. 32

    Watford M . Small amounts of dietary fructose dramatically increase hepatic glucose uptake through a novel mechanism of glucokinase activation. Nutr Rev 2002; 60: 253–257.

    Article  Google Scholar 

  33. 33

    Sun SZ, Empie MW . Fructose metabolism in humans - what isotopic tracer studies tell us. Nutr Metab 2012; 9: 89.

    Article  Google Scholar 

  34. 34

    Theytaz F, de Giorgi S, Hodson L, Stefanoni N, Rey V, Schneiter P et al. Metabolic fate of fructose ingested with and without glucose in a mixed meal. Nutrients 2014; 6: 2632–2649.

    CAS  Article  Google Scholar 

  35. 35

    Grand RJ, Schay MI, Jaksina S . Development and control of intestinal and hepatic fructokinase. Pediatr Res 1974; 8: 765–770.

    CAS  PubMed  Google Scholar 

  36. 36

    Korieh A, Crouzoulon G . Dietary regulation of fructose metabolism in the intestine and in the liver of the rat. Duration of the effects of a high fructose diet after the return to the standard diet. Arch Int Physiol Biochim Biophys 1991; 99: 455–460.

    CAS  PubMed  Google Scholar 

  37. 37

    Bjorkman O, Crump M, Phillips RW . Intestinal metabolism of orally administered glucose and fructose in Yucatan miniature swine. J Nutr 1984; 114: 1413–1420.

    CAS  Article  Google Scholar 

  38. 38

    Bjorkman O, Gunnarsson R, Hagstrom E, Felig P, Wahren J . Splanchnic and renal exchange of infused fructose in insulin-deficient type 1 diabetic patients and healthy controls. J Clin Invest 1989; 83: 52–59.

    CAS  Article  Google Scholar 

  39. 39

    Cozma AI, Sievenpiper JL, de Souza RJ, Chiavaroli L, Ha V, Wang DD et al. Effect of fructose on glycemic control in diabetes: a systematic review and meta-analysis of controlled feeding trials. Diabetes Care 2012; 35: 1611–1620.

    CAS  Article  Google Scholar 

  40. 40

    Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L . Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes 2005; 54: 1907–1913.

    CAS  Article  Google Scholar 

  41. 41

    Le KA, Faeh D, Stettler R, Ith M, Kreis R, Vermathen P 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.

    CAS  Article  Google Scholar 

  42. 42

    Aeberli I, Hochuli M, Gerber PA, Sze L, Murer SB, Tappy L et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care 2013; 36: 150–156.

    CAS  Article  Google Scholar 

  43. 43

    Tappy L, Le KA . Health effects of fructose and fructose-containing caloric sweeteners: where do we stand 10 years after the initial whistle blowings? Curr Diab Rep 2015; 15: 627.

    Article  Google Scholar 

  44. 44

    David Wang D, Sievenpiper JL, de Souza RJ, Cozma AI, Chiavaroli L, Ha V et al. Effect of fructose on postprandial triglycerides: a systematic review and meta-analysis of controlled feeding trials. Atherosclerosis 2014; 232: 125–133.

    CAS  Article  Google Scholar 

  45. 45

    Sievenpiper JL, Carleton AJ, Chatha S, Jiang HY, de Souza RJ, Beyene J et al. Heterogeneous effects of fructose on blood lipids in individuals with type 2 diabetes: systematic review and meta-analysis of experimental trials in humans. Diabetes Care 2009; 32: 1930–1937.

    CAS  Article  Google Scholar 

  46. 46

    Zhang YH, An T, Zhang RC, Zhou Q, Huang Y, Zhang J . Very high fructose intake increases serum LDL-cholesterol and total cholesterol: a meta-analysis of controlled feeding trials. J Nutr 2013; 143: 1391–1398.

    CAS  Article  Google Scholar 

  47. 47

    Schwarz JM, Noworolski SM, Wen MJ, Dyachenko A, Bergeron N, Bersot TP et al. Effect of a high-fructose weight-maintaining diet on lipogenesis and liver fat. J Clin Endocrinol Metab 2015; 100: 2434–2442.

    CAS  Article  Google Scholar 

  48. 48

    Egli L, Lecoultre V, Theytaz F, Campos V, Hodson L, Schneiter P et al. Exercise prevents fructose-induced hypertriglyceridemia in healthy young subjects. Diabetes 2013; 62: 2259–2265.

    CAS  Article  Google Scholar 

  49. 49

    Lowndes J, Sinnett S, Yu Z, Rippe J . The effects of fructose-containing sugars on weight, body composition and cardiometabolic risk factors when consumed at up to the 90th percentile population consumption level for fructose. Nutrients 2014; 6: 3153–3168.

    Article  Google Scholar 

  50. 50

    Lecoultre V, Egli L, Carrel G, Theytaz F, Kreis R, Schneiter P et al. Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans. Obesity 2013; 21: 782–785.

