|Year : 2021 | Volume
| Issue : 3 | Page : 246-251
High-fructose corn syrup effects on metabolic parameters and malignancy
Yasin Simsek1, Ulaş Serkan Topaloğlu2, Oguzhan Sitki Dizdar2
1 Department of Endocrinology and Metabolism, Kayseri City Hospital, Kayseri, Turkey
2 Department of Internal Medicine, Kayseri City Hospital, Kayseri, Turkey
|Date of Submission||22-Jun-2020|
|Date of Decision||06-Aug-2021|
|Date of Acceptance||13-Aug-2020|
|Date of Web Publication||30-Sep-2021|
Dr. Ulaş Serkan Topaloğlu
Kayseri Şehir Hastanesi, Şeker Mahallesi, Molu Caddesi, 38080 Kocasinan, Kayseri.
Source of Support: None, Conflict of Interest: None
In the last century, eating habits have changed. Refined, unnatural, including high-carbohydrate and high-calorie, which have many chemical additives foods, are becoming our dietary habits. High-fructose corn syrup (HFCS) is one of the most commonly used new generation foods, which is produced by enzymatic hydrolysis of corn starch. It is increasingly used more frequently because it is cost-effective and gives a more sugary taste than sucrose. There are many doubts about the effects of HFCS on human health, especially obesity, diabetes mellitus, metabolic syndrome, nonalcoholic fatty-liver disease, and malignancy. This review will specifically explore the links between increased dietary fructose consumption and development of these diseases.
Keywords: High-calorie foods, high-fructose corn syrup, sweetened beverages
|How to cite this article:|
Simsek Y, Topaloğlu US, Dizdar OS. High-fructose corn syrup effects on metabolic parameters and malignancy. J Diabetol 2021;12:246-51
| Introduction|| |
High-fructose corn syrup (HFCS) is a liquid sweetening agent alternative to sucrose produced by enzymatic hydrolysis of corn starch. It is also called “corn sugar” because it is derived from corn, and “corn syrup” or “high-fructose corn syrup” or “fructose syrup” for short because it is thick textured. Many commercial names are used in the market. Some of those are corn syrup, glucose syrup, glucose/fructose syrup, tapioka syrup, fruit fructose, and crystalline fructose. HFCS is generally produced by the liquefaction, fractionation, and isomerization steps of corn starch using chemical and enzymatic hydrolysis techniques. The first step in corn syrup production is mechanical processing of corn. Mechanical processes, which start with brewing to soften the corn, continue with wet grinding and separating into corn starch then enzymatic processes are started. Corn starch is reduced to simple glucose and fructose using three different enzymes which are α-amylase, amyloglucosidase, and glucose isomerase. As a result of enzymatic steps, 90% fructose and 10% glucose mixture isomers are obtained. This isomer is called as HFCS-90. Glucose syrup and HFCS-90 are mixed for obtaining HFCS-55 (55% fructose) and HFCS-42 (42% fructose); thus, products with lower fructose content are manufactured. Generally, 42% fructose syrup is used in foods and conserves where preservation of natural taste and moderate sweetness is desired, while 55% fructose syrup is used in soft drinks, ice cream, and desserts. 90% fructose syrup is used in foods where high sugar taste is desired with a small amount of sweetener. Starch-based sugars are most commonly taken through alcohol-free sugary drinks. Other common sources are grain products, fruit and fruit products, milk and milk products, desserts.
Fructose is found in foods either as monosaccharide (pure fructose) or disaccharide (sucrose) form. Pure fructose is absorbed directly from the intestine without disintegration. When sucrose arrives in the small intestine, it is decomposed into the fructose and glucose units by the sucrase enzyme. Glucose is actively transported in the intestine cells by sodium-glucose transporter protein and passes from the intestinal cell into the intercellular space and then into the capillary blood by glut-2 or simple diffusion. Dietary fructose is absorbed into the intestinal cell via GLUT5, a specific fructose carrier. Unlike glucose, this process is not Na + dependent and does not require energy. Fructose in the intestinal cell is then introduced into the blood via GLUT2 carriers on the basolateral of the enterocyte [Figure 1]., Fructose metabolism occurs in the liver. Fructose, which is transported to the liver after being absorbed in the small intestine, is phosphorylated by the enzyme fructokinase and converted to fructose-1-phosphate. Phosphorylation of glucose by glucokinase in glucose metabolism is the first-speed limiting step in the liver and phosphofructokinase is the second step. The formation step of fructose-1-phosphate from fructose is independent of the speed limiting phosphofructokinase enzyme. Thus, the fructose bypasses the checkpoint with inhibitory signals from citrate and ATP to inhibit phosphofructokinase production. This different metabolism makes fructose a faster source of glycerol-3-phosphate and acetyl-CoA for lipogenesis in the liver.
