Present in fruits and vegetables, fructose has long been considered a 'healthy' sugar. But its use in many processed foods leads to excessive consumption in connection with many pathologies (obesity, fatty liver steatosis, diabetes, cardiovascular diseases ...).
Fructose is a substance that is an important part of our current diet, especially that from the food industry (sweet drinks, pastries, etc.). This article presents a state of knowledge relating to the effects of fructose on human metabolism. After showing how fructose has a different metabolism from glucose and specifying the interest of its use in the medical field (diabetes) or sports, he explains its long-term effects and its involvement in metabolic diseases.
The consumption of fructose today is the subject of controversy regarding its effects on health. This sugar is found in raw foods, such as fruits (7 g of fructose in 100 g of apple, source) or honey (39 g of fructose and 31 g of glucose in 100 g of honey), their by-products such as juices, jams or syrups, but also in the form of additions in processed food products. The fructose consumed, therefore, comes from free fructose (fruit, honey), sucrose (after hydrolysis into glucose and fructose) or even glucose-fructose syrups.
1. Why use fructose?
Fructose has a relative sweetness of about 1.3. It is higher than that of sucrose, which makes up powdered or cubed sugar, and which corresponds to the standard of 1. Glucose, on the other hand, has a lower sweetening power of 0.7. Fructose is therefore considered an “intense sweetener” and is widely used in the manufacture of sodas since its sweetening power is highest when it is in acid solution and at low temperatures.
Fructose is also used in industrial food preparations for its Physico-chemical properties. It gives color and aroma, contributes to the texture of sweet foods (crispy biscuits, aeration of cake batters, diversity of texture in confectionery), increases the shelf life of jams, serves as a support for the crystallization of cocoa butter from chocolate, lowers the freezing point of water (making ice cream and sorbets), promotes yeast fermentation in bakery, etc.
The food industry mainly uses glucose-fructose syrups to provide specific properties to food (maintenance of hydration, inhibition of microbial development, browning during cooking, etc.), which depend on the relative contents of fructose and glucose...
These syrups or HFCS (high fructose corn syrup) were developed in the United States in the 1960s. Starch extracted from corn is hydrolyzed into glucose by α-amylase, which cuts the starch chains into oligosaccharides, and glucoamylase, which cuts these small chains into glucose molecules. Then glucose isomerase converts some of this glucose into fructose.
In the United States, the fructose contents of HFCS are 42% (HFCS 42) or 55% (HFCS 55). In France, the majority of glucose-fructose syrups contain between 20 and 30% fructose.
2. Fructose consumption
It was honey, which was first used as a sweetener. Sugar cane was known since prehistoric times in Asia and then travelled with humans, especially to the West Indies and South America, in the fifteenth century, when sugar became a colonial commodity at the origin of triangular trade. From the nineteenth century, the cultivation of sugar beet developed in Europe and industrialization allowed refined sugar to become a popular product.
Initially used to sweeten beverages (coffee and tea), this sugar was introduced into culinary preparations and its consumption increased considerably (by 1,500% in England between the eighteenth and nineteenth centuries). In the United States, it was 90 g per day per person in 1970. Sucrose consumption began to decline in the 1970s, as HFCS consumption increased. In the United States, the consumption of HFCS in 2004 was about 20 kg per person per year, like sucrose.
In France, the average fructose intake per person is estimated at 42 g per day. Since there are no specific data on simple carbohydrates added to the diet (half of the total intake of simple carbohydrates), this fructose intake is estimated from the average sugar intake.
Estimating fructose consumption
From an average consumption of simple carbohydrates of 100 g per day, in adults, from which 10 g of lactose is deducted, it is considered that 50% of sugar, or 45 g, is naturally present in food and 50%, or 45 g also, corresponds to added sugars. The naturally occurring sugar is estimated to contain 50% fructose or 22 g. 80% of the added sugar is sucrose, half of which is fructose, or 18 g, and 20% glucose-fructose syrup, 20% of which is fructose, or 2 g. The total fructose ingested per day is therefore estimated at 22 g + 18 g + 2 g or 42 g per day.
Fructose consumption is divided into 22 g present in fruits and honey, 18 g from sucrose and 2 g from glucose-fructose syrups added industrially to food. In the largest consumers of simple carbohydrates, fructose consumption is estimated at 77 g per day.
3. The specific treatment of fructose by the body
3.1. Two different hexoses
Fructose and glucose are two isomers: these molecules have the same crude formula, C6H12O6, but have different spatial configurations. Fructose differs from glucose by the presence of a ketone function (R-CO-R) in position 2, instead of an aldehyde function (R-CO-H) in position 1, of the carbon chain.
