Fructose metabolism in humans – what isotopic tracer studies tell us

Nutrition & Metabolism

Mark W Empie¹  Sam Z Sun¹ 

[1] Compliance, Archer Daniels Midland Company, 1001 North Brush College Road, Decatur, IL, 62521, USA

关键词: Metabolism;    Isotope tracer;    Glucose;    Fructose;   

Others  :  811938
DOI  :  10.1186/1743-7075-9-89

 received in 2012-08-03, accepted in 2012-09-24,  发布年份 2012

【 摘 要 】

Fructose consumption and its implications on public health are currently under study. This work reviewed the metabolic fate of dietary fructose based on isotope tracer studies in humans. The mean oxidation rate of dietary fructose was 45.0% ± 10.7 (mean ± SD) in non-exercising subjects within 3–6 hours and 45.8% ± 7.3 in exercising subjects within 2–3 hours. When fructose was ingested together with glucose, the mean oxidation rate of the mixed sugars increased to 66.0% ± 8.2 in exercising subjects. The mean conversion rate from fructose to glucose was 41% ± 10.5 (mean ± SD) in 3–6 hours after ingestion. The conversion amount from fructose to glycogen remains to be further clarified. A small percentage of ingested fructose (<1%) appears to be directly converted to plasma TG. However, hyperlipidemic effects of larger amounts of fructose consumption are observed in studies using infused labeled acetate to quantify longer term de novo lipogenesis. While the mechanisms for the hyperlipidemic effect remain controversial, energy source shifting and lipid sparing may play a role in the effect, in addition to de novo lipogenesis. Finally, approximately a quarter of ingested fructose can be converted into lactate within a few of hours. The reviewed data provides a profile of how dietary fructose is utilized in humans.

