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Agarwal V, Das S, Kapoor N, Prusty B, Das B. Dietary Fructose: A Literature Review of Current Evidence and Implications on Metabolic Health. Cureus 2024; 16:e74143. [PMID: 39712814 PMCID: PMC11663027 DOI: 10.7759/cureus.74143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 11/21/2024] [Indexed: 12/24/2024] Open
Abstract
With the increasing intake of dietary fructose, primarily from sucrose and sweetened beverages, metabolic illnesses such as type 2 diabetes mellitus, hypertension, fatty liver disease, dyslipidemia, and hyperuricemia have become more prevalent worldwide, and there is also growing concern about the development of malignancies. These negative health impacts have been validated in various meta-analyses and randomized controlled trials. In contrast, the naturally occurring fructose found in fruits and vegetables contains only a minimal amount of fructose and, when consumed in moderation, may be a healthier choice. This review focuses on the biology of fructose, including its dietary sources, the physiology of its metabolism, and the pathological basis of various disorders related to high dietary fructose intake.
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Affiliation(s)
- Vishal Agarwal
- Endocrinology, Diabetes and Metabolism, Kalinga Institute of Medical Sciences, Bhubaneswar, IND
| | - Sambit Das
- Endocrinology, Diabetes and Metabolism, Kalinga Institute of Medical Sciences, Bhubaneswar, IND
| | - Nitin Kapoor
- Endocrinology, Diabetes and Metabolism, Christian Medical College and Hospital, Vellore, IND
| | - Binod Prusty
- Endocrinology, Diabetes and Metabolism, Kalinga Institute of Medical Sciences, Bhubaneswar, IND
| | - Bijay Das
- Endocrinology, Diabetes and Metabolism, Kalinga Institute of Medical Sciences, Bhubaneswar, IND
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Hsu WF, Lee MH, Lii CK, Peng CY. No Difference in Liver Damage Induced by Isocaloric Fructose or Glucose in Mice with a High-Fat Diet. Nutrients 2024; 16:3571. [PMID: 39458565 PMCID: PMC11510609 DOI: 10.3390/nu16203571] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 10/13/2024] [Accepted: 10/17/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: The diverse effects of fructose and glucose on the progression of metabolic dysfunction-associated steatotic liver disease remain uncertain. This study investigated the effects, in animal models, of high-fat diets (HFDs) supplemented with either glucose or fructose. Methods: Six-week-old, male C57BL/6J mice were randomly allocated to four groups: normal diet (ND), HFD, HFD supplemented with fructose (30% w/v, HFD + Fru), and HFD supplemented with glucose (initially 30%, HFD + Glu). After 24 weeks, liver and plasma samples were gathered for analysis. In addition, 39 patients with obesity undergoing bariatric surgery with wedge liver biopsy were enrolled in the clinical study. Results: The HFD + Glu group consumed more water than did the HFD and HFD + Fru groups. Thus, we reduced the glucose concentration from 30% at baseline to 15% at week 2 and 10% starting from week 6. The HFD + Fru and HFD + Glu groups had a similar average caloric intake (p = 0.463). The HFD increased hepatic steatosis, plasma lipid levels, lipogenic enzymes, steatosis-related oxidative stress, hepatic inflammation, and early-stage liver fibrosis. Supplementation with fructose or glucose exacerbated liver damage, but no significant differences were identified between the two. The expression patterns of hepatic ceramides in HFD-fed mice (with or without supplemental fructose or glucose) were similar to those observed in patients with obesity and severe hepatic steatosis or metabolic dysfunction-associated steatohepatitis. Conclusions: Fructose and glucose similarly exacerbated liver damage when added to an HFD. Ceramides may be involved in the progression of hepatic lipotoxicity.
