Skip to main content

Advertisement

SpringerLink
Log in

Tissue-Specific Fructose Metabolism in Obesity and Diabetes

  • Pathogenesis of Type 2 Diabetes and Insulin Resistance (M-E Patti, Section Editor)
  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

The objective of this review is to provide up-to-date and comprehensive discussion of tissue-specific fructose metabolism in the context of diabetes, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD).

Recent Findings

Increased intake of dietary fructose is a risk factor for a myriad of metabolic complications. Tissue-specific fructose metabolism has not been well delineated in terms of its contribution to detrimental health effects associated with fructose intake. Since inhibitors targeting fructose metabolism are being developed for the management of NAFLD and diabetes, it is essential to recognize how inability of one tissue to metabolize fructose may affect metabolism in the other tissues. The primary sites of fructose metabolism are the liver, intestine, and kidney. Skeletal muscle and adipose tissue can also metabolize a large portion of fructose load, especially in the setting of ketohexokinase deficiency, the rate-limiting enzyme of fructose metabolism. Fructose can also be sensed by the pancreas and the brain, where it can influence essential functions involved in energy homeostasis. Lastly, fructose is metabolized by the testes, red blood cells, and lens of the eye where it may contribute to infertility, advanced glycation end products, and cataracts, respectively.

Summary

An increase in sugar intake, particularly fructose, has been associated with the development of obesity and its complications. Inhibition of fructose utilization in tissues primary responsible for its metabolism alters consumption in other tissues, which have not been traditionally regarded as important depots of fructose metabolism.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Chanmugam P, Guthrie JF, Cecilio S, Morton JF, Basiotis PP, Anand R. Did fat intake in the United States really decline between 1989-1991 and 1994-1996? J Am Diet Assoc. 2003;103:867–72.

    PubMed  Google Scholar 

  2. 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;79:537–43.

    CAS  PubMed  Google Scholar 

  3. Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ. Fructose, weight gain, and the insulin resistance syndrome. Am J Clin Nutr. 2002;76:911–22.

    CAS  PubMed  Google Scholar 

  4. Imamura F, O'Connor L, Ye Z, Mursu J, Hayashino Y, Bhupathiraju SN, et al. Consumption of sugar sweetened beverages, artificially sweetened beverages, and fruit juice and incidence of type 2 diabetes: systematic review, meta-analysis, and estimation of population attributable fraction. BMJ. 2015;351:h3576.

    PubMed  PubMed Central  Google Scholar 

  5. Collier R. FDA proposes new food labels. CMAJ. 2014;186:491.

    PubMed  PubMed Central  Google Scholar 

  6. Cawley J, Frisvold D, Hill A, Jones D. The impact of the Philadelphia beverage tax on purchases and consumption by adults and children. J Health Econ. 2019;67:102225.

    PubMed  Google Scholar 

  7. Falbe J, Thompson HR, Becker CM, Rojas N, McCulloch CE, Madsen KA. Impact of the Berkeley excise tax on sugar-sweetened beverage consumption. Am J Public Health. 2016;106:1865–71.

    PubMed  PubMed Central  Google Scholar 

  8. Bridge G, Lomazzi M, Bedi R. Implementation of a sugar-sweetened beverage tax in low- and middle-income countries: recommendations for policymakers. J Public Health Policy. 2020;41:84–97.

    PubMed  Google Scholar 

  9. Alviso-Orellana C, Estrada-Tejada D, Carrillo-Larco RM, Bernabe-Ortiz A. Sweetened beverages, snacks and overweight: findings from the Young Lives cohort study in Peru. Public Health Nutr. 2018;21:1627–33.

    PubMed  PubMed Central  Google Scholar 

  10. Caro JC, Corvalan C, Reyes M, Silva A, Popkin B, Taillie LS. Chile’s 2014 sugar-sweetened beverage tax and changes in prices and purchases of sugar-sweetened beverages: an observational study in an urban environment. PLoS Med. 2018;15:e1002597.

    PubMed  PubMed Central  Google Scholar 

  11. Makris A, Foster GD. Dietary approaches to the treatment of obesity. Psychiatr Clin North Am. 2011;34:813–27.

    PubMed  PubMed Central  Google Scholar 

  12. Softic S, Stanhope KL, Boucher J, Divanovic S, Lanaspa MA, Johnson RJ, et al. Fructose and hepatic insulin resistance. Crit Rev Clin Lab Sci. 2020:1–15.

  13. Beck-Nielsen H, Pedersen O, Lindskov HO. Impaired cellular insulin binding and insulin sensitivity induced by high-fructose feeding in normal subjects. Am J Clin Nutr. 1980;33:273–8.

    CAS  PubMed  Google Scholar 

  14. 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;54:1907–13.

    CAS  PubMed  Google Scholar 

  15. Le 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.

    CAS  PubMed  Google Scholar 

  16. Lecoultre V, Egli L, Carrel G, Theytaz F, Kreis R, Schneiter P, et al. Effects of fructose and glucose overfeeding on hepatic insulin sensitivity and intrahepatic lipids in healthy humans. Obesity (Silver Spring). 2013;21:782–5.

    CAS  Google Scholar 

  17. 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.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Taskinen MR, Soderlund S, Bogl LH, Hakkarainen A, Matikainen N, Pietilainen KH, et al. Adverse effects of fructose on cardiometabolic risk factors and hepatic lipid metabolism in subjects with abdominal obesity. J Intern Med. 2017;282:187–201.

    CAS  PubMed  Google Scholar 

  19. Aeberli I, Hochuli M, Gerber PA, Sze L, Murer SB, Tappy L, et al. Moderate amounts of fructose consumption impair insulin sensitivity in healthy young men: a randomized controlled trial. Diabetes Care. 2013;36:150–6.

    CAS  PubMed  Google Scholar 

  20. Schwarz JM, Noworolski SM, Wen MJ, Dyachenko A, Prior JL, Weinberg ME, et al. Effect of a high-fructose weight-maintaining diet on lipogenesis and liver fat. J Clin Endocrinol Metab. 2015;100:2434–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Hallfrisch J, Ellwood KC, Oet M, Reiser S, Odorisio TM, Prather ES. Effects of dietary fructose on plasma glucose and hormone responses in normal and hyperinsulinemic men. J Nutr. 1983;113:1819–26.

    CAS  PubMed  Google Scholar 

  22. Reiser S, Bohn E, Hallfrisch J, OEt M, Keeney M, Prather ES. Serum insulin and glucose in hyperinsulinemic subjects fed three different levels of sucrose. Am J Clin Nutr. 1981;34:2348–58.

    CAS  PubMed  Google Scholar 

  23. Reiser S, Handler HB, Gardner LB, Hallfrisch JG, OEt M, Prather ES. Isocaloric exchange of dietary starch and sucrose in humans. II. Effect on fasting blood insulin, glucose, and glucagon and on insulin and glucose response to a sucrose load. Am J Clin Nutr. 1979;32:2206–16.

    CAS  PubMed  Google Scholar 

  24. Malik VS, Popkin BM, Bray GA, Despres 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.

    PubMed  PubMed Central  Google Scholar 

  25. Mattes RD, Shikany JM, Kaiser KA, Allison DB. Nutritively sweetened beverage consumption and body weight: a systematic review and meta-analysis of randomized experiments. Obes Rev. 2011;12:346–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Bes-Rastrollo M, Schulze MB, Ruiz-Canela M, Martinez-Gonzalez MA. Financial conflicts of interest and reporting bias regarding the association between sugar-sweetened beverages and weight gain: a systematic review of systematic reviews. PLoS Med. 2013;10:e1001578 dicsussion e1001578.