3.2. Specific fructose metabolism
3.2.1. At the intestinal level
Fructose present in the intestine, regardless of its food origin, is absorbed through a different process than glucose which, unlike the latter, does not involve hydrolysis of ATP and is independent of sodium absorption.
Fructose is transported into the enterocyte by facilitated diffusion through the apical membrane, thanks to a specific fructose transporter, GLUT5. Once in the enterocyte, fructose passes through facilitated diffusion to the blood capillaries thanks to another transporter, GLUT2. This one, located at the basal pole of the enterocyte, has a lower affinity for fructose than GLUT5 and is also able to support glucose.
Compared to glucose, the intestinal absorption of fructose appears relatively limited and is influenced by many factors. In particular, there are individual variations (people who absorb low fructose are prone to diarrhea and flatulence), variations related to age (decrease in this absorption with ageing), or to the environment (in rats, the synthesis of GLUT5, low before weaning, can be increased by absorption of fructose; in addition, a diet rich in saturated fatty acids increases the absorption of fructose).
Once in the enterocyte, fructose is partly converted into lactate which passes into the portal blood. This conversion represents 12% of the fructose absorbed, compared to 2% of the glucose absorbed.
3.2.2. At the hepatic level
After its absorption by the intestine, the fructose present in the portal blood is entirely taken by the liver in a single pass. It is then quickly converted into fructose-1P thanks to a specific fructose enzyme, fructokinase.
People deficient in this enzyme have fructose in the urine (fruituria), indicating that no organ other than the liver is significantly involved in fructose metabolism. After ingestion of fructose, there is only a very small increase in its concentration in the general circulation (a few micromoles per liter). Although tissues other than the liver, such as kidney and adipose tissue, have GLUT5 transporters (whose role in these cell types is not known), no tissue other than the liver expresses the enzyme fructokinase.
If fructose and glucose enter the hepatocyte through the same GLUT2 transporters, the rest of their metabolism totally differs because they are then supported by different specific enzymes. The hepatic metabolism of fructose begins with its phosphorylation to fructose-1-P thanks to fructokinase, while glucose is phosphorylated to glucose-6-P by glucokinase (or hexokinase IV, a glucose-specific enzyme also found in the islets of Langerhans).
Glucose-6-P is then transformed into fructose-6-P, which is metabolized to fructose-1,6-biP (fructose-1,6-biphosphate) by phosphofructokinase, then split into two trioses-phosphates, one of which, glyceraldehyde-3-P, will give pyruvate, source of acetyl-CoA (and citrate) and therefore, via the Krebs cycle and the respiratory chain, ATP. The conversion of glucose to pyruvate (glycolysis) is a metabolic pathway regulated positively by insulin (which stimulates the expression of the glucokinase gene) and negatively by the inhibitory retro console exerted by citrate and ATP (i.e. the energy state of the hepatocyte), on phosphofructokinase, the enzyme that catalyzes the transformation of fructose-6-P into fructose-1,6-biP.
The transformation of fructose into trioses-phosphates occurs independently of insulin and occurs rapidly, both thanks to the high affinity of fructokinase for fructose and the absence of negative feedback. Indeed, fructose enters glycolysis at the level of trioses-phosphates (dihydroxyacetone-phosphate and glyceraldehyde-3-phosphate), thus "bypassing" the essential control point of glycolysis, that is to say, the inhibition exerted by ATP and citrate on phosphofructokinase.
Fructose metabolism can thus be an "unlimited", unregulated source of glycerol-3-phosphate and acetyl-CoA for hepatic lipogenesis.
In hamsters, a diet high in fructose leads, by conversion of fructose into fatty acids in the enterocyte, an increase in the blood level of triglycerides (an effect known in rats since the 1970s), which circulate in the form of chylomicrons.
Some of the trioses-phosphates from fructose are transformed into pyruvate and enter the Krebs cycle, another part is transformed into lactate. But the majority of trioses-phosphates from fructose are converted into glucose, which can participate in the synthesis of glycogen in the liver or be dropped into the general circulation.
It should be noted that the high content of fructose-1P in the hepatocyte, which follows fructose ingestion, can act on liver glucose levels. Indeed fructose-1P is an antagonist of a protein regulating glucokinase, an enzyme that catalyzes the transformation of glucose into glucose-6P but is also involved in inhibiting the release of glucose into the blood, in case of hyperglycemia in the portal blood. Thus activated by this inhibition of its inhibitory protein, glucokinase retains more glucose in the hepatocyte. The addition of a small dose of fructose (so-called "catalytic" dose) to a dish rich in glucose, can therefore further increase the level of hepatic glucose.
