Mini review on fructose metabolism

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1 Obesity Research & Clinical Practice (2013) 7, e89 e94 REVIEW Mini review on fructose metabolism M. Akram a,, Abdul Hamid b a Department of Eastern Medicine and Surgery, Faculty of Medical and Health Sciences, The University of Poonch, Rawalakot, Azad Jammu and Kashmir, Pakistan b Department of Horticulture, Faculty of Agriculture, The University of Poonch, Rawalakot, Azad Jammu and Kashmir, Pakistan Received 14 September 2012; received in revised form 1 November 2012; accepted 27 November 2012 KEYWORDS Fructose; Associated disorders Summary Fructose is a monosaccharide and reducing sugar. It is present in sucrose and honey. Researchers around the world have come together in a just-published study that offers new ideas about how fructose consumption results in obesity and metabolic syndrome, which can lead to diabetes. In this review, we discuss that how fructose causes fatty liver, obesity and insulin resistance. We also discuss the effects of consumption of high fructose corn syrup, dietary fructose, fructoseinduced changes in metabolism Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved. Contents Introduction Biomedical importance of fructose Sources of fructose Fructose metabolism in liver Kinetic of fructose metabolism Fructose metabolism in muscles Fructokinase deficiency (essential fructosuria) Hereditary fructose intolerance Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity Dietary fructose and glucose differentially affect lipid and glucose homeostasis Female rats are protected against fructose-induced changes in metabolism and blood pressure Fructose ingestion: dose-dependent responses in health research Fructose and hyperuricemia Fructose and metabolic syndrome Metabolic effects of fructose and the worldwide increase in obesity Corresponding author. Tel.: addresses: makram 0451@yahoo.com, makram 0451@hotmail.com (M. Akram) X/$ see front matter 2012 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

2 e90 M. Akram, A. Hamid Fructose induced obesity in rats Conclusion References Introduction Fructose is present more or less frequently than glucose in the juices of plants, fruits, and especially the honey, which is about half the solid matters [1]. It leads to an equal amount of glucose by the hydrolysis of sugar cane and a smaller proportion than some other less common sugars. It is used, such as glucose, in the production of glycogen. It enters the body through either be eaten as such or as the result of digestion of sugar cane. It is mainly changed into glycogen or triglycerides after reaching the liver, so do not enter largely in the blood circulation. Glucose and fructose are partially inter-convertible under the influence of very dilute alkali. It is not surprising; therefore, that fructose must be converted to glycogen in the liver, which on hydrolysis yields of glucose [2]. Dubois et al. reported that regular consumption of sugary drinks between meals increases risk of overweight among preschool children [3]. Biomedical importance of fructose Fructose is a good power source. Fructose is found in seminal fluid and sperm cells use for energy. High intake of fructose results in increased formation of triacylglycerol. In diabetic, fructose metabolism occurs via the sorbitol pathway that is responsible for the development of cataracts. Hereditary fructose intolerance is due to inherited deficiency of the enzyme aldolase B [4]. Sources of fructose It is located in fruits and honey. Main source is sucrose; the sucrose is hydrolyzed by sucrase into fructose and glucose. It is absorbed through facilitated diffusion and can be obtained from the portal blood to the liver where it is converted to glucose [5]. Fructose metabolism in liver Sugar is present in fruits. Sucrose is hydrolyzed by sucrase to glucose and fructose. Dietary fructose is transferred from the intestine to the liver for metabolism. Fructose is converted to fructose 1 phosphate which further converted to acetone and glyceraldehyde dihydroxy, which is further converted to glyceraldehyde 3 phosphate to enter glycolysis. In the well-fed state, fructose is converted to glycogen [6] or triglycerides [7]. Hyperlipidemia, diabetes mellitus and obesity are interlinked. Consumption of fructose is increasing and is considered responsible for overweight. Several studies show that fructose increases incidence of obesity, dyslipidemia, insulin resistance, and hypertension. Metabolism of fructose takes place mainly in the liver and high fructose stream leads to accumulation of triglycerides in the liver (hepatic steatosis). This results in impairment of lipid metabolism and enhancement of expression of proinflammatory cytokine. Fructose alters glucose induced expression of activated acetyl CoA carboxylase (ACC), pser hormone sensitive lipase (pserhsl) and adipose triglyceride lipase (ATGL) in HepG2 liver or primary liver cell cultures in vitro. This relates to the increased de novo synthesis of triglycerides in vitro and in vivo hepatic steatosis in fructose-fed versus glucose-and standard-diet mice fed. These studies provide new understanding of the mechanisms involved in fructose-mediated hepatic hypertriglyceridemia [8]. Kinetic of fructose metabolism Rate of metabolism of fructose is more rapid than glucose, because triose formed from fructose 1-phosphate by pass phosphofructokinase, the primary rate limiting step in glycolysis. Elevated levels of dietary fructose significantly elevate the rate of lipogenesis in the liver, because of the rapid production of acetyl-coenzyme A [9]. Fructose metabolism in muscles Fructose is phosphorylated in the presence of hexokinase to fructose 6 phosphate. Fructose 6- phosphate is converted to glycogen. Fructose also provides energy through glycolysis. Ahlborg et al., has stated that fructose infusion during exercise leads to increased oxidation of fructose in