Why fructose usage increased?
Differences of high-fructose corn syrup and sucrose
| Materials and Methods|| |
In this review, we describe dietary fructose to include HFCS and disaccharide form sucrose. We systematically examined the effects of HFCS. We administered a literature search of the MEDLINE, EMBASE, and Cochrane Library (Cochrane Central Register of Controlled Trials [CENTRAL]) databases. Firstly, we discussed the effects on metabolic parameters and then the effects on malignancy. Keywords for searching were used as fructose, fructose syrup, HFCS, and sucrose. Human and animal studies were included in the search. Inclusion criteria limited search as dietary fructose, glucose, sucrose, HFCS-related metabolic syndrome, cardiovascular disease, and malignancies. We excluded studies on participants with chronic renal failure, hepatic cirrhosis, heart failure, and terminal stage malignancy. In this review, data were synthesized by considering study designs, population characteristics, sources and forms of fructose, comparisons with other carbohydrates, and other dietary products. The term of isocaloric diet is defined as the diet that maintains current weight, the hypercaloric diet is weight gain, and the hypocaloric diet is defined as the weight loss diet.
High-fructose corn syrup effects
Effects on obesity
The prevalence of obesity has increased by more than 30% in the last 30 years. In many epidemiological studies, increased sugar in the diet has been associated with weight gain, obesity, increased cardiovascular risk, hypertension, hyperlipidemia, and diabetes formation., In many studies, the increase in obesity has been explained by the increase in total energy intake rather than the increase in sugar in the diet. In recent years, despite the restriction of dietary sugar intake in most countries, obesity incidence has continued to increase. In the TURDEP2 (2010) study, the frequency of obesity increased by 44% compared to the TURDEP1 (1998) study. The prevalence of obesity in TURDEP2 was found to be 32%., Many mechanisms have been blamed for the negative effects of fructose on obesity. One of the most important mechanisms in this regard; glucose secretes insulin, and leptin secretion is also increased by linked mechanisms. As a result, it contributes to the feeling of satiety. Fructose does not significantly increase insulin secretion and as a result, leptin will also be secreted less; the feeling of satiety decreases, hyperphagia, and obesity occurs. Animal studies show that a diet in which fructose accounts for 60% of total energy intake can cause obesity, insulin resistance, hypertriglyceridemia, hypertension, and hyperuricemia. Ecological analyses have linked HFCS (42%–55% fructose) with an outbreak of obesity in the United States over the past 30 years.
Evidence from observational studies and controlled nutrition trials suggests that consumption of sugary sweetened beverages, where HFCS is the main sweetener, shows a positive relationship between increased energy consumption and weight gain in both adult and child populations [Figure 2]. In the meta-analyses, no additional weight-gaining effect of fructose was observed in isocaloric studies, whereas weight gain was observed in hypocaloric diets caused by fructose. In hypercaloric studies, weight gain is similar to what can be predicted by consuming another energy-supplemented diet other than a similar amount of fructose. Therefore, it seems difficult to say the additional contribution of fructose to weight in an isocaloric diet.
|Figure 2: Two pathways by which sugar increases metabolic risk.,|
Direct pathway: Consumption of sugar leads to dysregulation of lipid and carbohydrate metabolism (A) which increases the risk for metabolic disease (B). Indirect pathway: Consumption of sugar promotes body weight and fat gain (C) which leads to dysregulation of lipid and carbohydrate metabolism (D) which increases in risk for metabolic disease (E). Thus, it is possible that risk for metabolic disease is exacerbated when added sugar is consumed with diets that allow for body weight and fat gain (F)
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High dietary sugar intake was associated with obesity and high risk of chronic disease, but the relationship with obesity was poor. The most consistent association was between high intake of sugary sweet drinks and the development of obesity.