【 授权许可】

   
2012 Sun and Empie; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]USDA-ERS: Food Availability: Spreadsheets-Added sugar and sweeteners. 2010. http://wwwersusdagov/Data/FoodConsumption/FoodAvailSpreadsheetshtm#sweets webcite
• [2]Johnson RJ, Segal MS, Sautin Y, Nakagawa T, Feig DI, Kang DH, Gersch MS, Benner S, Sanchez-Lozada LG: 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.
• [3]Bray GA, Nielsen SJ, Popkin BM: Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity. Am J Clin Nutr 2004, 79:537-543.
• [4]Teff KL, Elliott SS, Tschop M, Kieffer TJ, Rader D, Heiman M, Townsend RR, Keim NL, D'Alessio D, Havel PJ: Dietary fructose reduces circulating insulin and leptin, attenuates postprandial suppression of ghrelin, and increases triglycerides in women. J Clin Endocrinol Metab 2004, 89:2963-2972.
• [5]Teff KL, Grudziak J, Townsend RR, Dunn TN, Grant RW, Adams SH, Keim NL, Cummings BP, Stanhope KL, Havel PJ: Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses. J Clin Endocrinol Metab 2009, 94:1562-1569.
• [6]Melanson KJ, Zukley L, Lowndes J, Nguyen V, Angelopoulos TJ, Rippe JM: Effects of high-fructose corn syrup and sucrose consumption on circulating glucose, insulin, leptin, and ghrelin and on appetite in normal-weight women. Nutrition 2007, 23:103-112.
• [7]Sun SZ, Empie MW: Lack of findings for the association between obesity risk and usual sugar-sweetened beverage consumption in adults–a primary analysis of databases of CSFII-1989–1991, CSFII-1994–1998, NHANES III, and combined NHANES 1999–2002. Food Chem Toxicol 2007, 45:1523-1536.
• [8]Dolan LC, Potter SM, Burdock GA: Evidence-based review on the effect of normal dietary consumption of fructose on development of hyperlipidemia and obesity in healthy, normal weight individuals. Crit Rev Food Sci Nutr 2010, 50:53-84.
• [9]Dolan LC, Potter SM, Burdock GA: Evidence-based review on the effect of normal dietary consumption of fructose on blood lipids and body weight of overweight and obese individuals. Crit Rev Food Sci Nutr 2010, 50:889-918.
• [10]Livesey G: Fructose ingestion: dose-dependent responses in health research. J Nutr 2009, 139:1246S-1252S.
• [11]Livesey G, Taylor R: Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies. Am J Clin Nutr 2008, 88:1419-1437.
• [12]Sievenpiper JL, Carleton AJ, Chatha S, Jiang HY, de Souza RJ, Beyene J, Kendall CW, Jenkins DJ: Heterogeneous effects of fructose on blood lipids in individuals with type 2 diabetes: systematic review and meta-analysis of experimental trials in humans. Diabetes Care 2009, 32:1930-1937.
• [13]Sievenpiper JL, de Souza RJ, Mirrahimi A, Yu ME, Carleton AJ, Beyene J, Chiavaroli L, Di Buono M, Jenkins AL, Leiter LA, 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.
• [14]Welsh JA, Sharma AJ, Grellinger L, Vos MB: Consumption of added sugars is decreasing in the United States. Am J Clin Nutr 2011, 94:726-734.
• [15]Hall KD, Heymsfield SB, Kemnitz JW, Klein S, Schoeller DA, Speakman JR: Energy balance and its components: implications for body weight regulation. Am J Clin Nutr 2012, 95:989-994.
• [16]Swinburn B, Sacks G, Ravussin E: Increased food energy supply is more than sufficient to explain the US epidemic of obesity. Am J Clin Nutr 2009, 90:1453-1456.
• [17]Johnson RJ, Perez-Pozo SE, Sautin YY, Manitius J, Sanchez-Lozada LG, Feig DI, Shafiu M, Segal M, Glassock RJ, Shimada M, et al.: Hypothesis: could excessive fructose intake and uric acid cause type 2 diabetes? Endocr Rev 2009, 30:96-116.
• [18]Sun SZ, Flickinger BD, Williamson-Hughes PS, Empie MW: Lack of association between dietary fructose and hyperuricemia risk in adults. Nutr Metab (Lond) 2010, 7:16. BioMed Central Full Text
• [19]Lim JS, Mietus-Snyder M, Valente A, Schwarz JM, Lustig RH: The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 2010, 7:251-264.
• [20]Lustig RH: Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc 2010, 110:1307-1321.
• [21]Gambino R, Musso G, Cassader M: Redox balance in the pathogenesis of nonalcoholic Fatty liver disease: mechanisms and therapeutic opportunities. Antioxid Redox Signal 2011, 15:1325-1365.
