Effects of fructose restriction on liver steatosis (FRUITLESS); a double-blind randomized controlled trial
Open accessAbstract
BACKGROUND: There is an ongoing debate on whether fructose plays a role in the development of nonalcoholic fatty liver disease. OBJECTIVES: The aim of this study was to investigate the effects of fructose restriction on intrahepatic lipid (IHL) content in a double-blind randomized controlled trial using an isocaloric comparator. METHODS: Between March 2017 and October 2019, 44 adult overweight individuals with a fatty liver index ≥ 60 consumed a 6-wk fructose-restricted diet (<7.5 g/meal and <10 g/d) and were randomly assigned to supplementation with sachets of glucose (= intervention group) or fructose (= control group) 3 times daily. Participants and assessors were blinded to the allocation. IHL content, assessed by proton magnetic resonance spectroscopy, was the primary outcome and glucose tolerance and serum lipids were the secondary outcomes. All measurements were conducted in Maastricht University Medical Center. RESULTS: Thirty-seven participants completed the study protocol. After 6 wk of fructose restriction, dietary fructose intake and urinary fructose excretion were significantly lower in the intervention group (difference: -57.0 g/d; 95% CI: -77.9, -39.5 g/d; and -38.8 μmol/d; 95% CI: -91.2, -10.7 μmol/d, respectively). Although IHL content decreased in both the intervention and control groups (P < 0.001 and P = 0.003, respectively), the change in IHL content was more pronounced in the intervention group (difference: -0.7% point, 95% CI: -2.0, -0.03% point). The changes in glucose tolerance and serum lipids were not significantly different between groups. CONCLUSIONS: Six weeks of fructose restriction per se led to a small, but statistically significant, decrease in IHL content in comparison with an isocaloric control group.This trial was registered at clinicaltrials.gov as NCT03067428.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Evidence from RCTs and a large prospective observational study shows an association of dietary added sugars, especially in the form of sugar-sweetened beverages, with increased liver steatosis, the incidence and prevalence of MASLD, and potentially the risk of MASH.
“Evidence from RCTs and a large prospective observational study shows an association of dietary added sugars, especially in the form of sugarsweetened beverages, with increased liver steatosis, the incidence and prevalence of MASLD, 305 -307 and potentially the risk of MASH. 308”
From EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). (2024) · cites this paper as [305]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cook, R. J., Dickens, B. M., & Fathalla, M. F. (2003) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780199241323.003.0025 · Cited by 10,813 · see citing works
EASL–EASD–EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease
(2016) · Journal of Hepatology · doi:10.1016/j.jhep.2015.11.004 · Cited by 4,836 · see citing works
Bedogni, G., Bellentani, S., Miglioli, L., Masutti, F., Passalacqua, M., Castiglione, A., & Tiribelli, C. (2006) · BMC Gastroenterology · doi:10.1186/1471-230x-6-33 · Cited by 3,054 · see citing works
Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity
Bray, G. A., Nielsen, S. J., & Popkin, B. M. (2004) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/79.4.537 · Cited by 1,990 · see citing works
The Hawthorne Effect: a randomised, controlled trial
McCarney, R., Warner, J. P., Iliffe, S., van Haselen, R. A., Griffin, M., & Fisher, P. (2007) · BMC Medical Research Methodology · doi:10.1186/1471-2288-7-30 · Cited by 1,730 · see citing works
Schulze, M. B. (2004) · JAMA · doi:10.1001/jama.292.8.927 · Cited by 1,639 · see citing works
Szczepaniak, L. S., Nurenberg, P., Leonard, D. S., Browning, J. D., Reingold, J. S., Grundy, S. M., Hobbs, H. H., & Dobbins, R. L. (2004) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00064.2004 · Cited by 1,562 · see citing works
