What is fructose (fruit sugar) and what effect does it have on the human body?

Many elements of the relationship between fructose and obesity, dyslipidaemia, insulin resistance, hyperuricaemia, metabolic syndrome and cardiovascular risk have been elucidated. Based on the results of these studies, there is sufficient evidence for the need to minimise the content of free fructose in drinks and food and to reduce the consumption of free fructose, which of course does not apply to fruit.

What is fructose (fruit sugar) and where is it found?

Fructose or fruit sugar is a simple monosaccharide, an isomer of glucose, which occurs in a variety of foods either freely or in combination with glucose as part of the disaccharide sucrose. Chemically, it is a 6-carbon polyhydroxyketone that forms two ring structures in aqueous solution. At equilibrium, the proportion of D-fructofuranose is 30 % and the proportion of D-fructopyranose is 70 %. From a nutritional point of view, fructose was regarded as a normal monosaccharide that is even beneficial for diabetics. However, research over the last one and a half to two decades has changed this view. It is therefore worth investigating the presence of fructose in our diet, its intake, its metabolism and any health consequences that may be associated with fructose.

Fructose in our diet

Natural sources of fructose are fruit and honey. The addition of sucrose is justified as 50 % of it is released during digestion, but its physiological effect is not the same as that of free fructose. With the modest consumption of fruit and the even more modest consumption of honey, we don't have much of it. In recent years, however, corn syrup with a high fructose content has been widely used as a sweetener. Hydrolysed corn starch, which contains 35 % glucose, is enzymatically treated to convert glucose into fructose. In soft drinks, 55 % fructose syrup is usually used, about 60 %, while in other foods 42 % is used. Another solution or syrup that is also commonly used for sweetening is invert sugar, i.e. beet sugar treated with acid or the enzyme invertase. The solution contains 3-50 % invert sugar and the syrup contains more than 50 % invert sugar with equal proportions of glucose and fructose (3).

Fructose absorption

Fructose tends to be poorly absorbed on its own, but the process is facilitated by glucose and certain amino acids (L-alanine, L-glutamine, L-phenylalanine, L-proline) (4). The transport of fructose into the enterocytes is facilitated at the edge of the cell bordering the intestinal lumen at the brush border. Fructose alone is rather poorly absorbed, but the process is facilitated by glucose and certain amino acids (L-alanine, L-glutamine, L-phenylalanine, L-proline) (4). Fructose is transported into the enterocytes by the GLUT5 protein, which acts at the edge of the intestinal lumen at the brush border of the cell, although the process is thought to be active under the influence of the concentration gradient even without this protein. The GLUT5 protein is encoded by the SLC2A5 gene (5, 6). The same gene also controls the synthesis of the GLUT2 protein, which is responsible for the entry of fructose and glucose from the cells into the bloodstream and is therefore located on the basal side of the enterocytes. The uptake of fructose is mainly facilitated by glucose when it is present in equal amounts. The facilitation is a specific phenomenon because another protein, GLUT1, is responsible for the transport of glucose (and galactose, not to mention sodium ions). The genes coding for GLUT5 and GLUT1 are also identical. Depending on the fructose content of the diet, 5-50 g of fructose can be consumed per day.

Fructose metabolism

In the liver, fructose is phosphorylated by fructokinase (fructose-1-phosphate), which enters the glycolytic process at the triose phosphate level as dihydroxyacetone phosphate and glyceraldehyde-3-phosphate. Therefore, fructose bypasses the phosphofructokinase checkpoint that acts on glucose and causes feedback inhibition via citrate and ATP, limiting further glucose metabolism. Due to this difference, fructose can be an unregulated source of glycerol-3-phosphate and acetyl-coenzymeA, which leads to VLDL formation and promotes lipogenesis. Glucose also stimulates insulin production in the pancreas, whereas fructose does not. A high-fructose diet can lower 24-hour plasma insulin and leptin concentrations, but increases fasting triacylglyceride levels and does not attenuate the main appetite-stimulating hormone, ghrelin (7).

Fructose consumption is rising rapidly

In the United States, the amount of fructose syrup used for per capita sugar consumption already exceeded the amount of sugar consumed in the early 2000s, while the amount of total sugar consumed hardly changed during this period (8). In 1970, 35 million tonnes of fructose were used worldwide, in 1990 it was 55 million and in 2000 64 million. Sugar consumption increased from 70 million tonnes to 128 million tonnes in the same period (9).
According to data from the US NHANES III (Third National Health & Nutrition Examination Survey) from 1988-1994, the entire study population consumed an average of 54.7 g (38.4-72.8 g) of fructose, equivalent to 10.2 % of daily energy intake. Adolescents aged 12 to 18 years consumed the most with an average of 72.8 g per day, equivalent to 12 % of energy intake, but a much higher energy intake of 15 % was found in a quarter of the group.
The main sources of fructose for 2-5 year olds were soft drinks (27 %), fruit and whole fruit juices (19 % and 10 % respectively) and sweets (10 %). Among 12- to 18-year-olds, the proportion of soft drinks rose to 45 %, before falling again to 29 % among adults (10). In a group of 1400 14- to 15-year-olds, 32 % of energy intake came from added sugars, equivalent to 200 g, and half of this, around 100 g, was fructose (11).
There is no comprehensive national data on fructose consumption. However, the composition of sweetened foods shows that fructose-containing syrup is regularly found in both domestic and imported products.