• [22]Cortez-Pinto H, Machado MV: Uncoupling proteins and non-alcoholic fatty liver disease. J Hepatol 2009, 50:857-860.
• [23]Sievenpiper JL, de Souza RJ, Kendall CW, Jenkins DJ: Is fructose a story of mice but not men? J Am Diet Assoc 2011, 111:219-220. author reply 220–212
• [24]Lustig RH: Author’s Response to Letter to the editor. J Am Diet Assoc 2011, 111:220-222.
• [25]Livesey G: More on mice and men: fructose could put brakes on a vicious cycle leading to obesity in humans. J Am Diet Assoc 2011, 111:986-990. author reply 990–983
• [26]Lustig RH: Author’s Response to Letters to The Editor. J Am Diet Assoc 2011, 111:990-993.
• [27]Mayes PA: Intermediary metabolism of fructose. Am J Clin Nutr 1993, 58:754S-765S.
• [28]Tappy L, Le KA: Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev 2010, 90:23-46.
• [29]Sun SZ, Anderson GH, Flickinger BD, Williamson-Hughes PS, Empie MW: Fructose and non-fructose sugar intakes in the US population and their associations with indicators of metabolic syndrome. Food Chem Toxicol 2011, 49:2875-2882.
• [30]Marriott BP, Cole N, Lee E: National estimates of dietary fructose intake increased from 1977 to 2004 in the United States. J Nutr 2009, 139:1228S-1235S.
• [31]Chandramouli V, Kumaran K, Ekberg K, Wahren J, Landau BR: Quantitation of the pathways followed in the conversion of fructose to glucose in liver. Metabolism 1993, 42:1420-1423.
• [32]Folch N, Peronnet F, Pean M, Massicotte D, Lavoie C: Labeled CO(2) production and oxidative vs nonoxidative disposal of labeled carbohydrate administered at rest. Metabolism 2005, 54:1428-1434.
• [33]Hellerstein MK, Neese RA: Mass isotopomer distribution analysis at eight years: theoretical, analytic, and experimental considerations. Am J Physiol 1999, 276:E1146-E1170.
• [34]Riby JE, Fujisawa T, Kretchmer N: Fructose absorption. Am J Clin Nutr 1993, 58:748S-753S.
• [35]Ferraris RP: Dietary and developmental regulation of intestinal sugar transport. Biochem J 2001, 360:265-276.
• [36]Scheepers A, Joost HG, Schurmann A: The glucose transporter families SGLT and GLUT: molecular basis of normal and aberrant function. JPEN J Parenter Enteral Nutr 2004, 28:364-371.
• [37]Read N, French S, Cunningham K: The role of the gut in regulating food intake in man. Nutr Rev 1994, 52:1-10.
• [38]Lavin JH, Wittert GA, Andrews J, Yeap B, Wishart JM, Morris HA, Morley JE, Horowitz M, Read NW: Interaction of insulin, glucagon-like peptide 1, gastric inhibitory polypeptide, and appetite in response to intraduodenal carbohydrate. Am J Clin Nutr 1998, 68:591-598.
• [39]Ravich WJ, Bayless TM: Carbohydrate absorption and malabsorption. Clin Gastroenterol 1983, 12:335-356.
• [40]Latulippe ME, Skoog SM: Fructose Malabsorption and Intolerance: Effects of Fructose with and without Simultaneous Glucose Ingestion. Crit Rev Food Sci Nutr 2011, 51:583-592.
• [41]Gray GM, Ingelfinger FJ: Intestinal absorption of sucrose in man: interrelation of hydrolysis and monosaccharide product absorption. J Clin Invest 1966, 45:388-398.
• [42]Akgun S, Ertel NH: The effects of sucrose, fructose, and high-fructose corn syrup meals on plasma glucose and insulin in non-insulin-dependent diabetic subjects. Diabetes Care 1985, 8:279-283.
• [43]Heitlinger LA, Li BU, Murray RD, McClung HJ, Sloan HR, DeVore DR, Powers P: Glucose flux from dietary disaccharides: all sugars are not absorbed at equal rates. Am J Physiol 1991, 261:G818-G822.
• [44]Macdonald I, Turner LJ: Serum-fructose levels after sucrose or its constituent monosaccharides. Lancet 1968, 1:841-843.
• [45]Bornet F, Haardt MJ, Costagliola D, Blayo A, Slama G: Sucrose or honey at breakfast have no additional acute hyperglycaemic effect over an isoglucidic amount of bread in type 2 diabetic patients. Diabetologia 1985, 28:213-217.
• [46]Samanta A, Burden AC, Jones GR: Plasma glucose responses to glucose, sucrose, and honey in patients with diabetes mellitus: an analysis of glycaemic and peak incremental indices. Diabet Med 1985, 2:371-373.
• [47]Burelle Y, Peronnet F, Massicotte D, Brisson GR, Hillaire-Marcel C: Oxidation of 13C-glucose and 13C-fructose ingested as a preexercise meal: effect of carbohydrate ingestion during exercise. Int J Sport Nutr 1997, 7:117-127.