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Affiliation(s)
- Wei-Fan Hsu
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404327, Taiwan
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404333, Taiwan
- School of Chinese Medicine, China Medical University, Taichung 404328, Taiwan
| | - Ming-Hsien Lee
- Metabolic and Bariatric Surgical Department, Taichung Tzu Chi Hospital, Taichung 427003, Taiwan
| | - Chong-Kuei Lii
- Department of Nutrition, China Medical University, Taichung 404328, Taiwan
| | - Cheng-Yuan Peng
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404327, Taiwan
- School of Medicine, China Medical University, Taichung 406040, Taiwan
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Garvey SM, LeMoire A, Wang J, Lin L, Sharif B, Bier A, Boyd RC, Baisley J. Safety and Tolerability of Microbial Inulinase Supplementation in Healthy Adults: A Randomized, Placebo-Controlled Trial. GASTRO HEP ADVANCES 2024; 3:920-930. [PMID: 39318719 PMCID: PMC11419904 DOI: 10.1016/j.gastha.2024.05.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 05/31/2024] [Indexed: 09/26/2024]
Abstract
Background and Aims Dietary fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) contribute to gastrointestinal (GI) symptoms in individuals with FODMAP sensitivity and irritable bowel syndrome. Oral enzyme supplementation is a strategy to reduce dietary FODMAP exposure and limit FODMAP-associated GI distress. This clinical trial investigated the safety of dietary supplementation with a food-grade, microbial inulinase known to hydrolyze fructan-type or inulin-type FODMAPs and related fructo-oligosaccharides in vitro. Methods A randomized, double-blind, placebo-controlled, parallel design trial was conducted in 60 healthy adult participants of both sexes. Following a 2-week run-in placebo phase, participants were randomized to consume inulinase or placebo capsules twice daily with meals for 4 weeks. The total daily dose of inulinase was 2000 inulinase activity units. Safety measures included blood clinical chemistry, hematology, lipid profile, high-sensitivity C-reactive protein, insulin, lactate, and uric acid. GI symptoms were recorded weekly using the 15-item Gastrointestinal Symptom Rating Scale. Results Fifty-eight participants completed the study. There were no clinically meaningful between-group differences in blood biomarkers. During the 4-week intervention period, 5 (16.7%) of 30 participants reported 5 adverse events in the inulinase group, and 8 (26.7%) of 30 participants reported 13 adverse events in the placebo group. No statistically significant between-group differences were observed in the change from baseline to 1, 2, 3, or 4 weeks of supplementation with respect to the 15-item Gastrointestinal Symptom Rating Scale overall or domain scores. Conclusion Microbial inulinase supplementation demonstrated a favorable safety profile in healthy adults. Further investigation in a dose-ranging study in individuals with dietary FODMAP, fructan, or inulin sensitivity or irritable bowel syndrome is warranted. ClinicalTrials.gov: NCT05744700.
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Affiliation(s)
| | - Ashley LeMoire
- Nutrasource Pharmaceutical and Nutraceutical Services, Inc, Guelph, Ontario, Canada
| | - Jun Wang
- Nutrasource Pharmaceutical and Nutraceutical Services, Inc, Guelph, Ontario, Canada
| | - Lois Lin
- Nutrasource Pharmaceutical and Nutraceutical Services, Inc, Guelph, Ontario, Canada
| | - Bisma Sharif
- Nutrasource Pharmaceutical and Nutraceutical Services, Inc, Guelph, Ontario, Canada
| | - Anthony Bier
- Nutrasource Pharmaceutical and Nutraceutical Services, Inc, Guelph, Ontario, Canada
| | | | - Joshua Baisley
- Nutrasource Pharmaceutical and Nutraceutical Services, Inc, Guelph, Ontario, Canada
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Simonsson C, Nyman E, Gennemark P, Gustafsson P, Hotz I, Ekstedt M, Lundberg P, Cedersund G. A unified framework for prediction of liver steatosis dynamics in response to different diet and drug interventions. Clin Nutr 2024; 43:1532-1543. [PMID: 38754305 DOI: 10.1016/j.clnu.2024.05.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/11/2024] [Accepted: 05/07/2024] [Indexed: 05/18/2024]
Abstract
BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disorder, characterized by the accumulation of excess fat in the liver, and is a driving factor for various severe liver diseases. These multi-factorial and multi-timescale changes are observed in different clinical studies, but these studies have not been integrated into a unified framework. In this study, we aim to present such a unified framework in the form of a dynamic mathematical model. METHODS For model training and validation, we collected data for dietary or drug-induced interventions aimed at reducing or increasing liver fat. The model was formulated using ordinary differential equations (ODEs) and the mathematical analysis, model simulation, model formulation and the model parameter estimation were all performed in MATLAB. RESULTS Our mathematical model describes accumulation of fat in the liver and predicts changes in lipid fluxes induced by both dietary and drug interventions. The model is validated using data from a wide range of drug and dietary intervention studies and can predict both short-term (days) and long-term (weeks) changes in liver fat. Importantly, the model computes the contribution of each individual lipid flux to the total liver fat dynamics. Furthermore, the model can be combined with an established bodyweight model, to simulate even longer scenarios (years), also including the effects of insulin resistance and body weight. To help prepare for corresponding eHealth applications, we also present a way to visualize the simulated changes, using dynamically changing lipid droplets, seen in images of liver biopsies. CONCLUSION In conclusion, we believe that the minimal model presented herein might be a useful tool for future applications, and to further integrate and understand data regarding changes in dietary and drug induced changes in ectopic TAG in the liver. With further development and validation, the minimal model could be used as a disease progression model for steatosis.
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Affiliation(s)
- Christian Simonsson
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden; Department of Radiation Physics, Radiology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Elin Nyman
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden
| | - Peter Gennemark
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter Gustafsson
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Department of Media and Information Technology, Linköping University, Norrköping, Sweden
| | - Ingrid Hotz
- Department of Media and Information Technology, Linköping University, Norrköping, Sweden
| | - Mattias Ekstedt
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden; Department of Gastroenterology and Hepatology, Department of Health, Medicine and Caring Sciences, Linköping University, Sweden
| | - Peter Lundberg
- Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden; Department of Radiation Physics, Radiology, Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
| | - Gunnar Cedersund
- Department of Biomedical Engineering, Linköping University, Linköping, Sweden; Center for Medical Image Science and Visualization (CMIV), Linköping University, Linköping, Sweden.
