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 to support the need to reduce the levels of free fructose in beverages and foods and to reduce the consumption of free fructose, which of course does not include fruit.
What is fructose (fruit sugar) and where does it come from?
Fructose, or fruit sugar, is a simple monosaccharide, an isomer of glucose, found in a variety of foods either alone or in combination with glucose as part of the disaccharide sucrose. Chemically, it is a 6-carbon polyhydroxy ketone which forms two ring structures in aqueous solution. At equilibrium, D-fructofuranose is 30% and D-fructopyranose is 70%. From a nutritional point of view, fructose has been considered a normal monosaccharide, 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.
How do we eat and drink fructose?
Natural sources of fructose are fruits and honey. The addition of sucrose is justified because 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 do not have much of it. In recent years, however, high fructose corn syrup has been widely used as a sweetener. Hydrolysed corn starch containing 35% glucose is enzymatically treated to convert the glucose into fructose. Soft drinks typically use 55% fructose syrup, around 60%, while other foods use 42%.
Another solution or syrup commonly used for sweetening is inverted sugar, which is beet sugar treated with acid or the enzyme invertase. The solution contains 3-50% inverted sugar and the syrup contains more than 50% inverted sugar with equal proportions of glucose and fructose (3).
The absorption of fructose
Fructose is poorly absorbed by itself, but the process is facilitated by glucose and certain amino acids (L-alanine, L-glutamine, L-phenylalanine, L-proline) (4). Fructose is transported into 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 without this protein under the influence of the concentration gradient. 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 cells into the bloodstream and is therefore located on the basal side of enterocytes. The uptake of fructose is mainly facilitated by glucose when it is present in equal amounts. This facilitation is specific because another protein, GLUT1, is responsible for the transport of glucose (and galactose, not to mention sodium ions). The genes encoding GLUT5 and GLUT1 are also identical. Depending on the fructose content of the diet, 5-50 g of fructose can be consumed per day.
Metabolism of fructose
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. Because of this difference, fructose can be an unregulated source of glycerol-3-phosphate and acetyl-coenzyme A, leading to VLDL formation and promoting lipogenesis. Glucose also stimulates insulin production by 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).
The rapid increase in fructose consumption
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, 55 million tonnes in 1990 and 64 million tonnes in 2000. Although sugar consumption increased from 70 million tonnes to 128 million tonnes over the same period (9), data from the 1988-1994 US NHANES III (Third National Health & Nutrition Examination Survey) showed that the total study population consumed an average of 54.7 g (38.4-72.8 g) fructose, representing 10.2% of daily energy intake. Adolescents aged 12-18 years consumed the most, with an average of 72.8 g per day, or 12% of energy intake, but a quarter of the group had a much higher energy intake of 15%. 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%). In 12-18 year olds, the proportion of soft drinks increased to 45%, before falling back to 29% in adults (10). In a group of 1400 14- to 15-year-olds, 32% of energy intake came from added sugars, equivalent to 200 g, of which half, or about 100 g, was fructose (11). Comprehensive national data on fructose consumption are not available. However, the composition of sweetened foods shows that fructose-containing syrups are regularly present in both domestic and widely imported products.
Fructose and your health
It should be emphasised that the negative health effects of fructose are only likely to occur if the consumption of fructose, mainly as a sweetener, increases significantly. The natural fructose content of foods is not harmful, except in the case of extreme diets, so there is no need to consider restricting the consumption of fruit and whole fruit juices.
Fructose and dyslipidaemia, insulin resistance
Insulin and leptin are important elements of energy homeostasis, the long-term regulation of food intake. Both inhibit hunger in the central nervous system and increase energy expenditure by activating the sympathetic nervous system. Insulin also acts indirectly by stimulating the production of leptin in adipose tissue.
Insulin is secreted in the beta cells of the pancreas in response to glucose and amino acids, as well as 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 because they have virtually no GLUT5 transport protein. Ghrelin, a hormone produced in the stomach, increases hunger and reduces fat burning. Its secretion is suppressed by food, which is not the case with fructose. This is why drinks and other foods high in fructose increase the risk of obesity and type 2 diabetes. In children, one serving of a sugary drink can increase body mass index by 0.25 kg/m2 (12).
The first sign of a metabolic disorder caused by fructose is postprandial hypertriglyceridemia, which is a consequence of de novo lipogenesis by the liver. Fructose increases hepatic lipogenesis because (1) it bypasses the above-mentioned regulatory point of phosphofructokinase, (2) the liver is the major site of fructose metabolism, (3) fructose activates protein-1c-binding sterol receptor elements, which increase the expression of genes involved in lipogenesis.
Apolipoprotein B100 (ApoB) is essential for the incorporation of triglycerides into VLDL. Fructose can increase ApoB levels by up to 25%.