4. Fate of ingested fructose in a healthy subject
In healthy subjects, after ingesting fructose, plasma glucose and insulin levels change only slightly, and fructose levels rise from 50 to 500 micromoles per liter of blood. However, there is a sharp increase in carbohydrate oxidation.
Studies that have used fructose labelled with 13C indicate that almost all of an oral load of fructose (1.33 mmol.kg-1.h-1 for 3 h, source) is metabolized at the splanchnic level (mainly in the liver but also in the intestine). About 50% passes into the bloodstream as glucose, 25% as lactate, and about 15% as hepatic glycogen. The remaining 10% is used for the production of ATP in splanchnic tissues or participates in hepatic lipogenesis.
In vitro data have shown that lactate (rather than trioses-phosphates) is a lipogenic precursor and that activation of pyruvate-dehydrogenase by a high-fructose diet is an essential step in this lipogenesis. There is also, in the circulating blood, a disappearance of non-esterified fatty acids, which indicates an inhibition of lipolysis in adipose tissue. This could be due to the low increase in insulin levels observed after ingestion of fructose, given the high sensitivity of adipocytes to this hormone, or the high level of lactate.
The administration of fructose, like glucose, increases energy expenditure but the thermal effect of fructose is higher than that due to glucose, whether it is fructose alone or fructose added to a meal. This increase in basal metabolism is explained by the high need for ATP required by fructose-induced neoglucogenesis and neolipogenesis.
5. Use of fructose in people with diabetes
Over the past two decades, numerous studies have demonstrated a relationship between, on the one hand, a high intake of carbohydrate-rich foods with a high glycemic index (or GI) or a high glycemic load (GC =GI x amount of carbohydrates) and, on the other hand, the risk of diabetes, obesity and cardiovascular disease (K. Berneis and U. Keller, The significance of the glycemic index of foods containing carbohydrates).
In this context, fructose has two characteristics that make it a sweetener of interest for people with diabetes:
the glycemic index of fructose is very low compared to that of glucose. It is 19 against 100, by definition, for glucose, and therefore does not raise the level of glucose in the blood too much after ingestion.
it does not require the intervention of insulin, neither for its transport in the liver cell nor for the initial stages of its hepatic metabolism.
The glycemic index
The GI or glycemic index is a measure that evaluates the rate of absorption of glucose contained in food. To measure it, a person is given food containing 50 g of carbohydrates and his blood sugar is measured every half hour for 3 hours. The blood glucose curve is then compared to that obtained with a reference food, usually glucose or white bread (source). There is high individual variability and this GI also depends on the method of preparation of the food (cooking, purring, etc.). Finally, the association with proteins and/or fibers, in particular, delays the digestion of the food and lowers its glycemic index.
Fructose, when administered to diabetic patients, produces only small increases in blood sugar and plasma insulin levels, compared to what glucose would have caused, but the plasma increase in insulin levels is more pronounced than in non-diabetic subjects.
The increase in carbohydrate oxidation and gluconeogenesis, due to fructose ingestion, is, in diabetic subjects, identical to that of healthy subjects.
The increase in thermogenesis due to fructose in a diabetic subject is the same as in a healthy subject while that following glucose ingestion is weakened. This is explained by the fact that, in insulin-resistant people, the cellular metabolism of glucose is impaired, leading to thermogenesis by lower than normal glucose intake, while the hepatic metabolism of fructose is not affected.
Long-term studies, consisting of diabetic patients of providing part of the carbohydrate intake in the form of fructose, have given results lacking inhomogeneity (especially because of the diversity of protocols), only half of them note a significant drop in blood sugar. These studies also showed that fructose was associated with a significant increase in plasma triglycerides and a decrease in HDL cholesterol.
6. Use of fructose in athletes
Energy drinks are intended to avoid a drop in blood sugar and bring a glucose supplement to the muscles providing an effort. In the case of exogenous glucose intake alone, administered as a drink, the muscle metabolism of glucose does not exceed 1.1 g / min, probably because of the saturation of transporters in the intestinal tract. But if the drink contains a mixture of glucose and fructose, the oxidation of carbohydrates by the body can increase by 40%, this being due to the involvement of different transports and metabolisms for these two oses, hepatic for fructose and muscular for glucose. It has also been reported that fructose, in moderate doses, decreases the feeling of fatigue and allows an increase in physical performance.