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Hieronimus B, Medici V, Lee V, Nunez MV, Sigala DM, Bremer AA, Cox CL, Keim NL, Schwarz JM, Pacini G, Tura A, Havel PJ, Stanhope KL. Effects of Consuming Beverages Sweetened with Fructose, Glucose, High-Fructose Corn Syrup, Sucrose, or Aspartame on OGTT-Derived Indices of Insulin Sensitivity in Young Adults. Nutrients 2024; 16:151. [PMID: 38201980 PMCID: PMC10780640 DOI: 10.3390/nu16010151] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2023] [Revised: 12/28/2023] [Accepted: 12/29/2023] [Indexed: 01/12/2024] Open
Abstract
(1) Background: Clinical results on the effects of excess sugar consumption on insulin sensitivity are conflicting, possibly due to differences in sugar type and the insulin sensitivity index (ISI) assessed. Therefore, we compared the effects of consuming four different sugars on insulin sensitivity indices derived from oral glucose tolerance tests (OGTT). (2) Methods: Young adults consumed fructose-, glucose-, high-fructose corn syrup (HFCS)-, sucrose-, or aspartame-sweetened beverages (SB) for 2 weeks. Participants underwent OGTT before and at the end of the intervention. Fasting glucose and insulin, Homeostatic Model Assessment-Insulin Resistance (HOMA-IR), glucose and insulin area under the curve, Surrogate Hepatic Insulin Resistance Index, Matsuda ISI, Predicted M ISI, and Stumvoll Index were assessed. Outcomes were analyzed to determine: (1) effects of the five SB; (2) effects of the proportions of fructose and glucose in all SB. (3) Results: Fructose-SB and the fructose component in mixed sugars negatively affected outcomes that assess hepatic insulin sensitivity, while glucose did not. The effects of glucose-SB and the glucose component in mixed sugar on muscle insulin sensitivity were more negative than those of fructose. (4) Conclusion: the effects of consuming sugar-SB on insulin sensitivity varied depending on type of sugar and ISI index because outcomes assessing hepatic insulin sensitivity were negatively affected by fructose, and outcomes assessing muscle insulin sensitivity were more negatively affected by glucose.
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Affiliation(s)
- Bettina Hieronimus
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA; (B.H.)
- Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, 76131 Karlsruhe, Germany
| | - Valentina Medici
- Division of Gastroenterology and Hepatology, University of California, Davis, CA 95616, USA
| | - Vivien Lee
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA; (B.H.)
| | | | - Desiree M. Sigala
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA; (B.H.)
- Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, 76131 Karlsruhe, Germany
| | - Andrew A. Bremer
- Department of Pediatrics, School of Medicine, University of California, Davis, CA 95616, USA
| | - Chad L. Cox
- Department of Chemistry and Department of Family and Consumer Sciences, California State University, Sacramento, CA 95819, USA
| | - Nancy L. Keim
- United States Department of Agriculture, Western Human Nutrition Research Center, Davis, CA 95819, USA
| | - Jean-Marc Schwarz
- Department of Basic Sciences, College of Osteopathic Medicine, Touro University California, Vallejo, CA 94592, USA
- Department of Medicine, Division of Endocrinology, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA
| | - Giovanni Pacini
- Department of Medicine, Division of Endocrinology, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, I-35121 Padova, Italy
| | - Andrea Tura
- Department of Medicine, Division of Endocrinology, Zuckerberg San Francisco General Hospital, University of California San Francisco, San Francisco, CA 94110, USA
- Consiglio Nazionale delle Ricerche, Institute of Neuroscience, I-35121 Padova, Italy
| | - Peter J. Havel
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA; (B.H.)
- Department of Physiology and Biochemistry of Nutrition, Max Rubner-Institut, 76131 Karlsruhe, Germany
| | - Kimber L. Stanhope
- Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA 95616, USA; (B.H.)
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Liu Q, Chiavaroli L, Ayoub-Charette S, Ahmed A, Khan TA, Au-Yeung F, Lee D, Cheung A, Zurbau A, Choo VL, Mejia SB, de Souza RJ, Wolever TMS, Leiter LA, Kendall CWC, Jenkins DJA, Sievenpiper JL. Fructose-containing food sources and blood pressure: A systematic review and meta-analysis of controlled feeding trials. PLoS One 2023; 18:e0264802. [PMID: 37582096 PMCID: PMC10427023 DOI: 10.1371/journal.pone.0264802] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 06/30/2023] [Indexed: 08/17/2023] Open
Abstract
Whether food source or energy mediates the effect of fructose-containing sugars on blood pressure (BP) is unclear. We conducted a systematic review and meta-analysis of the effect of different food sources of fructose-containing sugars at different levels of energy control on BP. We searched MEDLINE, Embase and the Cochrane Library through June 2021 for controlled trials ≥7-days. We prespecified 4 trial designs: substitution (energy matched substitution of sugars); addition (excess energy from sugars added); subtraction (excess energy from sugars subtracted); and ad libitum (energy from sugars freely replaced). Outcomes were systolic and diastolic BP. Independent reviewers extracted data. GRADE assessed the certainty of evidence. We included 93 reports (147 trial comparisons, N = 5,213) assessing 12 different food sources across 4 energy control levels in adults with and without hypertension or at risk for hypertension. Total fructose-containing sugars had no effect in substitution, subtraction, or ad libitum trials but decreased systolic and diastolic BP in addition trials (P<0.05). There was evidence of interaction/influence by food source: fruit and 100% fruit juice decreased and mixed sources (with sugar-sweetened beverages [SSBs]) increased BP in addition trials and the removal of SSBs (linear dose response gradient) and mixed sources (with SSBs) decreased BP in subtraction trials. The certainty of evidence was generally moderate. Food source and energy control appear to mediate the effect of fructose-containing sugars on BP. The evidence provides a good indication that fruit and 100% fruit juice at low doses (up to or less than the public health threshold of ~10% E) lead to small, but important reductions in BP, while the addition of excess energy of mixed sources (with SSBs) at high doses (up to 23%) leads to moderate increases and their removal or the removal of SSBs alone (up to ~20% E) leads to small, but important decreases in BP in adults with and without hypertension or at risk for hypertension. Trial registration: Clinicaltrials.gov: NCT02716870.