    PubMed  PubMed Central  Google Scholar 

  27. Douard V, Ferraris RP. Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab. 2008;295:E227–37.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Thorens B, Mueckler M. Glucose transporters in the 21st century. Am J Physiol Endocrinol Metab. 2010;298(2):E141–5.

  29. Bonthron DT, Brady N, Donaldson IA, Steinmann B. Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase). Hum Mol Genet. 1994;3:1627–31.

    CAS  PubMed  Google Scholar 

  30. Diggle CP, Shires M, Leitch D, Brooke D, Carr IM, Markham AF, et al. Ketohexokinase: expression and localization of the principal fructose-metabolizing enzyme. J Histochem Cytochem. 2009;57:763–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Diggle CP, Shires M, McRae C, Crellin D, Fisher J, Carr IM, et al. Both isoforms of ketohexokinase are dispensable for normal growth and development. Physiol Genomics. 2010;42A:235–43.

    CAS  PubMed  Google Scholar 

  32. Asipu A, Hayward BE, O'Reilly J, Bonthron DT. Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria. Diabetes. 2003;52:2426–32.

    CAS  PubMed  Google Scholar 

  33. Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease. J Clin Invest. 2018;128:545–55.

    PubMed  PubMed Central  Google Scholar 

  34. Sillero MA, Sillero A, Sols A. Enzymes involved in fructose metabolism in lir and the glyceraldehyde metabolic crossroads. Eur J Biochem. 1969;10:345–50.

    CAS  PubMed  Google Scholar 

  35. Liu L, Li T, Liao Y, Wang Y, Gao Y, Hu H, Huang H, Wu F, Chen Y-G, Xu S, Fu S. Triose kinase controls the lipogenic potential of fructose and dietary tolerance. Cell Metab. 20200;S1550-4131(20):30413–7.

  36. Adelman RC, Spolter PD, Weinhouse S. Dietary and hormonal regulation of enzymes of fructose metabolism in rat liver. J Biol Chem. 1966;241:5467–72.

    CAS  PubMed  Google Scholar 

  37. Mascord D, Smith J, Starmer GA, Whitfield JB. The effect of fructose on alcohol metabolism and on the [lactate]/[pyruvate] ratio in man. Alcohol Alcohol. 1991;26:53–9.

    CAS  PubMed  Google Scholar 

  38. Thorne M, Carpenter RCL. The effects of fructose on the metabolism of ethyl alcohol in man. J Pharmacol Exp Ther. 1937;60:286–95.

    Google Scholar 

  39. Thieden HIDLF. The influence of fructose and its metabolites on ethanol metabolism in vitro. Biochem J. 1967;102.

  40. Lorenzi M. The polyol pathway as a mechanism for diabetic retinopathy: attractive, elusive, and resilient. Exp Diabetes Res. 2007;2007:61038.

    PubMed  PubMed Central  Google Scholar 

  41. Romero A, Gomez O, Terrado J, Mesonero JE. Expression of GLUT8 in mouse intestine: identification of alternative spliced variants. J Cell Biochem. 2009;106:1068–78.

    CAS  PubMed  Google Scholar 

  42. Mueckler M. Facilitative glucose transporters. Eur J Biochem. 1994;219:713–25.

    CAS  PubMed  Google Scholar 

  43. Barone S, Fussell SL, Singh AK, Lucas F, Xu J, Kim C, et al. Slc2a5 (Glut5) is essential for the absorption of fructose in the intestine and generation of fructose-induced hypertension. J Biol Chem. 2009;284:5056–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Patel C, Douard V, Yu S, Gao N, Ferraris RP. Transport, metabolism, and endosomal trafficking-dependent regulation of intestinal fructose absorption. FASEB J. 2015;29:4046–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Li Q, Manolescu A, Ritzel M, Yao S, Slugoski M, Young JD, et al. Cloning and functional characterization of the human GLUT7 isoform SLC2A7 from the small intestine. Am J Physiol Gastrointest Liver Physiol. 2004;287:G236–42.

    CAS  PubMed  Google Scholar 

  46. Kim HR, Park SW, Cho HJ, Chae KA, Sung JM, Kim JS, et al. Comparative gene expression profiles of intestinal transporters in mice, rats and humans. Pharmacol Res. 2007;56:224–36.

    CAS  PubMed  Google Scholar 

  47. Ferraris RP, Choe JY, Patel CR. Intestinal absorption of fructose. Annu Rev Nutr. 2018;38:41–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ebert K, Ludwig M, Geillinger KE, Schoberth GC, Essenwanger J, Stolz J, et al. Reassessment of GLUT7 and GLUT9 as putative fructose and glucose transporters. J Membr Biol. 2017;250:171–82.

    CAS  PubMed  Google Scholar 

  49. DeBosch BJ, Kluth O, Fujiwara H, Schurmann A, Moley K. Early-onset metabolic syndrome in mice lacking the intestinal uric acid transporter SLC2A9. Nat Commun. 2014;5:4642.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Patel C, Douard V, Yu S, Tharabenjasin P, Gao N, Ferraris RP. Fructose-induced increases in expression of intestinal fructolytic and gluconeogenic genes are regulated by GLUT5 and KHK. Am J Physiol Regul Integr Comp Physiol. 2015;309:R499–509.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Kishida K, Pearce SC, Yu S, Gao N, Ferraris RP. Nutrient sensing by absorptive and secretory progenies of small intestinal stem cells. Am J Physiol Gastrointest Liver Physiol. 2017;312:G592–605.

    PubMed  PubMed Central  Google Scholar 

  52. Jiang L, David ES, Espina N, Ferraris RP. GLUT-5 expression in neonatal rats: crypt-villus location and age-dependent regulation. Am J Physiol Gastrointest Liver Physiol. 2001;281:G666–74.

    CAS  PubMed  Google Scholar 

  53. Jiang L, Ferraris RP. Developmental reprogramming of rat GLUT-5 requires de novo mRNA and protein synthesis. Am J Physiol Gastrointest Liver Physiol. 2001;280:G113–20.

    CAS  PubMed  Google Scholar 

  54. Merino B, Fernandez-Diaz CM, Cozar-Castellano I, Perdomo G. Intestinal fructose and glucose metabolism in health and disease. Nutrients. 2019;12.

  55. Cui XL, Soteropoulos P, Tolias P, Ferraris RP. Fructose-responsive genes in the small intestine of neonatal rats. Physiol Genomics. 2004;18:206–17.

    CAS  Google Scholar 

  56. Yodoi J, Masutani H, Nakamura H. Redox regulation by the human thioredoxin system. Biofactors. 2001;15:107–11.

    CAS  PubMed  Google Scholar 

  57. Dotimas JR, Lee AW, Schmider AB, Carroll SH, Shah A, Bilen J, et al. Diabetes regulates fructose absorption through thioredoxin-interacting protein. Elife. 2016;5.

  58. Lee HJ, Cha JY. Recent insights into the role of ChREBP in intestinal fructose absorption and metabolism. BMB Rep. 2018;51:429–36.