Effect on metabolic parameters
HFCS is often blamed for their negative effects on metabolic parameters. The most important limitation of randomized controlled trials (RCTs) is that their duration is limited to several months. When studies in the literature are considered, there is no clear threshold in nutrition for the negative effect of HFCS on metabolic parameters. In a 10-week RCT where a group has maximum %18 HFCS in diet, no difference was observed in terms of blood pressure, LDL-HDL, and total cholesterol, and fasting blood glucose, except significant triglyceride and slight weight gain in the HFCS group when compared with controls. There are almost similar results in the meta-analysis. In a meta-analysis of 20 studies, HFCS had a negative effect on fasting blood sugar, but no adverse effects on HDL, systolic blood pressure, and triglyceride. The longest duration of the studies in the meta-analysis was 10 weeks.
Effect on the development of diabetes mellitus
From a clinical point of view, there are not enough and long-term RCTs to investigate whether sugar consumption in normoglycemia results in diabetes or even prediabetes. In many studies showing significant relationships, the amount of sugar given is planned to be very low and very high, but these two doses have no reference values. In the majority of studies, no significant relationship was found in the United States at exposure levels equal to or less than 50% for additional sugar or fructose intake. Significance was mostly seen in higher sugar concentrations. There are many cohorts made on this subject. During the follow-up period between 4 and 20 years, the development of diabetes in different cohorts was most commonly associated with the intake of nonalcoholic liquid beverages containing HFCS.,,,
Effect on liver fattening
Nonalcoholic steatohepatitis (NASH) is a rapidly increasing metabolic disorder in the last 20 years. It has been one of the most important causes of end-stage liver failure. High-fructose-containing foods are thought to play a role in the etiology of NASH because they cause de novo lipogenesis. In one study, 8%–18%–30% of daily energy intake was obtained from HFCS and sucrose and the participants were monitored for 10 weeks and no differences were observed in terms of liver fattening. In many studies, especially high doses of fructose intake have been shown to play a role in the development of NASH. In another study, a group has been given 1L of HFCS based drinks, diet drinks, milk, and water for 6 months and when compared with the group that has been given HFCS, liver fattening has been observed in the latter.
Effect on hypertension
There are many studies in the literature that have reached different conclusions about whether high sugar intake causes hypertension., One study has suggested that fructose metabolism can cause increased uric acid levels, which can increase the risk of hypertension by causing endothelial dysfunction. The Framingham Heart Study showed a relationship between consuming one or more carbonated soft drinks a day and developing high blood pressure. However, most studies have shown that fructose consumption up to 30% of daily calories does not cause an increase in blood pressure.,
In addition, in the meta-analysis of Ha et al. containing 376 studies revealed that when fructose was taken isolacorically, it provided slight decreases in both diastolic and mean arterial blood pressure. In addition, they showed that it did not cause an increase in blood pressure when taken hypercalorically.
Therefore, chronic intake of simple sugars on blood pressure is uncertain.
Effect on malignancy
In recent years, the incidence of hepatocellular carcinoma (HCC) has increased in parallel with the increase in the incidence of NASH. The relationship between this increase and high fructose nutrition has been investigated frequently. N-nitrosomorpholine-treated rats for 7 weeks showed a twofold increase in the incidence of liver tumors after fructose feeding, as well as increased metastasis and reduced survival. In a similar study, the rate of precancerous cell formation was found to be twofold higher in rats treated with diethylnitrosamine and subsequently given food with high fructose content. In a study evaluating stage 3 colon cancer patients, the relationship between glycemic load, glucose and fructose intake, and recurrence and survey was evaluated. No relationship was found between glycemic load and disease-free survival in patients with BMI <25kg/m2, whereas a decrease in BMI> 25kg/m2 was observed. Total fructose intake was significantly associated with relapse-free survival.