Fructose and health

It should be emphasised that the negative health consequences of fructose are only to be expected if fructose consumption, which is essentially due to sweetening with fructose, increases significantly. The natural fructose content of foods is not harmful, apart from extreme dietary habits, so there should be no thought of restricting the consumption of fruit and whole fruit juices.

Fructose and dyslipidaemia, insulin resistance

Insulin and leptin are important elements of energy homeostasis, i.e. the long-term regulation of food intake. Both inhibit the feeling of hunger in the central nervous system and increase energy consumption by activating the sympathetic nervous system. Insulin also has an indirect effect by stimulating the production of leptin in fatty tissue. Insulin is secreted in the beta cells of the pancreas in response to glucose and amino acids as well as to certain gastrointestinal hormones called incretins. In contrast, fructose and fat do not stimulate the production of insulin and therefore leptin. Fructose does not reach the beta cells as they have practically no GLUT5 transport protein.
The hormone ghrelin, which is produced in the stomach, increases the feeling of hunger and reduces fat burning. Its secretion is suppressed by food, which is not the case with fructose. Therefore, high fructose drinks and other foods increase the risk of obesity and type 2 diabetes. In children, one serving of a sugary drink can increase the body mass index by 0.25 kg/m2 (12).
The first sign of a metabolic disorder caused by fructose is postprandial hypertriglyceridaemia, which is a consequence of de novo lipogenesis by the liver. Fructose increases the formation of fat in the liver because
(1) avoids the above-mentioned regulatory point of phosphofructokinase,
(2) The liver is the main site of fructose metabolism,
(3) Fructose activates protein-1c-binding sterol receptor elements that enhance the expression of genes involved in lipogenesis.
Apolipoprotein B100 (ApoB) is essential for the incorporation of triglycerides into VLDL. Fructose can increase the concentration of ApoB by up to 25 %. Fructose causes a lesion similar to alcoholic fatty liver.
Fructose is the main contributor to visceral obesity. The consumption of a drink sweetened with sugar or fructose ad libitum led to an average weight gain of 1.5 kg under test conditions. However, CT studies have shown that intra-abdominal fat only accumulated in those who drank fructose-containing liquids (13). Free fatty acids, which are more easily released due to the more pronounced lipolytic tendency of visceral fat, are more likely to enter the liver directly and contribute to impaired liver metabolism than fatty acids from other adipose tissues of the body.
Visceral adipose tissue consists of larger fat cells, which are more insulin resistant than small cells and produce less adiponectin, leading to reduced lipid oxidation in the liver and reduced insulin sensitivity as AMP kinase is not activated. A consequence of all this is insulin resistance, to which hepatic TG accumulation contributes. As the liver is less sensitive to insulin, glycogen synthesis is reduced and gluconeogenesis and glycogenolysis are increased.
Insulin resistance leads to increased VLDL production. Insulin presumably promotes the degradation of apoB by inhibiting lipid transfer to the VLDL precursor apoB and regulating the protease responsible for apoB degradation.
Elevated VLDL and plasma TG levels are associated with proatherogenic and cardiovascular risk. This is due to postprandial hypertriglyceridaemia (observed with fructose), higher concentrations of TG-rich residual lipoproteins, not least low-density LDL and reduced HDL (13).
The revitalising effect lasts for up to 12 hours. In healthy men, fasting TG can double after 6 days of a diet with 25 % fructose (10).
Excessive fructose consumption is a risk factor for the development of metabolic syndrome, in which obesity, type 2 diabetes, dyslipidaemia and hypertension coexist (14). A huge dose of 250 g of fructose per day for 1 week, slightly less, 216 g for 28 days, led to insulin resistance, whereas 100 g for 4 weeks did not. In middle-aged men who already had insulin resistance, 15 % fructose for 5 weeks led to higher blood glucose and insulin levels. Humans are particularly sensitive to fructose, while laboratory animals (e.g. rats) are much less so. Fructose has a relatively low GI of 23 compared to 100 for glucose (15).