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Oh AR, Sohn S, Lee J, Park JM, Nam KT, Hahm KB, et al. ChREBP deficiency leads to diarrhea-predominant irritable bowel syndrome. Metabolism. 2018;85:286–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Kim M, Astapova II, Flier SN, Hannou SA, Doridot L, Sargsyan A, et al. Intestinal, but not hepatic, ChREBP is required for fructose tolerance. JCI Insight. 2017;2:e96703.

    PubMed Central  Google Scholar 

  61. Kato T, Iizuka K, Takao K, Horikawa Y, Kitamura T, Takeda J. ChREBP-knockout mice show sucrose intolerance and fructose malabsorption. Nutrients. 2018;10:340.

    PubMed Central  Google Scholar 

  62. . Jang C, Hui S, Lu W, Cowan AJ, Morscher RJ, Lee G, et al. The small intestine converts dietary fructose into glucose and organic acids. Cell Metab. 2018;27:351–361 e353 This original research article demonstrates that low doses of dietary fructose are primarily metabolized by the intestine; however, high doses of dietary fructose reach both the liver and colonic microbiota for further metabolism.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhao S, Jang C, Liu J, Uehara K, Gilbert M, Izzo L, et al. Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature. 2020;579:586–91.

    CAS  PubMed  PubMed Central  Google Scholar 

  64. . Andres-Hernando A, Orlicky DJ, Kuwabara M, Ishimoto T, Nakagawa T, Johnson RJ, et al. Deletion of fructokinase in the liver or in the intestine reveals differential effects on sugar-induced metabolic dysfunction. Cell Metab. 2020;32:117–127 e113 This original research article demonstrates that global deletion of KHK reduces sugar intake and prevents fructose-induced metabolic syndrome in mice. Meanwhile, sugar intake is regulated by intestinal KHK activity while metabolic syndrome is controlled by hepatic fructose metabolism.

    CAS  PubMed  Google Scholar 

  65. Laitakari A, Tapio J, Makela KA, Herzig KH, Dengler F, Gylling H, et al. HIF-P4H-2 inhibition enhances intestinal fructose metabolism and induces thermogenesis protecting against NAFLD. J Mol Med (Berl). 2020;98:719–31.

    CAS  Google Scholar 

  66. Helsley RN, Softic S. Fructose metabolism by the guts cuts liver fat. J Mol Med (Berl). 2020;98:733–4.

    Google Scholar 

  67. Corpe CP, Basaleh MM, Affleck J, Gould G, Jess TJ, Kellett GL. The regulation of GLUT5 and GLUT2 activity in the adaptation of intestinal brush-border fructose transport in diabetes. Pflugers Arch. 1996;432:192–201.

    CAS  PubMed  Google Scholar 

  68. Burant CF, Flink S, DePaoli AM, Chen J, Lee WS, Hediger MA, et al. Small intestine hexose transport in experimental diabetes. Increased transporter mRNA and protein expression in enterocytes. J Clin Invest. 1994;93:578–85.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Dyer J, Wood IS, Palejwala A, Ellis A, Shirazi-Beechey SP. Expression of monosaccharide transporters in intestine of diabetic humans. Am J Physiol Gastrointest Liver Physiol. 2002;282:G241–8.

    CAS  PubMed  Google Scholar 

  70. George Thompson AM, Ursu O, Babkin P, Iancu CV, Whang A, Oprea TI, et al. Discovery of a specific inhibitor of human GLUT5 by virtual screening and in vitro transport evaluation. Sci Rep. 2016;6:24240.

    PubMed  PubMed Central  Google Scholar 

  71. Kuhre RE, Gribble FM, Hartmann B, Reimann F, Windelov JA, Rehfeld JF, et al. Fructose stimulates GLP-1 but not GIP secretion in mice, rats, and humans. Am J Physiol Gastrointest Liver Physiol. 2014;306:G622–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Galderisi A, Giannini C, Van Name M, Caprio S. Fructose consumption contributes to hyperinsulinemia in adolescents with obesity through a GLP-1-mediated mechanism. J Clin Endocrinol Metab. 2019;104:3481–90.

    PubMed  PubMed Central  Google Scholar 

  73. Shojaee-Moradie F, Ma Y, Lou S, Hovorka R, Umpleby AM. Prandial hypertriglyceridemia in metabolic syndrome is due to an overproduction of both chylomicron and VLDL triacylglycerol. Diabetes. 2013;62:4063–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Haidari M, Leung N, Mahbub F, Uffelman KD, Kohen-Avramoglu R, Lewis GF, et al. Fasting and postprandial overproduction of intestinally derived lipoproteins in an animal model of insulin resistance. Evidence that chronic fructose feeding in the hamster is accompanied by enhanced intestinal de novo lipogenesis and ApoB48-containing lipoprotein overproduction. J Biol Chem. 2002;277:31646–55.

    CAS  PubMed  Google Scholar 

  75. Al-Jawadi A, Patel CR, Shiarella RJ, Romelus E, Auvinen M, Guardia J, et al. Cell-type-specific, ketohexokinase-dependent induction by fructose of lipogenic gene expression in mouse small intestine. J Nutr. 2020.

  76. Federico LM, Naples M, Taylor D, Adeli K. Intestinal insulin resistance and aberrant production of apolipoprotein B48 lipoproteins in an animal model of insulin resistance and metabolic dyslipidemia: evidence for activation of protein tyrosine phosphatase-1B, extracellular signal-related kinase, and sterol regulatory element-binding protein-1c in the fructose-fed hamster intestine. Diabetes. 2006;55:1316–26.

    CAS  PubMed  Google Scholar 

  77. Lewis GF, Uffelman K, Naples M, Szeto L, Haidari M, Adeli K. Intestinal lipoprotein overproduction, a newly recognized component of insulin resistance, is ameliorated by the insulin sensitizer rosiglitazone: studies in the fructose-fed Syrian golden hamster. Endocrinology. 2005;146:247–55.

    CAS  PubMed  Google Scholar 

  78. Xiao C, Dash S, Morgantini C, Lewis GF. Novel role of enteral monosaccharides in intestinal lipoprotein production in healthy humans. Arterioscler Thromb Vasc Biol. 2013;33:1056–62.

    CAS  PubMed  Google Scholar 

  79. Do MH, Lee E, Oh MJ, Kim Y, Park HY. High-glucose or -fructose diet cause changes of the gut microbiota and metabolic disorders in mice without body weight change. Nutrients. 2018;10:639.

    Google Scholar 

  80. Volynets V, Louis S, Pretz D, Lang L, Ostaff MJ, Wehkamp J, et al. Intestinal barrier function and the gut microbiome are differentially affected in mice fed a Western-style diet or drinking water supplemented with fructose. J Nutr. 2017;147:770–80.

    CAS  PubMed  Google Scholar 

  81. Pang J, Xu W, Zhang X, Wong GL, Chan AW, Chan HY, et al. Significant positive association of endotoxemia with histological severity in 237 patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2017;46:175–82.

    CAS  PubMed  Google Scholar 

  82. Cho YE, Kim DK, Seo W, Gao B, Yoo SH, Song BJ. Fructose promotes leaky gut, endotoxemia, and liver fibrosis through ethanol-inducible cytochrome P450-2E1-mediated oxidative and nitrative stress. Hepatology. 2019. https://doi.org/10.1002/hep.30652.