In contrast, the relationship between total fructose intake and disease-free or overall survival was not statistically significant. In animal studies, there are results that support and do not support the relationship between fructose and colon cancer. In an experimental colorectal cancer model inducted with azoxymethane, a single dose of fructose increased the number of abnormal focal crypts. Treatment of rats with a high-fat diet containing azoxymethane and oligofructose reduced the number of tumors. Further studies are needed to determine whether fructose plays a role in colorectal cancer. In a study conducted by the US National Cancer Institute, increased fructose and glucose intake were associated with an increased risk of pancreatic cancer. Similarly, a meta-analysis of 13 publications examining the links between carbohydrate intake and pancreatic cancer risk showed a positive association with fructose intake. In a study, however, no association was found between consumption of carbohydrate, fructose, and sucrose and the risk of pancreatic cancer.
| Conclusion|| |
Since many of the metabolic consequences of a high-calorie diet containing fructose in humans can also be observed with high-fat or high-glucose nutrition, it seems more accurate to blame excess calories as the main factor in the development of the metabolic syndrome and related conditions. Hypercaloric studies have shown that fructose-containing sugars can have more negative effects than other sugars. Most of the hypercaloric studies are inadequate due to the small sample size, short duration, and low quality of current studies. While there is no evidence that fructose, sucrose, or HFCS is associated with diabetes and other cardiometabolic parameters in isocaloric diets, there is a potential doubt about fructose in high-calorie diets containing high amounts of fructose. Although there is data showing the role of sugars in increasing diabetes prevalence, most of the available evidence is due to low-quality observational studies, animal models, and overexposure studies with high uptake levels. There are a limited number of studies in terms of causing malignancy and they are mostly animal studies. Although the level of evidence is weak, there is still doubt about it. HFCS appears to be more effective than other carbohydrates in the formation of said conditions due to their pharmacokinetic properties. As it is commercially advantageous, its use is increasing. Although no upper safe intake limit is universally accepted, WHO has stated that free sugar intake should be less than 10% of total energy intake. The solution to this problem is to reduce the high carbohydrate nutrition rates, to consume less liquids with high sugar content, and to limit the HFCS rates in foods.
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Conflicts of interest
There are no conflicts of interest.
| References|| |
Parker K, Salas M, Nwosu VC. High fructose corn syrup: Production, uses and public health concerns. Biotechnol Mol Biol Rev 2010;5:71-8.
Hanover LM, White JS. Manufacturing, composition, and applications of fructose. Am J Clin Nutr 1993;58:724-32.
Cozma AI, Sievenpiper JL. The role of fructose, sucrose and high-fructose corn syrup in diabetes. Eur Endocrinol 2014;10:51-60.
Jones HF, Butler RN, Brooks DA. Intestinal fructose transport and malabsorption in humans. Am J Physiol Gastrointest Liver Physiol 2011;300:G202-6.
Martínez-Quintana JA, Yepiz-Plascencia G. Glucose and other hexoses transporters in marine invertebrates: A mini review. Electron J Biotechnol2012;15:1-12.
Bizeau ME, Pagliassotti MJ. Hepatic adaptations to sucrose and fructose. Metabolism 2005;54:1189-201.
Francey C, Cros J, Rosset R, Crézé C, Rey V, Stefanoni N, et al
. The extra-splanchnic fructose escape after ingestion of a fructose-glucose drink: An exploratory study in healthy humans using a dual fructose isotope method. Clin Nutr ESPEN 2019;29:125-32.
Dills WL Jr. Protein fructosylation: Fructose and the maillard reaction. Am J Clin Nutr 1993;58:779-87S.
Canadian Sugar Institute. Available from: http://www.sugar.ca/english/healthprofessionals/functional.cfm. [Last accessed on 2013 Sep 1].
Karp JR, Johnston JD, Tecklenburg S, Mickleborough TD, Fly AD, Stager JM. Chocolate milk as a post-exercise recovery aid. Int J Sport Nutr Exerc Metab 2006;16:78-91.