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Affiliation(s)
- Qi Liu
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Laura Chiavaroli
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Sabrina Ayoub-Charette
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Amna Ahmed
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Tauseef A. Khan
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Fei Au-Yeung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- INQUIS Clinical Research Ltd. (formerly GI Labs), Toronto, Ontario, Canada
| | - Danielle Lee
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Annette Cheung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Andreea Zurbau
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- INQUIS Clinical Research Ltd. (formerly GI Labs), Toronto, Ontario, Canada
| | - Vivian L. Choo
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sonia Blanco Mejia
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Russell J. de Souza
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
- Population Health Research Institute, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada
| | - Thomas M. S. Wolever
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- INQUIS Clinical Research Ltd. (formerly GI Labs), Toronto, Ontario, Canada
| | - Lawrence A. Leiter
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - Cyril W. C. Kendall
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - David J. A. Jenkins
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
| | - John L. Sievenpiper
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada
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Inci MK, Park SH, Helsley RN, Attia SL, Softic S. Fructose impairs fat oxidation: Implications for the mechanism of western diet-induced NAFLD. J Nutr Biochem 2023; 114:109224. [PMID: 36403701 PMCID: PMC11042502 DOI: 10.1016/j.jnutbio.2022.109224] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 09/29/2022] [Accepted: 11/14/2022] [Indexed: 11/19/2022]
Abstract
Increased fructose intake from sugar-sweetened beverages and highly processed sweets is a well-recognized risk factor for the development of obesity and its complications. Fructose strongly supports lipogenesis on a normal chow diet by providing both, a substrate for lipid synthesis and activation of lipogenic transcription factors. However, the negative health consequences of dietary sugar are best observed with the concomitant intake of a HFD. Indeed, the most commonly used obesogenic research diets, such as "Western diet", contain both fructose and a high amount of fat. In spite of its common use, how the combined intake of fructose and fat synergistically supports development of metabolic complications is not fully elucidated. Here we present the preponderance of evidence that fructose consumption decreases oxidation of dietary fat in human and animal studies. We provide a detailed review of the mitochondrial β-oxidation pathway. Fructose affects hepatic activation of fatty acyl-CoAs, decreases acylcarnitine production and impairs the carnitine shuttle. Mechanistically, fructose suppresses transcriptional activity of PPARα and its target CPT1α, the rate limiting enzyme of acylcarnitine production. These effects of fructose may be, in part, mediated by protein acetylation. Acetylation of PGC1α, a co-activator of PPARα and acetylation of CPT1α, in part, account for fructose-impaired acylcarnitine production. Interestingly, metabolic effects of fructose in the liver can be largely overcome by carnitine supplementation. In summary, fructose decreases oxidation of dietary fat in the liver, in part, by impairing acylcarnitine production, offering one explanation for the synergistic effects of these nutrients on the development of metabolic complications, such as NAFLD.
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Affiliation(s)
| | - Se-Hyung Park
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Robert N Helsley
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Suzanna L Attia
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Samir Softic
- Department of Pediatrics, University of Kentucky College of Medicine, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA; Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA, USA.