  83. Bergheim I, Weber S, Vos M, Kramer S, Volynets V, Kaserouni S, et al. Antibiotics protect against fructose-induced hepatic lipid accumulation in mice: role of endotoxin. J Hepatol. 2008;48:983–92.

    CAS  PubMed  Google Scholar 

  84. Sen T, Cawthon CR, Ihde BT, Hajnal A, DiLorenzo PM, de La Serre CB, et al. Diet-driven microbiota dysbiosis is associated with vagal remodeling and obesity. Physiol Behav. 2017;173:305–17.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Ferrere G, Leroux A, Wrzosek L, Puchois V, Gaudin F, Ciocan D, et al. Activation of Kupffer cells is associated with a specific dysbiosis induced by fructose or high fat diet in mice. PLoS One. 2016;11:e0146177.

    PubMed  PubMed Central  Google Scholar 

  86. Wood IS, Trayhurn P. Glucose transporters (GLUT and SGLT): expanded families of sugar transport proteins. Br J Nutr. 2003;89:3–9.

    CAS  PubMed  Google Scholar 

  87. Debosch BJ, Chen Z, Saben JL, Finck BN, Moley KH. Glucose transporter 8 (GLUT8) mediates fructose-induced de novo lipogenesis and macrosteatosis. J Biol Chem. 2014;289:10989–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Schmidt S, Joost HG, Schurmann A. GLUT8, the enigmatic intracellular hexose transporter. Am J Physiol Endocrinol Metab. 2009;296:E614–8.

    CAS  PubMed  Google Scholar 

  89. Manolescu AR, Witkowska K, Kinnaird A, Cessford T, Cheeseman C. Facilitated hexose transporters: new perspectives on form and function. Physiology (Bethesda). 2007;22:234–40.

    CAS  Google Scholar 

  90. Zhang Y, Shaikh N, Ferey JL, Wankhade UD, Chintapalli SV, Higgins CB, et al. Lactotrehalose, an analog of trehalose, increases energy metabolism without promoting Clostridioides difficile infection in mice. Gastroenterology 2020;158:1402–1416 e1402.

    CAS  PubMed  Google Scholar 

  91. Ishimoto T, Lanaspa MA, Le MT, Garcia GE, Diggle CP, Maclean PS, et al. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci U S A. 2012;109:4320–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ishimoto T, Lanaspa MA, Rivard CJ, Roncal-Jimenez CA, Orlicky DJ, Cicerchi C, et al. High-fat and high-sucrose (western) diet induces steatohepatitis that is dependent on fructokinase. Hepatology. 2013;58:1632–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. . Softic S, Gupta MK, Wang GX, Fujisaka S, O'Neill BT, Rao TN, et al. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling. J Clin Invest. 2017;127:4059–74 This original research article demonstrates that fructose supplementation on a high-fat diet worsens metabolic complications as compared with a glucose-supplemented diet, despite similar caloric intake. Dietary fructose feeding led to increased SREBP1c-regulated gene expression and impaired hepatic insulin signaling, as compared to mice fed glucose.

    PubMed  PubMed Central  Google Scholar 

  94. Park TJ, Reznick J, Peterson BL, Blass G, Omerbasic D, Bennett NC, et al. Fructose-driven glycolysis supports anoxia resistance in the naked mole-rat. Science. 2017;356:307–11.

    CAS  PubMed  Google Scholar 

  95. Lanaspa MA, Sanchez-Lozada LG, Cicerchi C, Li N, Roncal-Jimenez CA, Ishimoto T, et al. Uric acid stimulates fructokinase and accelerates fructose metabolism in the development of fatty liver. PLoS One. 2012;7:e47948.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Shi JH, Lu JY, Chen HY, Wei CC, Xu X, Li H, et al. Liver ChREBP protects against fructose-induced glycogenic hepatotoxicity by regulating L-type pyruvate kinase. Diabetes. 2020;69:591–602.

    CAS  PubMed  Google Scholar 

  97. Ali M, Rellos P, Cox TM. Hereditary fructose intolerance. J Med Genet. 1998;35:353–65.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Lanaspa MA, Andres-Hernando A, Orlicky DJ, Cicerchi C, Jang C, Li N, et al. Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice. J Clin Invest. 2018;128:2226–38.

    PubMed  PubMed Central  Google Scholar 

  99. Softic S, Kirby M, Berger NG, Shroyer NF, Woods SC, Kohli R. Insulin concentration modulates hepatic lipid accumulation in mice in part via transcriptional regulation of fatty acid transport proteins. PLoS One. 2012;7:e38952.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Softic S, Cohen DE, Kahn CR. Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease. Dig Dis Sci. 2016;61:1282–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Swanson JE, Laine DC, Thomas W, Bantle JP. Metabolic effects of dietary fructose in healthy subjects. Am J Clin Nutr. 1992;55:851–6.

    CAS  PubMed  Google Scholar 

  102. Te Morenga LA, Howatson AJ, Jones RM, Mann J. Dietary sugars and cardiometabolic risk: systematic review and meta-analyses of randomized controlled trials of the effects on blood pressure and lipids. Am J Clin Nutr. 2014;100:65–79.

    Google Scholar 

  103. Taghibiglou C, Carpentier A, Van Iderstine SC, Chen B, Rudy D, Aiton A, et al. Mechanisms of hepatic very low density lipoprotein overproduction in insulin resistance. Evidence for enhanced lipoprotein assembly, reduced intracellular ApoB degradation, and increased microsomal triglyceride transfer protein in a fructose-fed hamster model. J Biol Chem. 2000;275:8416–25.

    CAS  PubMed  Google Scholar 

  104. Lustig RH, Mulligan K, Noworolski SM, Tai VW, Wen MJ, Erkin-Cakmak A, et al. Isocaloric fructose restriction and metabolic improvement in children with obesity and metabolic syndrome. Obesity (Silver Spring). 2016;24:453–60.

    CAS  Google Scholar 

  105. Gugliucci A, Lustig RH, Caccavello R, Erkin-Cakmak A, Noworolski SM, Tai VW, et al. Short-term isocaloric fructose restriction lowers apoC-III levels and yields less atherogenic lipoprotein profiles in children with obesity and metabolic syndrome. Atherosclerosis. 2016;253:171–7.

    CAS  PubMed  Google Scholar 

  106. Topping DL, Mayes PA. The concentration of fructose, glucose and lactate in the splanchnic blood vessels of rats absorbing fructose. Nutr Metab. 1971;13:331–8.

    CAS  PubMed  Google Scholar 

  107. Mendeloff AI, Weichselbaum TE. Role of the human liver in the assimilation of intravenously administered fructose. Metabolism. 1953;2:450–8.

    CAS  PubMed  Google Scholar 

  108. Heinz F, Lamprecht W, Kirsch J. Enzymes of fructose metabolism in human liver. J Clin Invest. 1968;47:1826–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  109. Ouyang X, Cirillo P, Sautin Y, McCall S, Bruchette JL, Diehl AM, et al. Fructose consumption as a risk factor for non-alcoholic fatty liver disease. J Hepatol. 2008;48:993–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  110. . Softic S, Meyer JG, Wang GX, Gupta MK, Batista TM, Lauritzen H, et al. Dietary sugars alter hepatic fatty acid oxidation via transcriptional and post-translational modifications of mitochondrial proteins. Cell Metab. 2019;30:735–753 e734 This original research article demonstrates that high-fat diet supplemented with fructose impairs mitochondrial size, function, and protein acetylation resulting in decreased fatty acid oxidation.