Rippe JM. Fructose, High Fructose Corn Syrup, Sucrose and Health. New York, NY: Humana Press; 2014. p. 13-33.
Emamian MH, Hashemi H, Fotouhi A. Obesity and underweight: Serious health problems in iranian primary school children. Pediatr Int 2019;61:1030-5.
Malik VS, Popkin BM, Bray GA, Després JP, Willett WC, Hu FB. Sugar-sweetened beverages and risk of metabolic syndrome and type 2 diabetes: A meta-analysis. Diabetes Care 2010;33:2477-83.
Bray GA, Popkin BM. Calorie-sweetened beverages and fructose: What have we learned 10 years later. Pediatr Obes 2013;8:242-8.
Kaiser KA, Shikany JM, Keating KD, Allison DB. Will reducing sugar‐sweetened beverage consumption reduce obesity? Evidence supporting conjecture is strong, but evidence when testing effect is weak. Obes Rev 2013;14:620-33.
Satman I, Yilmaz T, Sengül A, Salman S, Salman F, Uygur S, et al
. Population-based study of diabetes and risk characteristics in turkey: Results of the turkish diabetes epidemiology study (TURDEP). Diabetes Care 2002;25:1551-6.
Satman I, Omer B, Tutuncu Y, Kalaca S, Gedik S, Dinccag N, et al
; TURDEP-II Study Group. Twelve-year trends in the prevalence and risk factors of diabetes and prediabetes in turkish adults. Eur J Epidemiol 2013;28:169-80.
Teff KL, Elliott SS, Tschöp M, Kieffer TJ, Rader D, Heiman M, et al
. Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 2004;89:2963-72.
Johnson RJ, Perez-Pozo SE, Sautin YY, Manitius J, Sanchez-Lozada LG, Feig DI, et al
. Hypothesis: Could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev 2009;30:96-116.
Gross LS, Li L, Ford ES, Liu S. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the united states: An ecologic assessment. Am J Clin Nutr 2004;79:774-9.
Malik VS, Schulze MB, Hu FB. Intake of sugar-sweetened beverages and weight gain: A systematic review. Am J Clin Nutr 2006;84:274-88.
Mattes RD, Shikany JM, Kaiser KA, Allison DB. Nutritively sweetened beverage consumption and body weight: A systematic review and meta‐analysis of randomized experiments. Obesity Rev 2011;12:346-65.
Sievenpiper JL, de Souza RJ, Mirrahimi A, Yu ME, Carleton AJ, Beyene J, et al
. Effect of fructose on body weight in controlled feeding trials: A systematic review and meta-analysis. Ann Intern Med 2012;156:291-304.
Te Morenga L, Mallard S, Mann J. Dietary sugars and body weight: Systematic review and meta-analyses of randomised controlled trials and cohort studies. BMJ 2012;346:e7492.
Stanhope KL. Sugar consumption, metabolic disease and obesity: The state of the controversy. Crit Rev Clin Labor Sci 2016;53:52-67.
Angelopoulos TJ, Lowndes J, Sinnett S, Rippe JM. Fructose containing sugars at normal levels of consumption do not effect adversely components of the metabolic syndrome and risk factors for cardiovascular disease. Nutrients 2016;8:179.
Kelishadi R, Mansourian M, Heidari-Beni M. Association of fructose consumption and components of metabolic syndrome in human studies: A systematic review and meta-analysis. Nutrition 2014;30:503-10.
de Koning L, Malik VS, Rimm EB, Willett WC, Hu FB. Sugar-sweetened and artificially sweetened beverage consumption and risk of type 2 diabetes in men. Am J Clin Nutr 2011;93:1321-7.
Dhingra R, Sullivan L, Jacques PF, Wang TJ, Fox CS, Meigs JB, et al
. Soft drink consumption and risk of developing cardiometabolic risk factors and the metabolic syndrome in middle-aged adults in the community. Circulation 2007;116:480-8.
Palmer JR, Boggs DA, Krishnan S, Hu FB, Singer M, Rosenberg L. Sugar-sweetened beverages and incidence of type 2 diabetes mellitus in African American women. Arch Intern Med 2008;168:1487-92.