Moreover, if the effects of fructose on appetite remain controversial, it would lead to a feeling of satiety lower than that provided by glucose, especially because it has a low glycemic index and hyperglycemia normally plays an important effect in the feeling of satiety. In addition, after ingestion of dishes containing fructose, the decrease in the level of ghrelin, a hormone responsible for stimulating appetite, is less pronounced than after ingestion of glucose. The rise in leptin levels ("satiety hormone") is also less pronounced. Fructose would therefore be less effective than glucose in stopping food intake. It has even been shown that the absorption of high amounts of fructose in rats leads to hepatic resistance to leptin. However, since this hormone normally causes catabolism of liver fat, the ingestion of significant amounts of fructose promotes fatty liver disease (see below). An animal model of leptin resistance shows the presence of triglyceride deposits in the liver but also the muscles, heart or islets of Langerhans.
7. Long-term effects of fructose
Different deleterious influences of fructose on the metabolism have been experimentally demonstrated.
7.1. Fructose and dyslipidemia
In healthy subjects and diabetic subjects, a high-fructose diet, for more than a week, leads to an increase in the level of total triglycerides and in the form of VLDL. This is explained by the strong synthesis of trioses-phosphates, precursors of fatty acids, induced by fructose. In addition, this sugar stimulates the expression of the transcription factor SREBP-1c, which induces the expression of lipogenesis enzymes in the liver (independent effect of insulinemia). Fructose also activates a transcription factor-binding protein (ChREBP), thereby amplifying the expression of liver enzymes such as fatty acid synthase and acetyl-CoA carboxylase.
The hyperlipidemic effect of fructose is established, a meta-analysis has shown that ingestion of more than 50 g of fructose per day (which is close to the average in the United States) leads to an increase in blood triglycerides after meals and that taking more than 100 g of fructose per day leads to an increase in fasting triglycerides.
7.2. Fructose and lipid deposition in the liver
Beyond these changes in blood lipid levels, fructose causes the deposition of ectopic fats, that is to say outside the adipocytes, especially in the liver (fatty liver) and muscles. In rats, this effect of a high-fructose diet is visible within a week. In healthy men, the intake of 1.5 g of fructose per kilogram per day (about 2 liters of soda per day) does not change the level of fat in the liver and muscle, but the administration of double this dose for a week causes a significant increase in the amount of fat in these organs.
7.3. Fructose and insulin resistance
In rats fed a high-fructose diet, an increase in hepatic triglycerides is rapidly observed, then insulin resistance, first hepatic and then, after 5 weeks, of the whole organism.
In humans, since the 1960s, it has been known that insulin resistance is linked to dyslipidemia. Insulin-resistant subjects have ectopic lipid deposits that may provide toxic metabolic derivatives (diacyl-glycerol, fatty acids-acyl-CoA, ceramides) responsible for altering intracellular insulin signalling. For example, phosphorylation of IRS-1, insulin-receptor-substrate-1 decreases the hepatic response to this hormone.
Fructose has also been shown to cause a stress response in the rat's hepatocyte involving the activation of the JNK kinase. Providing fructose in the form of honey, rich in antioxidants, prevents both the onset of this stress and the decrease in insulin sensitivity.
7.4. Fructose and acid
Hyperuricemia is directly related to the appearance of diseases such as gout or kidney stones. It has often been noted, in studies of high-fructose diets, an increase in the level of uric acid in the blood. A fructose load leads, in fact, in the liver, a high consumption of ATP during its transformation into fructose-1P and therefore a sharp increase in AMP, leading to the synthesis of uric acid.
7.5. Fructose and hypertension
Animal studies have shown that a high-fructose diet leads to the development of hypertension. Different mechanisms have been invoked to explain this: insulin resistance and the resulting hyperinsulinemia, an increase in the activity of the orthosympathetic nervous system possibly related to hyperinsulinemia, as well as an increase in sodium reabsorption by the kidney (in rats a high-fructose diet increases the production of sodium and chlorine transporters, see V. Klein and H. Kiat, The mechanisms underlying fructose-induced hypertension: a review). Finally, trioses-phosphates derived from fructose can be converted into methylglyoxal, a highly reactive aldehyde that can modify the functioning of L-type calcium channels, thus increasing the intracellular concentration of calcium in smooth muscles, and therefore their tone.
An analysis of 4500 people spontaneously consuming a significant amount of fructose (of the order of 75 g of fructose per day, equivalent to two and a half cans of soda) showed a relationship with a high average blood pressure value (see D. I. Jalal, G. Smits, R. J. Johnson and M. Chondral, Increased Fructose Associates with Elevated Blood Pressure). However, in an interventional study consisting of 30% overeating of energy intake in the form of fructose in healthy men, hypertension was not observed. Further data must therefore be acquired in this area.