Speliotes, E. K., Yerges-Armstrong, L. M., Wu, J., Hernaez, R., Kim, L. J., Palmer, C. D., Gudnason, V., Eiriksdottir, G., Garcia, M. E., Launer, L. J., et al. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1001324 · Cited by 984 · see citing works
Fructose and sugar: A major mediator of non-alcoholic fatty liver disease
Jensen, T., Abdelmalek, M. F., Sullivan, S. A., Nadeau, K. J., Cree‐Green, M., Roncal, C., Nakagawa, T., Kuwabara, M., Sato, Y., Kang, D., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.01.019 · Cited by 952 · see citing works
Added sugar intake and cardiovascular diseases mortality among US adults
Yang, Q., Zhang, Z., Gregg, E. W., Flanders, W. D., Merritt, R., & Hu, F. B. (2014) · JAMA Internal Medicine · doi:10.1001/jamainternmed.2013.13563 · Cited by 947 · see citing works
Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress
Lanaspa, M. A., Sánchez‐Lozada, L. G., Choi, Y.-J., Cicerchi, C., Kanbay, M., Roncal-Jiménez, C. A., Ishimoto, T., Li, N., Marek, G. W., Duranay, M., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.399899 · Cited by 718 · see citing works
Lipid droplets and liver disease: from basic biology to clinical implications
Gluchowski, N. L., Becuwe, M., Walther, T. C., & Farese, R. V. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2017.32 · Cited by 675 · see citing works
The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids
Jang, C., Hui, S., Lu, W., Cowan, A. J., Morscher, R. J., Lee, G., Liu, W., Tesz, G. J., Birnbaum, M. J., & Rabinowitz, J. D. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.12.016 · Cited by 639 · see citing works
Fructose metabolism and metabolic disease
Hannou, S. A., Haslam, D. E., McKeown, N. M., & Herman, M. A. (2018) · Journal of Clinical Investigation · doi:10.1172/jci96702 · Cited by 561 · see citing works
Samuel, V. T., Liu, Z.-X., Wang, A., Beddow, S. A., Geisler, J. G., Kahn, M., Zhang, X.-M., Monia, B. P., Bhanot, S., & Shulman, G. I. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30400 · Cited by 497 · see citing works
Li, L., Liu, D., Yan, H., Wang, Z., Zhao, S. ‐., & Wang, B. (2016) · Obesity Reviews · doi:10.1111/obr.12407 · Cited by 445 · see citing works
Luukkonen, P. K., Sädevirta, S., Zhou, Y., Kayser, B., Ali, A., Ahonen, L., Lallukka, S., Pelloux, V., Gaggini, M., Jian, C., et al. (2018) · Diabetes Care · doi:10.2337/dc18-0071 · Cited by 428 · see citing works
Lê, K., Ith, M., Kreis, R., Faeh, D., Bortolotti, M., Tran, C., Boesch, C., & Tappy, L. (2009) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.27336 · Cited by 396 · see citing works
Koehler, E. M., Schouten, J. N. L., Hansen, B. E., Albert Hofman, D., Stricker, B. H. C., & Janssen, H. L. A. (2013) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2012.12.031 · Cited by 340 · see citing works
Chiu, S., Sievenpiper, J. L., de Souza, R. J., Cozma, A. I., Mirrahimi, A., Carleton, A. J., Ha, V, Di Buono, M., Jenkins, A. L., Leiter, L. A., et al. (2014) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2014.8 · Cited by 314 · see citing works
Fructose metabolism in humans – what isotopic tracer studies tell us
Sun, S. Z., & Empie, M. W. (2012) · Nutrition & Metabolism · doi:10.1186/1743-7075-9-89 · Cited by 311 · see citing works
Markova, M., Pivovarova‐Ramich, O., Hornemann, S., Sucher, S., Frahnow, T., Wegner, K., Machann, J., Petzke, K. J., Hierholzer, J., Lichtinghagen, R., et al. (2016) · Gastroenterology · doi:10.1053/j.gastro.2016.10.007 · Cited by 275 · see citing works
Schwarz, J., Noworolski, S. M., Erkin‐Cakmak, A., Korn, N. J., Wen, M., Tai, V., Jones, G. M., Palii, S. P., Velasco-Alin, M., Pan, K. D. H., et al. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.05.043 · Cited by 272 · see citing works
Sagun, K. C., Cárcamo, J. M., & Golde, D. W. (2005) · The FASEB Journal · doi:10.1096/fj.05-4107com · Cited by 243 · see citing works
Fructose-Induced Fatty Liver Disease