Odegaard AO, Koh WP, Arakawa K, Yu MC, Pereira MA. Soft drink and juice consumption and risk of physician-diagnosed incident type 2 diabetes: The Singapore Chinese health study. Am J Epidemiol 2010;171:701-8.
Ray K. NAFLD-the next global epidemic. Nat Rev Gastroenterol Hepatol 2013;10:621.
Bravo S, Lowndes J, Sinnett S, Yu Z, Rippe J. Consumption of sucrose and high-fructose corn syrup does not increase liver fat or ectopic fat deposition in muscles. Appl Physiol Nutr Metab 2013;38:681-8.
Chiu S, Sievenpiper JL, de Souza RJ, Cozma AI, Mirrahimi A, Carleton AJ, et al
. Effect of fructose on markers of non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of controlled feeding trials. Eur J Clin Nutr 2014;68:416-23.
Maersk M, Belza A, Stødkilde-Jørgensen H, Ringgaard S, Chabanova E, Thomsen H, et al
. Sucrose-sweetened beverages increase fat storage in the liver, muscle, and visceral fat depot: A 6-mo randomized intervention study. Am J Clin Nutr 2012;95:283-9.
Feig DI, Soletsky B, Johnson RJ. Effect of allopurinol on blood pressure of adolescents with newly diagnosed essential hypertension: A randomized trial. JAMA 2008;300:924-32.
Nguyen S, Choi HK, Lustig RH, Hsu CY. Sugar-sweetened beverages, serum uric acid, and blood pressure in adolescents. J Pediatr 2009;154:807-13.
Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, et al
. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr 2007;86:899-906.
Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al
. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans. J Clin Invest 2009;119:1322-34.
Lowndes J, Kawiecki D, Angelopoulos T, Melanson K, Rippe J. Components of the metabolic syndrome are not affected by regular consumption of sucrose or high fructose corn syrup. Endocr Rev 2010;31:S1411.
Ha V, Sievenpiper JL, de Souza RJ, Chiavaroli L, Wang DD, Cozma AI, et al
. Effect of fructose on blood pressure: A systematic review and meta-analysis of controlled feeding trials. Hypertension 2012;59:787-95.
Enzmann H, Ohlhauser D, Dettler T, Bannasch P. Enhancement of hepatocarcinogenesis in rats by dietary fructose. Carcinogenesis 1989;10:1247-52.
Kumamoto R, Uto H, Oda K, Ibusuki R, Tanoue S, Arima S, et al
. Dietary fructose enhances the incidence of precancerous hepatocytes induced by administration of diethylnitrosamine in rat. Eur J Med Res 2013;18:54.
Meyerhardt JA, Sato K, Niedzwiecki D, Ye C, Saltz LB, Mayer RJ, et al
. Dietary glycemic load and cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803. J Natl Cancer Inst 2012;104:1702-11.
Stamp D, Zhang XM, Medline A, Bruce WR, Archer MC. Sucrose enhancement of the early steps of colon carcinogenesis in mice. Carcinogenesis 1993;14:777-9.
Jacobsen H, Poulsen M, Dragsted LO, Ravn-Haren G, Meyer O, Lindecrona RH. Carbohydrate digestibility predicts colon carcinogenesis in azoxymethane-treated rats. Nutr Cancer 2006;55:163-70.
Jiao L, Flood A, Subar AF, Hollenbeck AR, Schatzkin A, Stolzenberg-Solomon R. Glycemic index, carbohydrates, glycemic load, and the risk of pancreatic cancer in a prospective cohort study. Cancer Epidemiol Biomarkers Prev 2009;18:1144-51.
Lê KA, Ith M, Kreis R, Faeh D, Bortolotti M, Tran C, et al
. Fructose overconsumption causes dyslipidemia and ectopic lipid deposition in healthy subjects with and without a family history of type 2 diabetes. Am J Clin Nutr 2009;89:1760-5.
Simon E, Joseph AJ, Choudhrie L, Eapen A, Vyas F, Sitaram V, et al
. Intraductal papillary mucinous neoplasm of the pancreas. Indian J Gastroenterol 2010;29:40.
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