Fructose and high uric acid levels

Fructose is phosphorylated in the liver by fructokinase (ketohexokinase), a process that requires ATP. This produces adenosine-5′-diphosphate, which is further broken down to adenosine-5′-monophosphate, then to inosine-5′-phosphate and finally to uric acid. High uric acid levels are a risk factor for cardiovascular disease because they reduce the availability of nitric oxide, which is necessary for the function of the vessel walls (endothelium) and the maintenance of normal blood pressure. Hyperuricaemia is an independent marker for high blood pressure, which also provides information on the likely occurrence of insulin resistance, type 2 diabetes and obesity.
The uric acid-forming xanthine oxidoreductase is also involved in adipogenesis (7, 15). Fructose is a pronounced risk factor for gout. In this context, fruits with a high fructose content (apples, oranges, bananas, grapes, pears) may play a role (16).
As the fructokinase utilises ATP as a substrate for phosphorylation, this has further consequences. The lack of back-regulation of the process can lead to an ATP deficiency, which causes a temporary mRNA deficiency and subsequently a stop in protein synthesis and lactic acid formation. Intravenous administration of 50 g of fructose already results in a hepatic ATP deficiency. In addition to the liver, the cells of the kidneys, digestive tract and fat cells also contain high amounts of fructokinase and are therefore particularly sensitive to the ATP-deficient effect of fructose.
The epithelial cells of the renal tubules react to 1 mmol of fructose with a stress response, ATP reduction and inflammatory signals: This corresponds to the blood level after fructose consumption. The increase in uric acid production reflects the intracellular ATP deficiency that can be triggered by as little as 0.5 g/kg body weight of fructose, especially in children. The metabolic syndrome, fatty liver, is often explained by a fructose intake that exceeds two to three times the permitted amount. Compared to other liver diseases, higher levels of fructokinase mRNA can be detected.
Fructose-induced hyperuricaemia also frequently occurs in hypertensive patients and patients with chronic kidney disease. A high-fructose diet leads to persistently high serum uric acid levels within a few weeks. Glucose and starch have no such consequences (15, 17).

Fructose and Diabetes

Fructose increases the amount of glucose excreted in the urine of diabetics because the conversion of fructose into glucose is increased in these patients (gluconeogenesis from lactate and pyruvate, which are derived from fructose, is more pronounced). Small amounts of fructose increase hepatic glucose uptake and glycogen synthesis and are therefore beneficial for the control of hyperglycaemia. On the other hand, long-term consumption of a high-fructose diet, especially in combination with fat and an inactive lifestyle, favours obesity and other cardiovascular risk factors and impairs insulin resistance.
The accumulation of fructose in tissues is associated with diabetic neuropathy and fructosylation of proteins, increases the risk of cataracts, lipid peroxidation and reduces antioxidant defence. The latter also contributes to the deterioration of beta cell function, not to mention insulin resistance. Although these observations come mainly from animal studies, they are most likely also transferable to humans.
Type 2 diabetics were given 60 g of fructose per day. After 6 months, unchanged values for total cholesterol, TG, ApoA1 and ApoB were measured, i.e. no increase in atherogenicity. However, adverse effects were observed in other studies: 20 en% fructose significantly increased total and LDL cholesterol concentrations. The negative effects are particularly pronounced when the diet has a high fat content (12).

Fructose and cardiovascular risk

Smaller LDL particles are associated with metabolic syndrome and may be risk factors for early atherosclerosis and type 2 diabetes. In addition, the prevalence of small LDL particles is also increased in obese individuals, particularly those with central obesity.
In a cross-sectional epidemiological study of children aged 6-14 years, it was found that obese children consumed significantly more fructose-sweetened snacks and drinks than normal-weight children and also had significantly higher TG levels and small LDL particles and lower HDL levels. LDL particle size was inversely related to body mass index. The size of fructose intake predicted a shift in the distribution of LDL particles towards smaller sizes (18).

Fructose and diarrhoea

It is clear from the above that the absorption of fructose from the intestinal tract is limited and essentially depends on the available GLUT5 capacity. If this capacity is insufficient or, as is often the case, the amount of fructose absorbed is high, the excess sugar is transported into the lower intestinal tract. This provides a nutrient that can be easily utilised by the bacterial flora of the large intestine. However, this utilisation is accompanied by gas formation and water retention due to the altered osmotic conditions. The result is a bloated stomach, excessive flatulence, loose stools and even diarrhoea. The severity of the symptoms depends on the amount of fructose and the type of food consumed at the same time. In general, up to 30 g of fructose on a single occasion and 50 g of fructose per day is considered to be an amount that does not cause discomfort (19).

Conclusions

A sustained positive energy balance, even if only moderate, convincingly promotes metabolic syndrome by increasing the accumulation of visceral fat, which increases the amount of free fatty acids entering the liver via the portal circulation. A diet rich in fructose leads more directly and rapidly to overfatting of the liver via de novo lipogenesis. This leads to the deposition of TG in the liver and to the accumulation and secretion of VLDL. The accumulation of TG in the liver is accompanied by an increase in diacylglyceride concentration, which activates the nPKC and interrupts insulin action. Signalling system. It is hypothesised that the production of TG and VLDL in the liver is related to hepatic insulin resistance.
Fructose in food increases energy intake by having a negative effect on appetite-regulating hormones (especially leptin and ghrelin) and thus contributes to the rapid spread of the obesity epidemic. It carries an increased cardiovascular risk due to dyslipidaemia, hyperuricaemia and nitric oxide dysfunction, which affect vascular endothelial function (20, 21, 22, 23). The need to limit fructose consumption, essentially by reducing the fructose used for sweetening and not by limiting the consumption of natural sources of fructose, i.e. fruit, is therefore well established.