    CAS  PubMed  Google Scholar 

  111. Meyer JG, Softic S, Basisty N, Rardin MJ, Verdin E, Gibson BW, et al. Temporal dynamics of liver mitochondrial protein acetylation and succinylation and metabolites due to high fat diet and/or excess glucose or fructose. PLoS One. 2018;13:e0208973.

    PubMed  PubMed Central  Google Scholar 

  112. Wang G, Meyer JG, Cai W, Softic S, Li ME, Verdin E, et al. Regulation of UCP1 and mitochondrial metabolism in brown adipose tissue by reversible succinylation. Mol Cell. 2019;74:844–57 e847.

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Abdelmalek MF, Suzuki A, Guy C, Unalp-Arida A, Colvin R, Johnson RJ, et al. Nonalcoholic steatohepatitis clinical research N: increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver disease. Hepatology. 2010;51:1961–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Jin R, Le NA, Liu S, Farkas Epperson M, Ziegler TR, Welsh JA, et al. Children with NAFLD are more sensitive to the adverse metabolic effects of fructose beverages than children without NAFLD. J Clin Endocrinol Metab. 2012;97:E1088–98.

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, et al. Fructose and sugar: a major mediator of non-alcoholic fatty liver disease. J Hepatol. 2018;68:1063–75.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. 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;7:251–64.

    CAS  PubMed  Google Scholar 

  117. Yilmaz Y. Review article: fructose in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2012;35:1135–44.

    CAS  PubMed  Google Scholar 

  118. Softic S, Kahn CR. Fatty liver disease: is it nonalcoholic fatty liver disease or obesity-associated fatty liver disease? Eur J Gastroenterol Hepatol. 2019;31:143.

    PubMed  PubMed Central  Google Scholar 

  119. Attia SL, Softic S, Mouzaki M. Evolving role for pharmacotherapy in NAFLD/NASH. Clin Transl Sci. 2020.

  120. Macdonald I, Turner LJ. Serum-fructose levels after sucrose or its constituent monosaccharides. Lancet. 1968;1:841–3.

    CAS  PubMed  Google Scholar 

  121. Holdsworth CD, Dawson AM. Absorption of fructose in man. Proc Soc Exp Biol Med. 1965;118:142–5.

    CAS  PubMed  Google Scholar 

  122. Bjorkman O, Felig P. Role of the kidney in the metabolism of fructose in 60-hour fasted humans. Diabetes. 1982;31:516–20.

    CAS  PubMed  Google Scholar 

  123. Burant CF, Saxena M. Rapid reversible substrate regulation of fructose transporter expression in rat small intestine and kidney. Am J Phys. 1994;267:G71–9.

    CAS  Google Scholar 

  124. Leturque A, Brot-Laroche E, Le Gall M. GLUT2 mutations, translocation, and receptor function in diet sugar managing. Am J Physiol Endocrinol Metab. 2009;296:E985–92.

    CAS  PubMed  Google Scholar 

  125. Keembiyehetty C, Augustin R, Carayannopoulos MO, Steer S, Manolescu A, Cheeseman CI, et al. Mouse glucose transporter 9 splice variants are expressed in adult liver and kidney and are up-regulated in diabetes. Mol Endocrinol. 2006;20:686–97.

    CAS  PubMed  Google Scholar 

  126. Horiba N, Masuda S, Ohnishi C, Takeuchi D, Okuda M, Inui K. Na(+)-dependent fructose transport via rNaGLT1 in rat kidney. FEBS Lett. 2003;546:276–80.

    CAS  PubMed  Google Scholar 

  127. Tazawa S, Yamato T, Fujikura H, Hiratochi M, Itoh F, Tomae M, et al. SLC5A9/SGLT4, a new Na+-dependent glucose transporter, is an essential transporter for mannose, 1,5-anhydro-D-glucitol, and fructose. Life Sci. 2005;76:1039–50.

    CAS  Google Scholar 

  128. Grempler R, Augustin R, Froehner S, Hildebrandt T, Simon E, Mark M, et al. Functional characterisation of human SGLT-5 as a novel kidney-specific sodium-dependent sugar transporter. FEBS Lett. 2012;586:248–53.

    CAS  PubMed  Google Scholar 

  129. Fukuzawa T, Fukazawa M, Ueda O, Shimada H, Kito A, Kakefuda M, et al. SGLT5 reabsorbs fructose in the kidney but its deficiency paradoxically exacerbates hepatic steatosis induced by fructose. PLoS One. 2013;8:e56681.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Gonzalez-Vicente A, Cabral PD, Hong NJ, Asirwatham J, Saez F, Garvin JL. Fructose reabsorption by rat proximal tubules: role of Na(+)-linked cotransporters and the effect of dietary fructose. American Journal of Physiology Renal Physiology. 2019;316:F473–80.

    PubMed  Google Scholar 

  131. Heinz F, Schlegel F, Krause PH. Enzymes of fructose metabolism in human kidney. Enzyme. 1975;19:85–92.

    CAS  PubMed  Google Scholar 

  132. Kawasaki T, Akanuma H, Yamanouchi T. Increased fructose concentrations in blood and urine in patients with diabetes. Diabetes Care. 2002;25:353–7.

    CAS  PubMed  Google Scholar 

  133. Gomez-Samano MA, Almeda-Valdes P, Cuevas-Ramos D, Navarro-Flores MF, Espinosa-Salazar HD, Martinez-Saavedra M, et al. A higher fructose intake is associated with greater albuminuria in subjects with type 2 diabetes mellitus. International Journal of Nephrology. 2018;2018:5459439.

    PubMed  PubMed Central  Google Scholar 

  134. Shoham DA, Durazo-Arvizu R, Kramer H, Luke A, Vupputuri S, Kshirsagar A, et al. Sugary soda consumption and albuminuria: results from the National Health and Nutrition Examination Survey, 1999-2004. PLoS One. 2008;3:e3431.

    PubMed  PubMed Central  Google Scholar 

  135. Brymora A, Flisinski M, Johnson RJ, Goszka G, Stefanska A, Manitius J. Low-fructose diet lowers blood pressure and inflammation in patients with chronic kidney disease. Nephrol Dial Transplant. 2012;27:608–12.

    CAS  PubMed  Google Scholar 

  136. Cirillo P, Sato W, Reungjui S, Heinig M, Gersch M, Sautin Y, et al. Uric acid, the metabolic syndrome and renal disease. Journal of the American Society of Nephrology. 2006;17:S165–8.

    CAS  PubMed  Google Scholar 

  137. Johnson RJ, Nakagawa T, Sanchez-Lozada LG, Shafiu M, Sundaram S, Le M, et al. Sugar, uric acid, and the etiology of diabetes and obesity. Diabetes. 2013;62:3307–15.