3 Mini review on fructose metabolism e91 exercising muscle and exerts glycogenic effect in resting muscle and liver after exercise [10]. Fructokinase deficiency (essential fructosuria) This disease is rare. In this condition fructose begins to accumulate in the blood and is excreted in the urine as well. This disease is most often seen in Jewish families and patients have normal life expectancy [11]. Hereditary fructose intolerance This disease occurs due to deficiency of aldolase B. It has been observed in children, when children receive fructose in the diet. The vomiting and hypoglycemia is an important feature of this disease. Fructose 1 phosphate accumulates in the liver. Accumulation exhausts inorganic phosphate thereby inhibiting both glycogen phosphorylase and the synthesis of ATP. Inhibition of these reactions leads to hypoglycaemia. AMP also accumulates and metabolism leads to increased production of uric acid leading to hyperuricemia and gout [12]. Treatment of this disease includes avoiding substances containing fructose [13]. Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity Obesity is a major epidemic, but its causes are still unclear. The relation between the intake of highfructose corn syrup (HFCS) and the development of obesity has been analyzed [14]. Food consumption patterns by using US Department of Agriculture food consumption tables from 1967 to 2000 was analyzed. The consumption of HFCS increased >1000% between 1970 and 1990, far exceeding the changes in intake of any other food or food group. HFCS now represents >40% of caloric sweeteners added to foods and beverages and is the sole caloric sweetener in soft drinks in the United States. Our most conservative estimate of the consumption of HFCS indicates a daily average of 132 kcal for all Americans aged 2 years, and the top 20% of consumers of caloric sweeteners ingest 316 kcal from HFCS/d. The increased use of HFCS in the United States mirrors the rapid increase in obesity. The digestion, absorption, and metabolism of fructose differ from those of glucose. Hepatic metabolism of fructose favors de novo lipogenesis. In addition, unlike glucose, fructose does not stimulate insulin secretion or enhance leptin production. Because insulin and leptin act as key afferent signals in the regulation of food intake and body weight, this suggests that dietary fructose may contribute to increased energy intake and weight gain. Furthermore, calorically sweetened beverages may enhance caloric over consumption. Thus, the increase in consumption of HFCS has a temporal relation to the epidemic of obesity, and the over consumption of HFCS in calorically sweetened beverages may play a role in the epidemic of obesity [15]. Dietary fructose and glucose differentially affect lipid and glucose homeostasis Absorbed glucose and fructose differ in that glucose largely escapes first-pass removal by the liver, whereas fructose does not, resulting in different metabolic effects of these two monosaccharides. In short-term controlled feeding studies, dietary fructose significantly increases postprandial triglyceride (TG) levels and has little effect on serum glucose concentrations, whereas dietary glucose has the opposite effects [16]. When dietary glucose and fructose have been directly compared at 20 25% of energy over a 4- to 6-week period, dietary fructose caused significant increases in fasting TG and LDL cholesterol concentrations, whereas dietary glucose did not [17]. But dietary glucose did increase serum glucose and insulin concentrations in the postprandial state whereas dietary fructose did not [2]. When fructose at g ( 4 12% of energy) was added to the diet in the free-living state, there were no significant effects on lipid or glucose biomarkers [18]. Sucrose and high-fructose corn syrup (HFCS) contain approximately equal amounts of fructose and glucose and no metabolic differences between them have been noted. Controlled feeding studies at more physiologic dietary intakes of fructose and glucose need to be conducted. High fructose fed showed a significant increase in final body weight with preservation of its correlation with all metabolic parameters and a significant increase in fasting serum glucose levels, fasting serum insulin levels, and HOMA- IR, High fructose fed also showed dyslipidemia proved by significant increase serum total cholesterol, serum triglyceride, VLDL-cholesterol levels, and LDL-cholesterol, accompanied by a significant decrease in HDL-cholesterol [19]. It has been