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8
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Chiavaroli L, Cheung A, Ayoub-Charette S, Ahmed A, Lee D, Au-Yeung F, Qi X, Back S, McGlynn N, Ha V, Lai E, Khan TA, Blanco Mejia S, Zurbau A, Choo VL, de Souza RJ, Wolever TM, Leiter LA, Kendall CW, Jenkins DJ, Sievenpiper JL. Important food sources of fructose-containing sugars and adiposity: A systematic review and meta-analysis of controlled feeding trials. Am J Clin Nutr 2023; 117:741-765. [PMID: 36842451 DOI: 10.1016/j.ajcnut.2023.01.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 12/29/2022] [Accepted: 01/18/2023] [Indexed: 02/25/2023] Open
Abstract
BACKGROUND Sugar-sweetened beverages (SSBs) providing excess energy increase adiposity. The effect of other food sources of sugars at different energy control levels is unclear. OBJECTIVES To determine the effect of food sources of fructose-containing sugars by energy control on adiposity. METHODS In this systematic review and meta-analysis, MEDLINE, Embase, and Cochrane Library were searched through April 2022 for controlled trials ≥2 wk. We prespecified 4 trial designs by energy control: substitution (energy-matched replacement of sugars), addition (energy from sugars added), subtraction (energy from sugars subtracted), and ad libitum (energy from sugars freely replaced). Independent authors extracted data. The primary outcome was body weight. Secondary outcomes included other adiposity measures. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of evidence. RESULTS We included 169 trials (255 trial comparisons, n = 10,357) assessing 14 food sources at 4 energy control levels over a median 12 wk. Total fructose-containing sugars increased body weight (MD: 0.28 kg; 95% CI: 0.06, 0.50 kg; PMD = 0.011) in addition trials and decreased body weight (MD: -0.96 kg; 95% CI: -1.78, -0.14 kg; PMD = 0.022) in subtraction trials with no effect in substitution or ad libitum trials. There was interaction/influence by food sources on body weight: substitution trials [fruits decreased; added nutritive sweeteners and mixed sources (with SSBs) increased]; addition trials [dried fruits, honey, fruits (≤10%E), and 100% fruit juice (≤10%E) decreased; SSBs, fruit drink, and mixed sources (with SSBs) increased]; subtraction trials [removal of mixed sources (with SSBs) decreased]; and ad libitum trials [mixed sources (with/without SSBs) increased]. GRADE scores were generally moderate. Results were similar across secondary outcomes. CONCLUSIONS Energy control and food sources mediate the effect of fructose-containing sugars on adiposity. The evidence provides a good indication that excess energy from sugars (particularly SSBs at high doses ≥20%E or 100 g/d) increase adiposity, whereas their removal decrease adiposity. Most other food sources had no effect, with some showing decreases (particularly fruits at lower doses ≤10%E or 50 g/d). This trial was registered at clinicaltrials.gov as NCT02558920 (https://clinicaltrials.gov/ct2/show/NCT02558920).
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Affiliation(s)
- Laura Chiavaroli
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Annette Cheung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Sabrina Ayoub-Charette
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Amna Ahmed
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Danielle Lee
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Fei Au-Yeung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - XinYe Qi
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Songhee Back
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Néma McGlynn
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Vanessa Ha
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; School of Medicine, Queen's University, Kingston, Ontario, Canada
| | - Ethan Lai
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Tauseef A Khan
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Sonia Blanco Mejia
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Andreea Zurbau
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; INQUIS Clinical Research Ltd. (formerly GI Labs), Toronto, Ontario, Canada
| | - Vivian L Choo
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Russell J de Souza
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada; Population Health Research Institute, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada
| | - Thomas Ms Wolever
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; INQUIS Clinical Research Ltd. (formerly GI Labs), Toronto, Ontario, Canada; Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Lawrence A Leiter
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Cyril Wc Kendall
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - David Ja Jenkins
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
| | - John L Sievenpiper
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada; Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada; Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada.
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Lee D, Chiavaroli L, Ayoub-Charette S, Khan TA, Zurbau A, Au-Yeung F, Cheung A, Liu Q, Qi X, Ahmed A, Choo VL, Blanco Mejia S, Malik VS, El-Sohemy A, de Souza RJ, Wolever TMS, Leiter LA, Kendall CWC, Jenkins DJA, Sievenpiper JL. Important Food Sources of Fructose-Containing Sugars and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis of Controlled Trials. Nutrients 2022; 14:2846. [PMID: 35889803 PMCID: PMC9325155 DOI: 10.3390/nu14142846] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/28/2022] [Accepted: 06/29/2022] [Indexed: 12/15/2022] Open
Abstract
Background: Fructose providing excess calories in the form of sugar sweetened beverages (SSBs) increases markers of non-alcoholic fatty liver disease (NAFLD). Whether this effect holds for other important food sources of fructose-containing sugars is unclear. To investigate the role of food source and energy, we conducted a systematic review and meta-analysis of controlled trials of the effect of fructose-containing sugars by food source at different levels of energy control on non-alcoholic fatty liver disease (NAFLD) markers. Methods and Findings: MEDLINE, Embase, and the Cochrane Library were searched through 7 January 2022 for controlled trials ≥7-days. Four trial designs were prespecified: substitution (energy-matched substitution of sugars for other macronutrients); addition (excess energy from sugars added to diets); subtraction (excess energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced by other macronutrients). The primary outcome was intrahepatocellular lipid (IHCL). Secondary outcomes were alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Independent reviewers extracted data and assessed risk of bias. The certainty of evidence was assessed using GRADE. We included 51 trials (75 trial comparisons, n = 2059) of 10 food sources (sugar-sweetened beverages (SSBs); sweetened dairy alternative; 100% fruit juice; fruit; dried fruit; mixed fruit sources; sweets and desserts; added nutritive sweetener; honey; and mixed sources (with SSBs)) in predominantly healthy mixed weight or overweight/obese younger adults. Total fructose-containing sugars increased IHCL (standardized mean difference = 1.72 [95% CI, 1.08 to 2.36], p < 0.001) in addition trials and decreased AST in subtraction trials with no effect on any outcome in substitution or ad libitum trials. There was evidence of influence by food source with SSBs increasing IHCL and ALT in addition trials and mixed sources (with SSBs) decreasing AST in subtraction trials. The certainty of evidence was high for the effect on IHCL and moderate for the effect on ALT for SSBs in addition trials, low for the effect on AST for the removal of energy from mixed sources (with SSBs) in subtraction trials, and generally low to moderate for all other comparisons. Conclusions: Energy control and food source appear to mediate the effect of fructose-containing sugars on NAFLD markers. The evidence provides a good indication that the addition of excess energy from SSBs leads to large increases in liver fat and small important increases in ALT while there is less of an indication that the removal of energy from mixed sources (with SSBs) leads to moderate reductions in AST. Varying uncertainty remains for the lack of effect of other important food sources of fructose-containing sugars at different levels of energy control.