• [48]Chong MF, Fielding BA, Frayn KN: Mechanisms for the acute effect of fructose on postprandial lipemia. Am J Clin Nutr 2007, 85:1511-1520.
• [49]Delarue J, Normand S, Pachiaudi C, Beylot M, Lamisse F, Riou JP: The contribution of naturally labelled 13C fructose to glucose appearance in humans. Diabetologia 1993, 36:338-345.
• [50]Jandrain BJ, Pallikarakis N, Normand S, Pirnay F, Lacroix M, Mosora F, Pachiaudi C, Gautier JF, Scheen AJ, Riou JP, et al.: Fructose utilization during exercise in men: rapid conversion of ingested fructose to circulating glucose. J Appl Physiol 1993, 74:2146-2154.
• [51]Lecoultre V, Benoit R, Carrel G, Schutz Y, Millet GP, Tappy L, Schneiter P: Fructose and glucose co-ingestion during prolonged exercise increases lactate and glucose fluxes and oxidation compared with an equimolar intake of glucose. Am J Clin Nutr 2010, 92:1071-1079.
• [52]Paquot N, Schneiter P, Jequier E, Gaillard R, Lefebvre PJ, Scheen A, Tappy L: Effects of ingested fructose and infused glucagon on endogenous glucose production in obese NIDDM patients, obese non-diabetic subjects, and healthy subjects. Diabetologia 1996, 39:580-586.
• [53]Miller BF, Fattor JA, Jacobs KA, Horning MA, Navazio F, Lindinger MI, Brooks GA: Lactate and glucose interactions during rest and exercise in men: effect of exogenous lactate infusion. J Physiol 2002, 544:963-975.
• [54]Roef MJ, de Meer K, Kalhan SC, Straver H, Berger R, Reijngoud DJ: Gluconeogenesis in humans with induced hyperlactatemia during low-intensity exercise. Am J Physiol Endocrinol Metab 2003, 284:E1162-E1171.
• [55]Guezennec CY, Satabin P, Duforez F, Merino D, Peronnet F, Koziet J: Oxidation of corn starch, glucose, and fructose ingested before exercise. Med Sci Sports Exerc 1989, 21:45-50.
• [56]Decombaz J, Sartori D, Arnaud MJ, Thelin AL, Schurch P, Howald H: Oxidation and metabolic effects of fructose or glucose ingested before exercise. Int J Sports Med 1985, 6:282-286.
• [57]Selivanov VA, Sukhomlin T, Centelles JJ, Lee PW, Cascante M: Integration of enzyme kinetic models and isotopomer distribution analysis for studies of in situ cell operation. BMC Neurosci 2006, 7(Suppl 1):S7. BioMed Central Full Text
• [58]Lee WN, Go VL: Nutrient-gene interaction: tracer-based metabolomics. J Nutr 2005, 135:3027S-3032S.
• [59]Vinnakota KC, Wu F, Kushmerick MJ, Beard DA: Multiple ion binding equilibria, reaction kinetics, and thermodynamics in dynamic models of biochemical pathways. Methods Enzymol 2009, 454:29-68.
• [60]Burelle Y, Lamoureux MC, Peronnet F, Massicotte D, Lavoie C: Comparison of exogenous glucose, fructose and galactose oxidation during exercise using 13C-labelling. Br J Nutr 2006, 96:56-61.
• [61]Adopo E, Peronnet F, Massicotte D, Brisson GR, Hillaire-Marcel C: Respective oxidation of exogenous glucose and fructose given in the same drink during exercise. J Appl Physiol 1994, 76:1014-1019.
• [62]Massicotte D, Peronnet F, Adopo E, Brisson GR, Hillaire-Marcel C: Effect of metabolic rate on the oxidation of ingested glucose and fructose during exercise. Int J Sports Med 1994, 15:177-180.
• [63]Massicotte D, Peronnet F, Allah C, Hillaire-Marcel C, Ledoux M, Brisson G: Metabolic response to [13C]glucose and [13C]fructose ingestion during exercise. J Appl Physiol 1986, 61:1180-1184.
• [64]Massicotte D, Peronnet F, Brisson G, Bakkouch K, Hillaire-Marcel C: Oxidation of a glucose polymer during exercise: comparison with glucose and fructose. J Appl Physiol 1989, 66:179-183.
• [65]Massicotte D, Peronnet F, Brisson G, Boivin L, Hillaire-Marcel C: Oxidation of exogenous carbohydrate during prolonged exercise in fed and fasted conditions. Int J Sports Med 1990, 11:253-258.
• [66]Jentjens RL, Moseley L, Waring RH, Harding LK, Jeukendrup AE: Oxidation of combined ingestion of glucose and fructose during exercise. J Appl Physiol 2004, 96:1277-1284.
• [67]Jentjens RL, Shaw C, Birtles T, Waring RH, Harding LK, Jeukendrup AE: Oxidation of combined ingestion of glucose and sucrose during exercise. Metabolism 2005, 54:610-618.
