Fructose Consumption-Free Sugars and Their Health Effects

Abstract

Background: The excessive consumption of free sugars, including fructose, is considered a cause of overweight and metabolic syndrome throughout the Western world. In Germany, the prevalence of overweight and obesity among adults (54%, 18%) and children (15%, 6%) has risen in the past few decades and has now become stable at a high level. The causative role of fructose is unclear.

Methods: This review is based on publications retrieved by a selective search in PubMed and the Cochrane Library, with special attention to international guidelines and expert recommendations.

Results: The hepatic metabolism of fructose is insulin-independent; because of the lack of a feedback mechanism, it leads to substrate accumulation, with de novo lipogenesis and gluconeogenesis. Recent meta-analyses with observation periods of one to ten weeks have shown that the consumption of fructose in large amounts leads to weight gain (+ 0.5 kg [0.26; 0.79]), elevated triglyceride levels (+ 0.3 mmol/L [0.11; 0.41]), and steatosis hepatis (intrahepatocellular fat content: + 54% [29; 79%]) when it is associated with a positive energy balance (fructose dose + 25-40% of the total caloric requirement). Meta-analyses in the isocaloric setting have not shown any comparable effects. Children, with their preference for sweet foods and drinks, are prone to excessive sugar consumption. Toddlers under age two are especially vulnerable.

Conclusion: The effects that have been observed with the consumption of large amounts of fructose cannot be reliably distinguished from the effects of a generally excessive caloric intake. Further randomized and controlled intervention trials of high quality are needed in order to determine the metabolic effects of fructose consumed under isocaloric conditions. To lessen individual consumption of sugar, sugary dietary items such as sweetened soft drinks, fruit juice, and smoothies should be avoided in favor of water as a beverage and fresh fruit.

Figure 1

The hepatic metabolism of fructose and glucose The uptake of fructose in the intestinal epithelium and its transport into the portal venous circulation take place independently of insulin by means of the highly specific fructose transporter GLUT5. In the liver, hepatocellular uptake of fructose and glucose is facilitated by the insulin-independet transporter GLUT2. Degradation of glucose to fructose-1,6-phosphate occurs with the aid of the key enzyme of glycolisis phosphofructokinase-1, whereas degradation of fructose circumvents this regulatory mechanism. The metabolism of both monosaccharides leads to the generation of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate, which are degraded to pyruvate in glycolysis. As there is no feedback mechanism regulating fructose metabolism, acetyl-CoA substrate accumulation ensues, exceeding the capacity of the citrate cycle. Excess citrate serves as a substrate for de novo lipogenesis. Fructose is converted to fructose-1-phosphate with the consumption of ATP. The resulting ADP is degraded to uric acid, which inhibits endothelial NO synthase, thereby contributing to arterial hypertension. ADP, adenosine diphosphate; AMP, adenosine monophosphate; ATP, adenosine triphosphate; GLUT, glucose transporter; P, phosphate; VLDL, very low density lipoproteins. Adapted from (e25).

Figure 2

The multifactorial pathogenesis of NAFLD Hepatic lipid accumulation due to the arrival of increased amounts of lipids in the liver is sustained by intestinal dysbiosis (dysequilibrium of the intestinal microbiota), free fatty acids from the diet, and visceral fat deposits, as well as by fructose-induced de novo lipogenesis. Lipid degradation via ß-oxidation is inhibited by fructose metabolites and genetic predisposition. The transition from NAFLD to NASH is promoted by inflammation, which is triggered by endotoxins (LPS and others) released by the altered microbiome, as well as by reactive oxygen species (ROS) arising as by-products of fructose metabolism. ChREBP, carbohydrate-responsive element binding protein; DNL, de novo lipogenesis; FFA, free fatty acids; LPS, lipopolysaccharide; NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; ROS, reactive oxygen species; PNPLA3, papatin-like phospholipase domain-containing 3; TM6SF2, transmembrane 6 superfamily member 2; VLDL, very low density lipoproteins. Figure modified from (e25).