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Affiliation(s)
- Danielle Lee
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Laura Chiavaroli
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Sabrina Ayoub-Charette
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Tauseef A. Khan
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Andreea Zurbau
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- INQUIS Clinical Research Ltd. (Formerly GI Labs), Toronto, ON M5C 2N8, Canada
| | - Fei Au-Yeung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- INQUIS Clinical Research Ltd. (Formerly GI Labs), Toronto, ON M5C 2N8, Canada
| | - Annette Cheung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Qi Liu
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Xinye Qi
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Amna Ahmed
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Vivian L. Choo
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, ON M5G 1V7, Canada
| | - Sonia Blanco Mejia
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
| | - Vasanti S. Malik
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Ahmed El-Sohemy
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
| | - Russell J. de Souza
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada
- Population Health Research Institute, Hamilton Health Sciences Corporation, Hamilton, ON L8L 2X2, Canada
| | - Thomas M. S. Wolever
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- INQUIS Clinical Research Ltd. (Formerly GI Labs), Toronto, ON M5C 2N8, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Lawrence A. Leiter
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
| | - Cyril W. C. Kendall
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK S7N 5E5, Canada
| | - David J. A. Jenkins
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
| | - John L. Sievenpiper
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada; (D.L.); (L.C.); (S.A.-C.); (T.A.K.); (A.Z.); (F.A.-Y.); (A.C.); (Q.L.); (X.Q.); (A.A.); (V.L.C.); (S.B.M.); (V.S.M.); (A.E.-S.); (R.J.d.S.); (T.M.S.W.); (L.A.L.); (C.W.C.K.); (D.J.A.J.)
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael’s Hospital, Toronto, ON M5C 2T2, Canada
- Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON M5B 1T8, Canada
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EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch‐Ernst KI, Knutsen HK, Maciuk A, Mangelsdorf I, McArdle HJ, Naska A, Peláez C, Pentieva K, Siani A, Thies F, Tsabouri S, Adan R, Emmett P, Galli C, Kersting M, Moynihan P, Tappy L, Ciccolallo L, de Sesmaisons‐Lecarré A, Fabiani L, Horvath Z, Martino L, Muñoz Guajardo I, Valtueña Martínez S, Vinceti M. Tolerable upper intake level for dietary sugars. EFSA J 2022; 20:e07074. [PMID: 35251356 PMCID: PMC8884083 DOI: 10.2903/j.efsa.2022.7074] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Following a request from five European Nordic countries, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was tasked to provide scientific advice on a tolerable upper intake level (UL) or a safe level of intake for dietary (total/added/free) sugars based on available data on chronic metabolic diseases, pregnancy-related endpoints and dental caries. Specific sugar types (fructose) and sources of sugars were also addressed. The intake of dietary sugars is a well-established hazard in relation to dental caries in humans. Based on a systematic review of the literature, prospective cohort studies do not support a positive relationship between the intake of dietary sugars, in isocaloric exchange with other macronutrients, and any of the chronic metabolic diseases or pregnancy-related endpoints assessed. Based on randomised control trials on surrogate disease endpoints, there is evidence for a positive and causal relationship between the intake of added/free sugars and risk of some chronic metabolic diseases: The level of certainty is moderate for obesity and dyslipidaemia (> 50-75% probability), low for non-alcoholic fatty liver disease and type 2 diabetes (> 15-50% probability) and very low for hypertension (0-15% probability). Health effects of added vs. free sugars could not be compared. A level of sugars intake at which the risk of dental caries/chronic metabolic diseases is not increased could not be identified over the range of observed intakes, and thus, a UL or a safe level of intake could not be set. Based on available data and related uncertainties, the intake of added and free sugars should be as low as possible in the context of a nutritionally adequate diet. Decreasing the intake of added and free sugars would decrease the intake of total sugars to a similar extent. This opinion can assist EU Member States in setting national goals/recommendations.