Ackerman, Z., Oron‐Herman, M., Grozovski, M., Rosenthal, T., Pappo, O., Link, G., & Sela, B. (2005) · Hypertension · doi:10.1161/01.hyp.0000164570.20420.67 · Cited by 223 · see citing works
Impairment of hepatic Stat-3 activation and reduction of PPARα activity in fructose-fed rats
Roglans, N., Vilà, L., Farré, M., Alegret, M., Sánchez, R. M., Vázquez‐Carrera, M., & Laguna, J. C. (2007) · Hepatology · doi:10.1002/hep.21499 · Cited by 221 · see citing works
Nonalcoholic fatty liver disease and serum lipoproteins: The Multi-Ethnic Study of Atherosclerosis
DeFilippis, A. P., Blaha, M. J., Martin, S. S., Reed, R. M., Jones, S. R., Nasir, K., Blumenthal, R. S., & Budoff, M. J. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.01.022 · Cited by 219 · see citing works
Sevastianova, K., Santos, A., Kotronen, A., Hakkarainen, A., Makkonen, J., Silander, K., Peltonen, M., Romeo, S., Lundbom, J., Lundbom, N., et al. (2012) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.112.038695 · Cited by 211 · see citing works
Kechagias, S., Ernersson, Å., Dahlqvist, O. L., Lundberg, P., Lindström, T., Nyström, F. H., & for the Fast Food Study Group (2008) · Gut · doi:10.1136/gut.2007.131797 · Cited by 200 · see citing works
Guiu, B., Petit, J., Loffroy, R., Salem, D. B., Aho, S., Masson, D., Hillon, P., Krause, D., & Cercueil, J. (2008) · Radiology · doi:10.1148/radiol.2493080217 · Cited by 189 · see citing works
Urinary Sucrose and Fructose as Biomarkers for Sugar Consumption
Tasevska, N., Runswick, S. A., McTaggart, A., & Bingham, S. A. (2005) · Cancer Epidemiology Biomarkers & Prevention · doi:10.1158/1055-9965.epi-04-0827 · Cited by 179 · see citing works
Cuthbertson, D. J., Weickert, M. O., Lythgoe, D. T., Sprung, V. S., Dobson, R., Shoajee-Moradie, F., Umpleby, A. M., Pfeiffer, A. F. H., Thomas, E. L., Bell, J. D., et al. (2014) · European Journal of Endocrinology · doi:10.1530/eje-14-0112 · Cited by 164 · see citing works
Sobrecases, H., Lê, K.-A., Bortolotti, M., Schneiter, P., Ith, M., Kreis, R., Boesch, C., & Tappy, L. (2010) · Diabetes & Metabolism · doi:10.1016/j.diabet.2010.03.003 · Cited by 161 · see citing works
Yang, B.-L., Wu, W.-C., Fang, K., Wang, Y., Huo, T., Huang, Y., Yang, H., Su, C., Lin, H.-C., Lee, F., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0120443 · Cited by 158 · see citing works
Stimulating Effects of Low-Dose Fructose on Insulin-Stimulated Hepatic Glycogen Synthesis in Humans
Petersen, K. F., Laurent, D., Yu, C., Cline, G. W., & Shulman, G. I. (2001) · Diabetes · doi:10.2337/diabetes.50.6.1263 · Cited by 149 · see citing works
High protein intake reduces intrahepatocellular lipid deposition in humans
Bortolotti, M., Kreis, R., Debard, C., Cariou, B., Faeh, D., Chetiveaux, M., Ith, M., Vermathen, P., Stefanoni, N., Lê, K.-A., et al. (2009) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.2008.27296 · Cited by 146 · see citing works
Johnson, R. J., Stenvinkel, P., Andrews, P., et al. (2019) · Journal of Internal Medicine · doi:10.1111/joim.12993 · Cited by 122 · see citing works
Koo, H.-Y., Miyashita, M., Cho, B. H. S., & Nakamura, M. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.09.109 · Cited by 105 · see citing works
Thymosin alpha 1 attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats
Armutçu, F., Çoşkun, Ö., Gürel, A., Kanter, M., Can, M., Uçar, F., & Ünalacak, M. (2005) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2005.01.013 · Cited by 102 · see citing works
DiStefano, J. K. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03390-0 · Cited by 82 · see citing works
Shiota, M., Moore, M. C., Galassetti, P. R., Monohan, M., Neal, D. W., Shulman, G. I., & Cherrington, A. D. (2002) · Diabetes · doi:10.2337/diabetes.51.2.469 · Cited by 76 · see citing works
Fructose consumption in the Netherlands: the Dutch national food consumption survey 2007–2010
Sluik, D., Engelen, A. I., & Feskens, E. J. M. (2014) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2014.267 · Cited by 72 · see citing works