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Maahs DM, Caramori L, Cherney DZ, Galecki AT, Gao C, Jalal D, et al. Uric acid lowering to prevent kidney function loss in diabetes: the Preventing Early Renal Function Loss (PERL) allopurinol study. Current Diabetes Reports. 2013;13:550–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Sanchez-Lozada LG, Soto V, Tapia E, Avila-Casado C, Sautin YY, Nakagawa T, et al. Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia. American Journal of Physiology Renal Physiology. 2008;295:F1134–41.

    CAS  PubMed  PubMed Central  Google Scholar 

  140. Lanaspa MA, Ishimoto T, Cicerchi C, Tamura Y, Roncal-Jimenez CA, Chen W, et al. Endogenous fructose production and fructokinase activation mediate renal injury in diabetic nephropathy. Journal of the American Society of Nephrology. 2014;25:2526–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Cirillo P, Gersch MS, Mu W, Scherer PM, Kim KM, Gesualdo L, et al. Ketohexokinase-dependent metabolism of fructose induces proinflammatory mediators in proximal tubular cells. Journal of the American Society of Nephrology. 2009;20:545–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Gersch MS, Mu W, Cirillo P, Reungjui S, Zhang L, Roncal C, et al. Fructose, but not dextrose, accelerates the progression of chronic kidney disease. American Journal of Physiology Renal Physiology. 2007;293:F1256–61.

    CAS  PubMed  Google Scholar 

  143. Nakayama T, Kosugi T, Gersch M, Connor T, Sanchez-Lozada LG, Lanaspa MA, et al. Dietary fructose causes tubulointerstitial injury in the normal rat kidney. American Journal of Physiology Renal Physiology. 2010;298:F712–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Burch HB, Choi S, Dence CN, Alvey TR, Cole BR, Lowry OH. Metabolic effects of large fructose loads in different parts of the rat nephron. J Biol Chem. 1980;255:8239–44.

    CAS  PubMed  Google Scholar 

  145. Doke T, Ishimoto T, Hayasaki T, Ikeda S, Hasebe M, Hirayama A, et al. Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice. Metab Clin Exp. 2018;85:161–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  146. Li X, Qian X, Peng LX, Jiang Y, Hawke DH, Zheng Y, et al. A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation. Nat Cell Biol. 2016;18:561–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Roncal Jimenez CA, Ishimoto T, Lanaspa MA, Rivard CJ, Nakagawa T, Ejaz AA, et al. Fructokinase activity mediates dehydration-induced renal injury. Kidney Int. 2014;86:294–302.

    CAS  PubMed  Google Scholar 

  148. Dvornik E, Simard-Duquesne N, Krami M, Sestanj K, Gabbay KH, Kinoshita JH, et al. Polyol accumulation in galactosemic and diabetic rats: control by an aldose reductase inhibitor. Science. 1973;182:1146–8.

    CAS  PubMed  Google Scholar 

  149. Roncal-Jimenez CA, Ishimoto T, Lanaspa MA, Milagres T, Hernando AA, Jensen T, et al. Aging-associated renal disease in mice is fructokinase dependent. American Journal of Physiology Renal Physiology. 2016;311:F722–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Andres-Hernando A, Li N, Cicerchi C, Inaba S, Chen W, Roncal-Jimenez C, et al. Protective role of fructokinase blockade in the pathogenesis of acute kidney injury in mice. Nat Commun. 2017;8:14181.

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Madero M, Perez-Pozo SE, Jalal D, Johnson RJ, Sanchez-Lozada LG. Dietary fructose and hypertension. Curr Hypertens Rep. 2011;13:29–35.

    CAS  PubMed  Google Scholar 

  152. Singh AK, Amlal H, Haas PJ, Dringenberg U, Fussell S, Barone SL, et al. Fructose-induced hypertension: essential role of chloride and fructose absorbing transporters PAT1 and Glut5. Kidney Int. 2008;74:438–47.

    CAS  PubMed  Google Scholar 

  153. Queiroz-Leite GD, Crajoinas RO, Neri EA, Bezerra CN, Girardi AC, Reboucas NA, et al. Fructose acutely stimulates NHE3 activity in kidney proximal tubule. Kidney & blood pressure research. 2012;36:320–34.

    CAS  Google Scholar 

  154. Hayasaki T, Ishimoto T, Doke T, Hirayama A, Soga T, Furuhashi K, et al. Fructose increases the activity of sodium hydrogen exchanger in renal proximal tubules that is dependent on ketohexokinase. J Nutr Biochem. 2019;71:54–62.

    CAS  PubMed  Google Scholar 

  155. Froesch ER, Ginsberg JL. Fructose metabolism of adipose tissue. I. Comparison of fructose and glucose metabolism in epididymal adipose tissue of normal rats. J Biol Chem. 1962;237:3317–24.

    CAS  PubMed  Google Scholar 

  156. Kayano T, Burant CF, Fukumoto H, Gould GW, Fan YS, Eddy RL, et al. Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem. 1990;265:13276–82.

    CAS  Google Scholar 

  157. Hajduch E, Darakhshan F, Hundal HS. Fructose uptake in rat adipocytes: GLUT5 expression and the effects of streptozotocin-induced diabetes. Diabetologia. 1998;41:821–8.

    CAS  PubMed  Google Scholar 

  158. Wood IS, Wang B, Lorente-Cebrian S, Trayhurn P. Hypoxia increases expression of selective facilitative glucose transporters (GLUT) and 2-deoxy-D-glucose uptake in human adipocytes. Biochem Biophys Res Commun. 2007;361:468–73.

    PubMed  Google Scholar 

  159. Zwarts I, van Zutphen T, Kruit JK, Liu W, Oosterveer MH, Verkade HJ, et al. Identification of the fructose transporter GLUT5 (SLC2A5) as a novel target of nuclear receptor LXR. Sci Rep. 2019;9:9299.

    PubMed  PubMed Central  Google Scholar 

  160. Matosin-Matekalo M, Mesonero JE, Laroche TJ, Lacasa M, Brot-Laroche E. Glucose and thyroid hormone co-regulate the expression of the intestinal fructose transporter GLUT5. Biochem J. 1999;339(Pt 2):233–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Mochizuki K, Yagi E, Sakaguchi N, Mochizuki H, Takabe S, Kuranuki S, et al. The critical period for thyroid hormone responsiveness through thyroid hormone receptor isoform alpha in the postnatal small intestine. Biochim Biophys Acta. 2007;1770:609–16.

    CAS  PubMed  Google Scholar 

  162. Douard V, Choi HI, Elshenawy S, Lagunoff D, Ferraris RP. Developmental reprogramming of rat GLUT5 requires glucocorticoid receptor translocation to the nucleus. J Physiol. 2008;586:3657–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Shepherd PR, Gibbs EM, Wesslau C, Gould GW, Kahn BB. Human small intestine facilitative fructose/glucose transporter (GLUT5) is also present in insulin-responsive tissues and brain. Investigation of biochemical characteristics and translocation. Diabetes. 1992;41:1360–5.

    CAS  PubMed  Google Scholar 

  164. Varma V, Boros LG, Nolen GT, Chang CW, Wabitsch M, Beger RD, et al. Metabolic fate of fructose in human adipocytes: a targeted (13)C tracer fate association study. Metabolomics. 2015;11:529–44.