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11
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Bergwall S, Johansson A, Sonestedt E, Acosta S. High versus low-added sugar consumption for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2022; 1:CD013320. [PMID: 34986271 PMCID: PMC8730703 DOI: 10.1002/14651858.cd013320.pub2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND High intake of added sugar have been suggested to impact the risk for cardiovascular disease (CVD). Knowledge on the subject can contribute to preventing CVD. OBJECTIVES To assess the effects of a high versus low-added sugar consumption for primary prevention of CVD in the general population. SEARCH METHODS We searched Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, Embase, Conference Proceedings Citation Index-Science (CPCI-S) on 2 July 2021. We also conducted a search of ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) Search Portal for ongoing or unpublished trials. The search was performed together with reference checking, citation searching and contact with study authors to identify additional studies. We imposed no restriction on language of publication or publication status. SELECTION CRITERIA We included randomised controlled trials (RCTs), including cross-over trials, that compared different levels of added sugar intake. Exclusion criteria were: participants aged below 18 years; diabetes mellitus (type 1 and 2); and previous CVD. Primary outcomes were incident cardiovascular events (coronary, carotid, cerebral and peripheral arterial disease) and all-cause mortality. Secondary outcomes were changes in systolic and diastolic blood pressure, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, fasting plasma glucose and adverse events (gastrointestinal symptoms and impaired dental health). DATA COLLECTION AND ANALYSIS We used the standard methodological procedures expected by Cochrane. MAIN RESULTS We included 21 RCTs (1110 participants completing the interventions) examining the effects of different levels of added sugar intake with a mean duration of 14 weeks. The study participants were generally described as healthy and the mean age ranged from 22 to 57 years. No studies reported on cardiovascular events or all-cause mortality. There was minimal effect of low intake of added sugar on total cholesterol levels (MD 0.11, 95% CI 0.01 to 0.21; I² = 0%; 16 studies; 763 participants; low certainty of evidence) and triglycerides (MD 0.10, 95% CI 0.03 to 0.17; I² = 3%; 14 studies; 725 participants) but no evidence of effect on LDL-cholesterol and HDL-cholesterol. There was minimal effect on diastolic blood pressure (MD 1.52, 95% CI 0.67 to 2.37; I² = 0%; 13 studies; 873 participants) and on systolic blood pressure (MD 1.44, 95% 0.08 to 2.80; I² = 27%, 14 studies; 873 participants; low certainty of evidence), but no evidence of effect on fasting plasma glucose. Only one study reported on dental health, with no events. No other trials reported adverse events (impaired dental health or gastrointestinal symptoms). All results were judged as low-quality evidence according to GRADE. The risk of bias was generally unclear, five studies were classified at an overall low risk of bias (low risk in at least four domains, not including other bias). AUTHORS' CONCLUSIONS No trials investigating the effect of added sugar on cardiovascular events or all-cause mortality were identified in our searches. Evidence is uncertain whether low intake of added sugar has an effect on risk factors for CVD; the effect was small and the clinical relevance is, therefore, uncertain. Practical ways to achieve reductions in dietary added sugar includes following current dietary recommendations. Future trials should have longer follow-up time and report on all-cause mortality and cardiovascular events in order to clarify the effect of added sugar on these outcomes. Future trials should also aim for more direct interventions and preferably be more independent of industry funding.
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Affiliation(s)
- Sara Bergwall
- Department of Clinical Sciences Malmö, Vascular Diseases, Lund University, Malmö, Sweden
| | - Anna Johansson
- Department of Clinical Sciences Malmö, Vascular Diseases, Lund University, Malmö, Sweden
| | - Emily Sonestedt
- Department of Clinical Sciences Malmö, Nutritional Epidemiology, Lund University, Malmö, Sweden
| | - Stefan Acosta
- Department of Vascular Diseases, Malmö University Hospital, Malmö, Sweden
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12
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Yki-Järvinen H, Luukkonen PK, Hodson L, Moore JB. Dietary carbohydrates and fats in nonalcoholic fatty liver disease. Nat Rev Gastroenterol Hepatol 2021; 18:770-786. [PMID: 34257427 DOI: 10.1038/s41575-021-00472-y] [Citation(s) in RCA: 147] [Impact Index Per Article: 36.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/14/2021] [Indexed: 02/06/2023]
Abstract
The global prevalence of nonalcoholic fatty liver disease (NAFLD) has dramatically increased in parallel with the epidemic of obesity. Controversy has emerged around dietary guidelines recommending low-fat-high-carbohydrate diets and the roles of dietary macronutrients in the pathogenesis of metabolic disease. In this Review, the topical questions of whether and how dietary fats and carbohydrates, including free sugars, differentially influence the accumulation of liver fat (specifically, intrahepatic triglyceride (IHTG) content) are addressed. Focusing on evidence from humans, we examine data from stable isotope studies elucidating how macronutrients regulate IHTG synthesis and disposal, alter pools of bioactive lipids and influence insulin sensitivity. In addition, we review cross-sectional studies on dietary habits of patients with NAFLD and randomized controlled trials on the effects of altering dietary macronutrients on IHTG. Perhaps surprisingly, evidence to date shows no differential effects between free sugars, with both glucose and fructose increasing IHTG in the context of excess energy. Moreover, saturated fat raises IHTG more than polyunsaturated or monounsaturated fats, with adverse effects on insulin sensitivity, which are probably mediated in part by increased ceramide synthesis. Taken together, the data support the use of diets that have a reduced content of free sugars, refined carbohydrates and saturated fat in the treatment of NAFLD.