Self-citationLindeboom, L., Nabuurs, C. I. H. C., Hesselink, M. K. C., Wildberger, J. E., Schrauwen, P., & Schrauwen‐Hinderling, V. B. (2014) · American Journal of Clinical Nutrition · doi:10.3945/ajcn.114.094730 · Cited by 67 · see citing works
Self-citationBuziau, A. M., Schalkwijk, C. G., Stehouwer, C. D. A., Tolan, D. R., & Brouwers, M. C. G. J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03348-2 · Cited by 60 · see citing works
Self-citationPatients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content
Simons, N., Debray, F., Schaper, N. C., Kooi, M. E., Feskens, E. J. M., Hollak, C. E. M., Lindeboom, L., Koek, G. H., Bons, J. A. P., Lefeber, D. J., et al. (2019) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-02795 · Cited by 55 · see citing works
Self-citationFructose vs. glucose and metabolism
Sievenpiper, J. L., de Souza, R. J., Cozma, A. I., Chiavaroli, L., Ha, V., & Mirrahimi, A. (2013) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000042 · Cited by 50 · see citing works
Independent tissue contributors to obesity-associated insulin resistance
Kusters, Y. H. A. M., Schalkwijk, C. G., Houben, A. J. H. M., Kooi, M. E., Lindeboom, L., Roodt, J. O. ’., Joris, P. J., Plat, J., Mensink, R. P., Barrett, E. J., et al. (2017) · JCI Insight · doi:10.1172/jci.insight.89695 · Cited by 42 · see citing works
Self-citationWang, B., Li, M., Zhao, Z., Wang, S., Lu, J., Chen, Y., Xu, M., Wang, W., Ning, G., Bi, Y., et al. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa112 · Cited by 26 · see citing works
Sugar: fruit fructose is still healthy
Sievenpiper, J. L., de Souza, R. J., & Jenkins, D. J. A. (2012) · Nature · doi:10.1038/482470e · Cited by 23 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Tacke, F., Horn, P., Wai-Sun Wong, V., Ratziu, V., Bugianesi, E., Francque, S., Zelber-Sagi, S., Valenti, L., Roden, M., Schick, F., et al. (2024) · Journal of Hepatology · doi:10.1016/j.jhep.2024.04.031 · Cited by 2,210 · see citing works
Lifestyle interventions in nonalcoholic fatty liver disease
Younossi, Z. M., Zelber-Sagi, S., Henry, L., & Gerber, L. H. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00800-4 · Cited by 281 · see citing works
One size does not fit all; practical, personal tailoring of the diet to <scp>NAFLD</scp> patients
Zelber‐Sagi, S., Grinshpan, L. S., Ivancovsky‐Wajcman, D., Goldenshluger, A., & Gepner, Y. (2022) · Liver International · doi:10.1111/liv.15335 · Cited by 49 · see citing works
- Authors
- Simons, N., Veeraiah, P., Simons, P. I., Schaper, N. C., Kooi, M. E., Schrauwen-Hinderling, V. B., Feskens, E. J., van der Ploeg, E. (., Van den Eynde, M. D., Schalkwijk, C. G., Stehouwer, C. D., & Brouwers, M. C.
- Affiliations
- Maastricht University Medical Centre (NL)
- Wageningen University & Research (NL)
- Corresponding author
- Brouwers, Martijn CGJ
- ORCID
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 113
- Issue
- 2
- Pages
- 391-400
- ISSN
- 0002-9165 (ISSN-L)
- PMC
- PMC7851818
- OpenAlex
- W3114385977
- Cited by
- 74
- References
- 50
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 13 · 2023: 12 · 2022: 17 · 2021: 11 · 2020: 1 · 2018: 1
- FWCI
- 7.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- American Journal of Clinical Nutrition (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by-nc)
- Socio-Environmental Systems Modeling (acceptedVersion, cc-by-nc)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc)
- Funders
- Nutricia Research Foundation (2016-33)
- Netherlands Heart Foundation (2015T042)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Keywords
- fructose restriction, non-alcoholic fatty liver disease, dietary fructose, glucose supplementation, isocaloric diet, glucose tolerance, serum lipids, overweight adults
- MeSH terms
- Adult, Blood Glucose, Diet, Dietary Carbohydrates, Double-Blind Method, Female, Fructose, Humans, Liver, Male, Middle Aged, Glucose Intolerance, Non-alcoholic Fatty Liver Disease
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