4 e92 M. Akram, A. Hamid estimated that to reduce the current high prevalence of obesity, intake of high fructose diet should be limited and consumption of vegetables, vegetable oils, fish, fruit, whole grains, and fiber should be increased [20]. Female rats are protected against fructose-induced changes in metabolism and blood pressure In one study, it was evaluated that whether the effects of a fructose diet, which causes hyperinsulinemia, insulin resistance, and hypertension in male rats, are dependent on sex. Maris et al. [21] reported that males have slightly higher systolic pressure than female rats. Blood pressure was measured via the tail-cuff method, and oral glucose tolerance tests were performed to assess insulin sensitivity. In male cohort, blood pressure began to increase in the treated group of fructose compared to the control group by 3 weeks of treatment and continued to increase throughout the study (150 and 115 mmhg respectively at week 9). Blood pressure in female rats did not differ between fructose-fed and control rats at any time point (126 ± 5 and 125 ± 3 mmhg at week 9 for fructose-fed and control rats, respectively) nor was there a difference in any metabolic parameter measured. Furthermore, the vascular insulin resistance that was present in male fructose-fed rats was not observed. After ovariectomy, fructose caused a significant change in systolic blood pressure from baseline compared with fructose-fed ovary-intact rats (change of 21 ± 5 vs. 2 ± 4 mmhg). The results demonstrated that females do not develop hypertension or hyperinsulinemia upon fructose feeding except after ovariectomy, suggesting that female sex hormones may confer protection against the effects of a fructose diet. Fructose ingestion: dose-dependent responses in health research Many hypotheses of disease risk and prevention depend on inferences about the metabolic effects of fructose; however, there is inadequate attention to dose dependency. Fructose is proving to have bidirectional effects. At moderate or high doses, an effect on any one marker may be absent or even the opposite of that observed at very high or excessive doses; examples include fasting plasma triglyceride, insulin sensitivity, and the putative marker uric acid. Among markers, changes can be beneficial for some (e.g., glycated hemoglobin from moderate to high fructose intake) but adverse for others (e.g., plasma triglycerides at very high or excessive fructose intake). Evidence on body weight indicates no effect from moderate to high fructose intakes, but information is scarce for high or excessive intakes. By focusing on the adverse effects of very high and excessive doses, there is a risk of not noticing the potential benefits of moderate or higher doses, which might moderate the advent and progress of type-2 diabetes, cardiovascular disease, and might even contribute to longevity. A salutary rather than hyperbolic examination of the evidence base needs to be undertaken [22]. Fructose and hyperuricemia Increased intake of fructose is associated with hyperuricemia. Various studies indicate that that increased intake of sugar sweetened soft drinks and fructose is associated with risk of hyperuricemia in men [23]. Fructose and metabolic syndrome It is hypothesized that fructose induces metabolic syndrome in health individuals. Study was carried out to investigate the role of uric acid in the hypertensive response. In this study, allopurinol was given to patients to lower the serum uric acid level. Ultimately it was found that excessive intake of fructose can increase the blood pressure and is responsible of metabolic syndrome but the lowering of serum uric acid level by allopurinol prevents the increase in mean arterial blood pressure [24]. Metabolic effects of fructose and the worldwide increase in obesity Fructose is almost similar to glucose because they are isomers to each other. Difference is in their metabolic pathway due to its almost complete hepatic extraction and rapid hepatic conversion into glucose, glycogen, lactate, and fat. In initial period when science was not so progressed, the diabetics patients were using fructose due to its low glycemic index. It has been observed now that obesity, diabetes mellitus, insulin resistance and hypertension are associated with chronic consumption of fructose. Dyslipidemia and impairment in hepatic insulin resistance are also due to increase

5 Mini review on fructose metabolism e93 intake of fructose in the diet. Adverse metabolic effects of fructose are responsible for hepatic de novo lipogenesis, hyperuricemia, oxidative stress and lipotoxicity. Epidemiological studies show that obesity, metabolic and cardiovascular disorders are also due to consumption of sweetened beverages (containing either sucrose or a mixture of glucose and fructose). Adverse metabolic effects of fructose are usually on high consumption and there is lack of evidence of adverse effect on moderate consumption of fructose. Study shows that free fructose is more dangerous than consumption of fructose consumed with sucrose [25]. Fructose induced obesity in rats A study was conducted to investigate the body weight, plasma glucose level, caloric intakes and glucose tolerance in male Sprague-Dawley rats. For this study, rats were divided into different groups. A single standard diet was given to control group and standard diet plus one of four sources of sugar: (1) a 32% glucose solution, (2) a 32% fructose solution, (3) a 32% sucrose solution or (4) granulated sucrose were given to test group. After 50 days, blood was collected from fasted animals for analyses of serum glucose, triglycerides and insulin levels. Livers, kidneys, epididymal and retroperitoneal fat depots and shoulder brown adipose tissue (BAT) were removed and weighed. The animals given sugar solutions and the standard diet consumed significantly more calories, gained more weight and had significantly more retroperitoneal fat than controls given only the standard diet. Despite the fact that the rats did not eat more granular sucrose and the standard diet but they did gain significantly more weight per kilocalorie consumed and has more fat than control. Rats given the sucrose solution had significantly more BAT than controls or rats given the fructose solution or granulated sucrose. Rats receiving glucose had significantly more BAT than controls. We propose that intake of fructose, sucrose and glucose solution in particular increases caloric intake, resulting in obesity in rats. This study shows that sucrose and fructose and glucose all are associated with weight gain [26]. Conclusion In this review article it has been concluded that high fructose ingestion increases risk of obesity. Fructose intake also increases triglycerides and cholesterol level in blood. Fructose induced changes in metabolism and blood pressure are more common in male rats than female rats. References [1] Ischayek JI, Kern M. US honeys varying in glucose and fructose content elicit similar glycemic indexes. J Am Diet Assoc 2006;106(8): [2] Faiq A. Carbohydrate metabolism. In: Biochemistry review. 1st ed. 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