    CAS  Article  Google Scholar 

  51. 51

    Sobrecases H, Le KA, Bortolotti M, Schneiter P, Ith M, Kreis R et al. Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men. Diabetes Metab 2010; 36: 244–246.

    CAS  Article  Google Scholar 

  52. 52

    Johnston RD, Stephenson MC, Crossland H, Cordon SM, Palcidi E, Cox EF et al. No difference between high-fructose and high-glucose diets on liver triacylglycerol or biochemistry in healthy overweight men. Gastroenterology 2013; 145: 1016–1025; e1012.

    CAS  Article  Google Scholar 

  53. 53

    Te Morenga L, Mallard S, Mann J . Dietary sugars and body weight: systematic review and meta-analyses of randomised controlled trials and cohort studies. Br Med J 2013; 346: e7492.

    Article  Google Scholar 

  54. 54

    Yang Q, Zhang Z, Gregg EW, Flanders WD, Merritt R, Hu FB . Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern Med 2014; 174: 516–524.

    CAS  Article  Google Scholar 

  55. 55

    Jayalath VH, Sievenpiper JL, de Souza RJ, Ha V, Mirrahimi A, Santaren ID et al. Total fructose intake and risk of hypertension: a systematic review and meta-analysis of prospective cohorts. J Am Coll Nutr 2014; 33: 328–339.

    Article  Google Scholar 

  56. 56

    Hu FB, Malik VS . Sugar-sweetened beverages and risk of obesity and type 2 diabetes: epidemiologic evidence. Physiol Behav 2010; 100: 47–54.

    CAS  Article  Google Scholar 

  57. 57

    Choi HK, Willett W, Curhan G . Fructose-rich beverages and risk of gout in women. JAMA 2010; 304: 2270–2278.

    CAS  Article  Google Scholar 

  58. 58

    Choi HK, Curhan G . Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. Br Med J 2008; 336: 309–312.

    Article  Google Scholar 

  59. 59

    Montonen J, Jarvinen R, Knekt P, Heliovaara M, Reunanen A . Consumption of sweetened beverages and intakes of fructose and glucose predict type 2 diabetes occurrence. J Nutr 2007; 137: 1447–1454.

    CAS  Article  Google Scholar 

  60. 60

    Blum JW, Jacobsen DJ, Donnelly JE . Beverage consumption patterns in elementary school aged children across a two-year period. J Am Coll Nutr 2005; 24: 93–98.

    Article  Google Scholar 

  61. 61

    Rodriguez-Artalejo F, Garcia EL, Gorgojo L, Garces C, Royo MA, Martin Moreno JM et al. Consumption of bakery products, sweetened soft drinks and yogurt among children aged 6-7 years: association with nutrient intake and overall diet quality. Br J Nutr 2003; 89: 419–429.

    CAS  Article  Google Scholar 

  62. 62

    Kvaavik E, Andersen LF, Klepp KI . The stability of soft drinks intake from adolescence to adult age and the association between long-term consumption of soft drinks and lifestyle factors and body weight. Public Health Nutr 2005; 8: 149–157.

    Article  Google Scholar 

  63. 63

    Ebbeling CB, Feldman HA, Chomitz VR, Antonelli TA, Gortmaker SL, Osganian SK et al. A randomized trial of sugar-sweetened beverages and adolescent body weight. N Engl J Med 2012; 367: 1407–1416.

    CAS  Article  Google Scholar 

  64. 64

    de Ruyter JC, Olthof MR, Seidell JC, Katan MB . A trial of sugar-free or sugar-sweetened beverages and body weight in children. N Engl J Med 2012; 367: 1397–1406.

    CAS  Article  Google Scholar 

  65. 65

    Campos VC, Despland C, Brandejsky V, Kreis R, Schneiter Ph, Chioléro A et al. Sugar- and artificially sweetened beverages and intrahepatic fat: a randomized controlled trial. Obesity 2015; 23: 2335–2339.

    CAS  Article  Google Scholar 

Download references

Acknowledgements

This article is based on a symposium entitled ‘Sweeteners and Health: Findings from Recent Research and their Impact on Obesity and Related Metabolic Conditions’ presented at the European Congress on Obesity on 7 May 2015 with sponsorship from Rippe Lifestyle Institute. The work reported in this review has been supported by the Swiss National Science Foundation grant to Luc Tappy (Numbers 32003B_156167 and 320030_138428).

Author information

Affiliations

Authors

Corresponding author

Correspondence to L Tappy.

Ethics declarations

Competing interests

LT has received lecture fees from Rippe Lifestyle Institute, Nestlé SA and Soremartec. He has also received grant support from Swiss National Foundation for Science and Federal Office for Sport BASPO, Switzerland and serves as an expert witness for the French food security agency ANSES. The VC declares no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Campos, V., Tappy, L. Physiological handling of dietary fructose-containing sugars: implications for health. Int J Obes 40, S6–S11 (2016). https://doi.org/10.1038/ijo.2016.8

Download citation

Further reading

Search

Quick links