Fructose causes a lesion similar to alcoholic fatty liver, and fructose is a major contributor to visceral obesity. Under experimental conditions, ad libitum consumption of a sugar or fructose-sweetened beverage resulted in an average weight gain of 1.5 kg. However, CT scans have shown that intra-abdominal fat only accumulated in those who drank fructose-containing fluids (13). Free fatty acids, which are more readily released due to the greater 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 is made up of larger fat cells that are more insulin resistant than small cells and produce less adiponectin, resulting in decreased lipid oxidation in the liver and decreased insulin sensitivity because AMP kinase is not activated. A consequence of all this is insulin resistance, to which hepatic TG accumulation contributes. As the liver becomes less sensitive to insulin, glycogen synthesis is reduced and gluconeogenesis and glycogenolysis are increased. Insulin resistance results in increased VLDL production. It is thought that insulin promotes apoB degradation by inhibiting lipid transfer to the VLDL precursor apoB and by regulating the protease responsible for apoB degradation. Elevated plasma VLDL and TG levels are associated with proatherogenic and cardiovascular risk. This is due to postprandial hypertriglyceridemia (observed with fructose), higher concentrations of TG-rich remnant lipoproteins, not least low-density LDL and reduced HDL (13). The stimulating effect lasts up to 12 hours.
In healthy men, fasting TG can double after 6 days on a diet containing 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 high dose of 250 g of fructose per day for 1 week, slightly less, 216 g for 28 days, caused 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 sugar and insulin levels.
Humans are very sensitive to fructose, but laboratory animals (e.g. rats) are much less sensitive. 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 into adenosine 5′-monophosphate, then inosine 5′-phosphate and finally 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.
Hyperuricemia is an independent marker of hypertension that also provides information about the likely occurrence of insulin resistance, type 2 diabetes and obesity. Uric acid-producing xanthine oxidoreductase is also involved in adipogenesis (7, 15). Fructose is a clear risk factor for gout. Fruits high in fructose (apples, oranges, bananas, grapes, pears) may play a role (16).
As fructokinase uses ATP as a substrate for phosphorylation, this has further implications. The lack of back-regulation of the process can lead to an ATP deficiency, resulting in a temporary mRNA deficiency and subsequently a halt in protein synthesis and lactic acid formation. A hepatic ATP deficiency can be observed after intravenous administration of 50 g fructose. In addition to the liver, cells of the kidney, digestive tract and fat cells contain high levels of fructokinase and are therefore particularly sensitive to the ATP-depleting effects of fructose.
The epithelial cells of the renal tubules respond to 1 mmol 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 fructose intake of more than two to three times the recommended limit. Higher levels of fructokinase mRNA can be detected compared to other liver diseases. Fructose-induced hyperuricemia is also common in patients with hypertension and 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 effect (15, 17).
High fructose corn syrup and diabetes
Fructose increases the amount of glucose excreted in the urine in diabetics because the conversion of fructose to glucose is increased in these patients (gluconeogenesis from fructose-derived lactate and pyruvate is more pronounced). Small amounts of fructose increase hepatic glucose uptake and glycogen synthesis and are therefore beneficial in controlling hyperglycaemia. On the other hand, prolonged consumption of a high fructose diet, especially in combination with fat and an inactive lifestyle, promotes obesity and other cardiovascular risk factors and impairs insulin resistance.
The accumulation of fructose in tissues is associated with diabetic neuropathy and protein fructosylation, increases the risk of cataracts, and lipid peroxidation and reduces antioxidant defences. The latter also contributes to the deterioration of beta-cell function, not to mention insulin resistance.
Although these observations are mainly from animal studies, they are very likely to apply to humans. Type 2 diabetics were given 60 g of fructose per day. After 6 months, the levels of total cholesterol, TG, apoA1 and apoB were unchanged, i.e. no increase in atherogenicity. However, other studies have shown adverse effects: 20 % fructose significantly increased total and LDL cholesterol concentrations. The adverse effects are particularly pronounced when the diet is high in fat (12).
Fructose and the risk of cardiovascular disease
Small 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 increased in obese individuals, particularly those with central obesity.
In a cross-sectional epidemiological study of children aged 6-14 years, obese children consumed significantly more fructose-sweetened snacks and beverages than normal-weight children and had significantly higher TG levels and small LDL particles and lower HDL levels. LDL particle size was inversely related to body mass index. 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 fructose absorption from the intestinal tract is limited and essentially depends on the available GLUT5 capacity. If this capacity is insufficient or, as is more often the case, the amount of fructose absorbed is high, and the excess sugar is transported to 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 bloating, excessive flatulence, loose stools and even diarrhoea. The severity of the symptoms depends on the amount of fructose consumed and the type of food eaten at the same time. In general, up to 30g of fructose on a single occasion and 50g of fructose a day is considered to be the amount that does not cause symptoms (19).
Conclusions Regarding to fructose consumption
A sustained, even moderate, positive energy balance is a strong predictor of 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 high fructose diet leads more directly and rapidly to hepatic hyperlipidaemia via de novo lipogenesis. This leads to the deposition of TG in the liver and the accumulation and secretion of VLDL. The accumulation of TG in the liver is accompanied by an increase in diacylglyceride concentration, which activates nPKC and interferes with insulin action. Signalling system. The production of TG and VLDL in the liver is thought to be related to hepatic insulin resistance.
Dietary fructose increases energy intake by interfering with appetite-regulating hormones (especially leptin and ghrelin), contributing to the rapid spread of the obesity epidemic. It is associated with increased cardiovascular risk due to dyslipidaemia, hyperuricaemia and nitric oxide dysfunction affecting vascular endothelial function (20, 21, 22, 23). The need to limit fructose consumption, mainly by reducing the fructose used for sweetening, rather than by limiting the consumption of natural sources of fructose, i.e. fruit, is therefore well established.
Read the article in German: Was ist Fruktose (Fruchtzucker) und welche Wirkung hat sie auf den menschlichen Körper?