    CAS  PubMed  Google Scholar 

  165. Du L, Heaney AP. Regulation of adipose differentiation by fructose and GluT5. Mol Endocrinol. 2012;26:1773–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Marek G, Pannu V, Shanmugham P, Pancione B, Mascia D, Crosson S, et al. Adiponectin resistance and proinflammatory changes in the visceral adipose tissue induced by fructose consumption via ketohexokinase-dependent pathway. Diabetes. 2015;64:508–18.

    CAS  PubMed  Google Scholar 

  167. Pollock NK, Bundy V, Kanto W, Davis CL, Bernard PJ, Zhu H, et al. Greater fructose consumption is associated with cardiometabolic risk markers and visceral adiposity in adolescents. J Nutr. 2012;142:251–7.

    CAS  PubMed  Google Scholar 

  168. Bremer AA, Stanhope KL, Graham JL, Cummings BP, Wang W, Saville BR, et al. Fructose-fed rhesus monkeys: a nonhuman primate model of insulin resistance, metabolic syndrome and type 2 diabetes. Clin Transl Sci. 2011;4:243–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Softic S, Boucher J, Solheim MH, Fujisaka S, Haering MF, Homan EP, et al. Lipodystrophy due to adipose tissue-specific insulin receptor knockout results in progressive NAFLD. Diabetes. 2016;65:2187–200.

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Laron Z. Essential benign fructosuria. Arch Dis Child. 1961;36:273–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Tran C. Inborn errors of fructose metabolism. What can we learn from them? Nutrients. 2017;9:356.

    PubMed Central  Google Scholar 

  172. Ahlborg G, Bjorkman O. Splanchnic and muscle fructose metabolism during and after exercise. J Appl Physiol (1985). 1990;69:1244–51.

    CAS  Google Scholar 

  173. Thurmond DC, Pessin JE. Molecular machinery involved in the insulin-regulated fusion of GLUT4-containing vesicles with the plasma membrane (review). Mol Membr Biol. 2001;18:237–45.

    CAS  PubMed  Google Scholar 

  174. Darakhshan F, Hajduch E, Kristiansen S, Richter EA, Hundal HS. Biochemical and functional characterization of the GLUT5 fructose transporter in rat skeletal muscle. Biochem J. 1998;336(Pt 2):361–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  175. Hajduch E, Litherland GJ, Turban S, Brot-Laroche E, Hundal HS. Insulin regulates the expression of the GLUT5 transporter in L6 skeletal muscle cells. FEBS Lett. 2003;549:77–82.

    CAS  PubMed  Google Scholar 

  176. Stuart CA, Howell ME, Yin D. Overexpression of GLUT5 in diabetic muscle is reversed by pioglitazone. Diabetes Care. 2007;30:925–31.

    CAS  PubMed  Google Scholar 

  177. Miller CO, Yang X, Lu K, Cao J, Herath K, Rosahl TW, et al. Ketohexokinase knockout mice, a model for essential fructosuria, exhibit altered fructose metabolism and are protected from diet-induced metabolic defects. Am J Physiol Endocrinol Metab. 2018;315:E386–93.

    CAS  PubMed  Google Scholar 

  178. Rai AK, Jaiswal N, Maurya CK, Sharma A, Ahmad I, Ahmad S, et al. Fructose-induced AGEs-RAGE signaling in skeletal muscle contributes to impairment of glucose homeostasis. J Nutr Biochem. 2019;71:35–44.

    CAS  PubMed  Google Scholar 

  179. Baena M, Sanguesa G, Davalos A, Latasa MJ, Sala-Vila A, Sanchez RM, et al. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues. Sci Rep. 2016;6:26149.

    CAS  PubMed  PubMed Central  Google Scholar 

  180. Togashi N, Ura N, Higashiura K, Murakami H, Shimamoto K. The contribution of skeletal muscle tumor necrosis factor-alpha to insulin resistance and hypertension in fructose-fed rats. J Hypertens. 2000;18:1605–10.

    CAS  PubMed  Google Scholar 

  181. Austin RL, Rune A, Bouzakri K, Zierath JR, Krook A. siRNA-mediated reduction of inhibitor of nuclear factor-kappaB kinase prevents tumor necrosis factor-alpha-induced insulin resistance in human skeletal muscle. Diabetes. 2008;57:2066–73.

    CAS  PubMed  PubMed Central  Google Scholar 

  182. del Aguila LF, Claffey KP, Kirwan JP. TNF-alpha impairs insulin signaling and insulin stimulation of glucose uptake in C2C12 muscle cells. Am J Phys. 1999;276:E849–55.

    Google Scholar 

  183. Rattanavichit Y, Chukijrungroat N, Saengsirisuwan V. Sex differences in the metabolic dysfunction and insulin resistance of skeletal muscle glucose transport following high fructose ingestion. Am J Physiol Regul Integr Comp Physiol. 2016;311:R1200–12.

    PubMed  Google Scholar 

  184. Douard V, Ferraris RP. The role of fructose transporters in diseases linked to excessive fructose intake. J Physiol. 2013;591:401–14.

    CAS  PubMed  Google Scholar 

  185. Mueckler M, Thorens B. The SLC2 (GLUT) family of membrane transporters. Mol Asp Med. 2013;34:121–38.

    CAS  Google Scholar 

  186. Kyriazis GA, Soundarapandian MM, Tyrberg B. Sweet taste receptor signaling in beta cells mediates fructose-induced potentiation of glucose-stimulated insulin secretion. Proc Natl Acad Sci U S A. 2012;109:E524–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Grant AM, Christie MR, Ashcroft SJ. Insulin release from human pancreatic islets in vitro. Diabetologia. 1980;19:114–7.

    CAS  PubMed  Google Scholar 

  188. Hayward BE, Bonthron DT. Structure and alternative splicing of the ketohexokinase gene. Eur J Biochem. 1998;257:85–91.

    CAS  PubMed  Google Scholar 

  189. Springer N, Lindbloom-Hawley S, Schermerhorn T. Tissue expression of ketohexokinase in cats. Res Vet Sci. 2009;87:115–7.

    CAS  PubMed  Google Scholar 

  190. Sener A, Giroix MH, Malaisse WJ. Hexose metabolism in pancreatic islets. The phosphorylation of fructose. Eur J Biochem. 1984;144:223–6.

    CAS  PubMed  Google Scholar 

  191. Malaisse WJ, Malaisse-Lagae F, Davies DR, Van Schaftingen E. Presence of fructokinase in pancreatic islets. FEBS Lett. 1989;255:175–8.

    CAS  PubMed  Google Scholar 

  192. Giroix MH, Jijakli H, Courtois P, Zhang Y, Sener A, Malaisse WJ. Fructokinase activity in rat liver, ileum, parotid gland, pancreas, pancreatic islet, B and non-B islet cell homogenates. Int J Mol Med. 2006;17:517–22.

    CAS  Google Scholar 

  193. Thurston JH, Levy CA, Warren SK, Jones EM. Permeability of the blood-brain barrier to fructose and the anaerobic use of fructose in the brains of young mice. J Neurochem. 1972;19:1685–96.

    CAS  PubMed  Google Scholar 

  194. Wolfgang MJ, Cha SH, Sidhaye A, Chohnan S, Cline G, Shulman GI, et al. Regulation of hypothalamic malonyl-CoA by central glucose and leptin. Proc Natl Acad Sci U S A. 2007;104:19285–90.