7.6. Comparison of fructose effects and glucose effects
Supplementing overweight women with 30% of energy needs, provided in the form of glucose or fructose, resulted in the same weight gain. However, fructose resulted in higher postprandial elevations in triglycerides and LDLs, elevated hepatic lipogenesis, and decreased insulin sensitivity.
7.7. Influence of the dietary form of fructose
The total fructose measured in epidemiological studies can have different origins: simple fructose added to the diet, simple fructose consumed with glucose (ratio close to 1) in the form of glucose-fructose syrups (HFCS), or fructose associated with glucose in the form of a diose, sucrose, in sugar.
The effects of HFCS appear similar to those of fructose alone; the same response of hepatocytes, the same elevation of plasma triglycerides.
In healthy, voluntary women, HFCS and sucrose (a comparison of bound glucose-fructose and free fructose glucose) produce the same effects on glucose, insulin, ghrelin and leptin levels.
In the current state of knowledge, the effects of fructose seem identical regardless of the molecular form in which it is found in the diet.
8. Involvement of fructose in metabolic diseases
As early as 2007, the epidemiological study "Framingham Heart Study", carried out on more than 6000 people, showed that the consumption of more than one can of sugary drink per day was significantly associated with the prevalence (number of existing cases) of metabolic syndrome. In addition, in healthy subjects, this consumption of sugary drinks increases the risk of this syndrome developing (increase in the number of new cases or incidence).
Metabolic syndrome
Metabolic syndrome is defined by the presence of at least three of the following clinical features: high blood pressure, a waist circumference greater than 35 inches (89 cm) for women and 40 inches for men (101.5 cm), fasting hyperglycemia (100 mg.dl-1) as well as high triglycerides (150 mg.dl-1) and low fasting HDL-cholesterol (40 mg. dl -1 for men and 50 mg.dl-1 for women), spring.
In a Swiss study of 74 children aged 6 to 14 years, it was shown that overweight children had a similar fructose intake to normal-weight children but consumed a higher percentage of sweets and sugary drinks. In this population, fructose intake was associated with an increase in the concentration of low-density lipoproteins (LDL, known to be linked to a high risk of atherosclerosis).
The relationship between sugar-sweetened beverages and coronary heart disease was finally demonstrated by the Nurse Health Study of 88,520 women, with much of the relationship based on the influence of body mass. The hypothesis of the influence of overweight itself on the incidence of cardiovascular risk was therefore considered, but this association remains significant after adjusting the results according to weight and may have originated from either the high glycemic index or the high fructose content of these sugary drinks.
9. Perspectives in the field of public health
To date, epidemiological studies give only incomplete and sometimes discordant results on the relationships between fructose intake and metabolic and cardiovascular diseases, due in particular to the imprecision of data on the different forms of carbohydrates consumed.
Short-term interventional studies, however, suggest that high intakes of fructose, in the form of sugary drinks, juices or pastries may increase the risk of developing this type of disease. Fructose, in high doses, has three main effects, all of which can ultimately lead to cardiovascular diseases (hypertension, atherosclerosis, etc.).
- increased calorie intake that can lead to obesity, then insulin resistance, diabetes and finally cardiovascular disease
- Insulin resistance
- dyslipidemia
In view of current knowledge, even if there is no evidence that a moderate intake of fructose, free or in the form of fruit (whose fiber limits intestinal absorption) or honey, can have harmful effects, it nevertheless seems important:
- to ensure that the intake of fructose in food, especially in the form of glucose-fructose syrups, does not increase compared to current values.
- to take into account fructose intakes in the medical follow-up of diabetic or overweight patients
- inform consumers, in particular young people, about the risk of excessive consumption of fructose, in particular in the form of sugar-sweetened beverages (aiming for maximum consumption of 50 g per day).
11. What are the health benefits?
12. Calories
13. Fructose intolerance: what to do?
- Honey, cane sugar syrups, corn syrup, fructose syrup, glucose-fructose syrup, fructose-glucose syrup, table sugar (sucrose), agave sugar syrup, beetroot, various sugars...
- All sweet products
- Sweeteners: sorbitol, maltitol, mannitol, xylitol, isomalt, taggatose, sucralose, saccharin, ...
- Industrial products
- Fruits except for citrus fruits
- Wheat, barley and rye (rich in fructans)
- Onions, garlic and artichokes (rich in fructans)
- Legumes: lentils, weight, chick weights, dried beans, .... (rich in fructans)
- Vegetables rich in fructans (artichoke, asparagus, beans, broccoli, cabbage, chicory, leek, onion, tomato, zucchini)
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