• [68]Jentjens RL, Underwood K, Achten J, Currell K, Mann CH, Jeukendrup AE: Exogenous carbohydrate oxidation rates are elevated after combined ingestion of glucose and fructose during exercise in the heat. J Appl Physiol 2006, 100:807-816.
• [69]Jentjens RL, Venables MC, Jeukendrup AE: Oxidation of exogenous glucose, sucrose, and maltose during prolonged cycling exercise. J Appl Physiol 2004, 96:1285-1291.
• [70]Tran C, Jacot-Descombes D, Lecoultre V, Fielding BA, Carrel G, Le KA, Schneiter P, Bortolotti M, Frayn KN, Tappy L: Sex differences in lipid and glucose kinetics after ingestion of an acute oral fructose load. Br J Nutr 2010, 104:1139-1147.
• [71]Surmely JF, Paquot N, Schneiter P, Jequier E, Temler E, Tappy L: Non oxidative fructose disposal is not inhibited by lipids in humans. Diabetes Metab 1999, 25:233-240.
• [72]Nilsson LH, Hultman E: Liver and muscle glycogen in man after glucose and fructose infusion. Scand J Clin Lab Invest 1974, 33:5-10.
• [73]Dirlewanger M, Schneiter P, Jequier E, Tappy L: Effects of fructose on hepatic glucose metabolism in humans. Am J Physiol Endocrinol Metab 2000, 279:E907-E911.
• [74]Blom PC, Hostmark AT, Vaage O, Kardel KR, Maehlum S: Effect of different post-exercise sugar diets on the rate of muscle glycogen synthesis. Med Sci Sports Exerc 1987, 19:491-496.
• [75]Coss-Bu JA, Sunehag AL, Haymond MW: Contribution of galactose and fructose to glucose homeostasis. Metabolism 2009, 58:1050-1058.
• [76]Sobrecases H, Le KA, Bortolotti M, Schneiter P, Ith M, Kreis R, Boesch C, Tappy L: Effects of short-term overfeeding with fructose, fat and fructose plus fat on plasma and hepatic lipids in healthy men. Diabetes Metab 2010, 36:244-246.
• [77]Le KA, Ith M, Kreis R, Faeh D, Bortolotti M, Tran C, Boesch C, Tappy L: 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, 89:1760-1765.
• [78]Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L: Effect of fructose overfeeding and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy men. Diabetes 2005, 54:1907-1913.
• [79]Hulston CJ, Wallis GA, Jeukendrup AE: Exogenous CHO oxidation with glucose plus fructose intake during exercise. Med Sci Sports Exerc 2009, 41:357-363.
• [80]Jentjens RL, Jeukendrup AE: High rates of exogenous carbohydrate oxidation from a mixture of glucose and fructose ingested during prolonged cycling exercise. Br J Nutr 2005, 93:485-492.
• [81]Daly ME, Vale C, Walker M, Littlefield A, George K, Alberti M, Mathers J: Acute fuel selection in response to high-sucrose and high-starch meals in healthy men. Am J Clin Nutr 2000, 71:1516-1524.
• [82]Rowlands DS, Thorburn MS, Thorp RM, Broadbent S, Shi X: Effect of graded fructose coingestion with maltodextrin on exogenous 14C-fructose and 13C-glucose oxidation efficiency and high-intensity cycling performance. J Appl Physiol 2008, 104:1709-1719.
• [83]Vedala A, Wang W, Neese RA, Christiansen MP, Hellerstein MK: Delayed secretory pathway contributions to VLDL-triglycerides from plasma NEFA, diet, and de novo lipogenesis in humans. J Lipid Res 2006, 47:2562-2574.
• [84]Hellerstein MK, Schwarz JM, Neese RA: Regulation of hepatic de novo lipogenesis in humans. Annu Rev Nutr 1996, 16:523-557.
• [85]Parks EJ, Skokan LE, Timlin MT, Dingfelder CS: Dietary sugars stimulate fatty acid synthesis in adults. J Nutr 2008, 138:1039-1046.
• [86]Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, Hatcher B, Cox CL, Dyachenko A, Zhang W, 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, 119:1322-1334.
• [87]Human Metablome Database - Acetic acid. 2011. http://wwwhmdbca/metabolites/HMDB00042 webcite
• [88]Richards RH, Dowling JA, Vreman HJ, Feldman C, Weiner MW: Acetate levels in human plasma. Proc Clin Dial Transplant Forum 1976, 6:73-79.
• [89]Lundquist F: Production and Utilization of Free Acetate in Man. Nature 1962, 193:579-580.
• [90]Lundquist F, Tygstrup N, Winkler K, Mellemgaard K, Munck-Petersen S: Ethanol metabolism and production of free acetate in the human liver. J Clin Invest 1962, 41:955-961.
• [91]Beynen AC, Buechler KF, Van der Molen AJ, Geelen MJ: The effects of lactate and acetate on fatty acid and cholesterol biosynthesis by isolated rat hepatocytes. Int J Biochem 1982, 14:165-169.