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Payne J, Maher F, Simpson I, Mattice L, Davies P. Glucose transporter Glut 5 expression in microglial cells. Glia. 1997;21:327–31.

    CAS  PubMed  Google Scholar 

  196. Mantych GJ, James DE, Devaskar SU. Jejunal/kidney glucose transporter isoform (Glut-5) is expressed in the human blood-brain barrier. Endocrinology. 1993;132:35–40.

    CAS  PubMed  Google Scholar 

  197. Nualart F, Godoy A, Reinicke K. Expression of the hexose transporters GLUT1 and GLUT2 during the early development of the human brain. Brain Res. 1999;824:97–104.

    CAS  PubMed  Google Scholar 

  198. Shu HJ, Isenberg K, Cormier RJ, Benz A, Zorumski CF. Expression of fructose sensitive glucose transporter in the brains of fructose-fed rats. Neuroscience. 2006;140:889–95.

    CAS  PubMed  Google Scholar 

  199. Vannucci SJ, Maher F, Simpson IA. Glucose transporter proteins in brain: delivery of glucose to neurons and glia. Glia. 1997;21:2–21.

    CAS  PubMed  Google Scholar 

  200. Cunningham P, Afzal-Ahmed I, Naftalin RJ. Docking studies show that D-glucose and quercetin slide through the transporter GLUT1. J Biol Chem. 2006;281:5797–803.

    CAS  PubMed  Google Scholar 

  201. Oldendorf WH. Brain uptake of radiolabeled amino acids, amines, and hexoses after arterial injection. Am J Phys. 1971;221:1629–39.

    CAS  Google Scholar 

  202. Hwang JJ, Johnson A, Cline G, Belfort-DeAguiar R, Snegovskikh D, Khokhar B, et al. Fructose levels are markedly elevated in cerebrospinal fluid compared to plasma in pregnant women. PLoS One. 2015;10:e0128582.

    PubMed  PubMed Central  Google Scholar 

  203. Hwang JJ, Jiang L, Hamza M, Dai F, Belfort-DeAguiar R, Cline G, et al. The human brain produces fructose from glucose. JCI Insight. 2017;2:e90508.

    PubMed  PubMed Central  Google Scholar 

  204. Oppelt SA, Zhang W, Tolan DR. Specific regions of the brain are capable of fructose metabolism. Brain Res. 2017;1657:312–22.

    CAS  PubMed  Google Scholar 

  205. Gaitonde MK, Richter D. Changes with age in the utilization of glucose carbon in liver and brain. J Neurochem. 1966;13:1309–16.

    CAS  PubMed  Google Scholar 

  206. Lowette K, Roosen L, Tack J, Vanden Berghe P. Effects of high-fructose diets on central appetite signaling and cognitive function. Front Nutr. 2015;2(5).

  207. Luo S, Monterosso JR, Sarpelleh K, Page KA. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards. Proc Natl Acad Sci U S A. 2015;112:6509–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Bantle JP. Is fructose the optimal low glycemic index sweetener? Nestle Nutr Workshop Ser Clin Perform Programme. 2006;11:83–95.

    CAS  PubMed  Google Scholar 

  209. Page KA, Chan O, Arora J, Belfort-Deaguiar R, Dzuira J, Roehmholdt B, et al. Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways. JAMA. 2013;309:63–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Cha SH, Wolfgang M, Tokutake Y, Chohnan S, Lane MD. Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake. Proc Natl Acad Sci U S A. 2008;105:16871–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  211. Woods SC, Lotter EC, McKay LD, Porte D Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 1979;282:503–5.

    CAS  PubMed  Google Scholar 

  212. Suga A, Hirano T, Kageyama H, Osaka T, Namba Y, Tsuji M, et al. Effects of fructose and glucose on plasma leptin, insulin, and insulin resistance in lean and VMH-lesioned obese rats. Am J Physiol Endocrinol Metab. 2000;278:E677–83.

    CAS  PubMed  Google Scholar 

  213. Lindqvist A, Baelemans A, Erlanson-Albertsson C. Effects of sucrose, glucose and fructose on peripheral and central appetite signals. Regul Pept. 2008;150:26–32.

    CAS  PubMed  Google Scholar 

  214. Burant CF, Takeda J, Brot-Laroche E, Bell GI, Davidson NO. Fructose transporter in human spermatozoa and small intestine is GLUT5. J Biol Chem. 1992;267:14523–6.

    CAS  Google Scholar 

  215. Shibata K, Fukuwatari T. High d(+)-fructose diet adversely affects testicular weight gain in weaning rats horizontal line protection by moderate d(+)-glucose diet. Nutr Metab Insights. 2013;6:29–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Concha II, Velasquez FV, Martinez JM, Angulo C, Droppelmann A, Reyes AM, et al. Human erythrocytes express GLUT5 and transport fructose. Blood. 1997;89:4190–5.

    CAS  PubMed  Google Scholar 

  217. Petersen A, Kappler F, Szwergold BS, Brown TR. Fructose metabolism in the human erythrocyte. Phosphorylation to fructose 3-phosphate. Biochem J. 1992;284(Pt 2):363–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Hamada Y, Araki N, Koh N, Nakamura J, Horiuchi S, Hotta N. Rapid formation of advanced glycation end products by intermediate metabolites of glycolytic pathway and polyol pathway. Biochem Biophys Res Commun. 1996;228:539–43.

    CAS  PubMed  Google Scholar 

  219. Kuck JF Jr. Glucose metabolism and fructose synthesis in the diabetic rat lens. Investig Ophthalmol. 1962;1:390–5.

    CAS  Google Scholar 

  220. Lal S, Szwergold BS, Taylor AH, Randall WC, Kappler F, Wells-Knecht K, et al. Metabolism of fructose-3-phosphate in the diabetic rat lens. Arch Biochem Biophys. 1995;318:191–9.

    CAS  PubMed  Google Scholar 

  221. Lee AY, Chung SK, Chung SS. Demonstration that polyol accumulation is responsible for diabetic cataract by the use of transgenic mice expressing the aldose reductase gene in the lens. Proc Natl Acad Sci U S A. 1995;92:2780–4.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Robert N. Helsley and Francois Moreau contributed equally to this work.

Authors and Affiliations

  1. Division of Pediatric Gastroenterology, Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, 40506, USA

    Robert N. Helsley & Samir Softic

  2. Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA

    Francois Moreau & Samir Softic

  3. Islet Cell and Regenerative Medicine, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA, 02215, USA

    Manoj K. Gupta

  4. Department of Pediatrics, University of Kentucky College of Medicine and Kentucky Children’s Hospital, Lexington, KY, 40536, USA

    Aurelia Radulescu

  5. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63131, USA

    Brian DeBosch

  6. Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, 138 Leader Ave, Lexington, KY, 40506, USA

    Samir Softic

Authors
  1. Robert N. Helsley
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Francois Moreau
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Manoj K. Gupta
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aurelia Radulescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Brian DeBosch
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Samir Softic
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Samir Softic.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Pathogenesis of Type 2 Diabetes and Insulin Resistance

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Helsley, R.N., Moreau, F., Gupta, M.K. et al. Tissue-Specific Fructose Metabolism in Obesity and Diabetes. Curr Diab Rep 20, 64 (2020). https://doi.org/10.1007/s11892-020-01342-8

Download citation

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11892-020-01342-8

Keywords

Search

Navigation