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Affiliation(s)
- Hannele Yki-Järvinen
- Department of Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland. .,Minerva Foundation Institute for Medical Research, Helsinki, Finland.
| | - Panu K Luukkonen
- Department of Medicine, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.,Minerva Foundation Institute for Medical Research, Helsinki, Finland.,Department of Internal Medicine, Yale University, New Haven, CT, USA
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.,National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
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13
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Reply to: "Comments on 'Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis - A randomized controlled trial' ". J Hepatol 2021; 75:754-756. [PMID: 34129885 DOI: 10.1016/j.jhep.2021.06.005] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 06/05/2021] [Indexed: 12/04/2022]
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14
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Ayoub-Charette S, Chiavaroli L, Liu Q, Khan TA, Zurbau A, Au-Yeung F, Cheung A, Ahmed A, Lee D, Choo VL, Blanco Mejia S, de Souza RJ, Wolever TM, Leiter LA, Kendall CW, Jenkins DJ, Sievenpiper JL. Different Food Sources of Fructose-Containing Sugars and Fasting Blood Uric Acid Levels: A Systematic Review and Meta-Analysis of Controlled Feeding Trials. J Nutr 2021; 151:2409-2421. [PMID: 34087940 PMCID: PMC8349131 DOI: 10.1093/jn/nxab144] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/11/2021] [Accepted: 04/21/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Although fructose as a source of excess calories increases uric acid, the effect of the food matrix is unclear. OBJECTIVES To assess the effects of fructose-containing sugars by food source at different levels of energy control on uric acid, we conducted a systematic review and meta-analysis of controlled trials. METHODS MEDLINE, Embase, and the Cochrane Library were searched (through 11 January 2021) for trials ≥ 7 days. We prespecified 4 trial designs by energy control: substitution (energy-matched replacement of sugars in diets); addition (excess energy from sugars added to diets); subtraction (energy from sugars subtracted from diets); and ad libitum (energy from sugars freely replaced in diets) designs. Independent reviewers (≥2) extracted data and assessed the risk of bias. Grading of Recommendations, Assessment, Development, and Evaluation was used to assess the certainty of evidence. RESULTS We included 47 trials (85 comparisons; N = 2763) assessing 9 food sources [sugar-sweetened beverages (SSBs), sweetened dairy, fruit drinks, 100% fruit juice, fruit, dried fruit, sweets and desserts, added nutritive sweetener, and mixed sources] across 4 energy control levels in predominantly healthy, mixed-weight adults. Total fructose-containing sugars increased uric acid levels in substitution trials (mean difference, 0.16 mg/dL; 95% CI: 0.06-0.27 mg/dL; P = 0.003), with no effect across the other energy control levels. There was evidence of an interaction by food source: SSBs and sweets and desserts increased uric acid levels in the substitution design, while SSBs increased and 100% fruit juice decreased uric acid levels in addition trials. The certainty of evidence was high for the increasing effect of SSBs in substitution and addition trials and the decreasing effect of 100% fruit juice in addition trials and was moderate to very low for all other comparisons. CONCLUSIONS Food source more than energy control appears to mediate the effects of fructose-containing sugars on uric acid. The available evidence provides reliable indications that SSBs increase and 100% fruit juice decreases uric acid levels. More high-quality trials of different food sources are needed. This trial was registered at clinicaltrials.gov as NCT02716870.
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Affiliation(s)
- Sabrina Ayoub-Charette
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Laura Chiavaroli
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Qi Liu
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Tauseef Ahmad Khan
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Andreea Zurbau
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- INQUIS Clinical Research Ltd. (formerly Glycemic Index Laboratories, Inc.),
Toronto, Ontario, Canada
| | - Fei Au-Yeung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- INQUIS Clinical Research Ltd. (formerly Glycemic Index Laboratories, Inc.), Toronto, Ontario, Canada
| | - Annette Cheung
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Amna Ahmed
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Danielle Lee
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Vivian L Choo
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Sonia Blanco Mejia
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Russell J de Souza
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Health Research Methods, Evidence, and Impact, Faculty of Health Sciences, McMaster University, Hamilton, Ontario, Canada
- Population Health Research Institute, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada
| | - Thomas Ms Wolever
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- INQUIS Clinical Research Ltd. (formerly Glycemic Index Laboratories, Inc.), Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Lawrence A Leiter
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Cyril Wc Kendall
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - David Ja Jenkins
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
| | - John L Sievenpiper
- Department of Nutritional Sciences, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Toronto 3D Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St. Michael's Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada
- Department of Medicine, Temerty Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada
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15
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Dietary fructose intake is correlated with fat distribution in the Newfoundland population. Nutrition 2021; 93:111434. [PMID: 34492622 DOI: 10.1016/j.nut.2021.111434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 07/08/2021] [Accepted: 07/18/2021] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Increased dietary fructose intake is associated with elevated body weight and body mass index. Few studies are available regarding the relationship between fat distribution and dietary fructose intake. The aim of this study was to investigate the association between dietary fructose intake and fat distribution in adults in a large Newfoundland cohort. METHODS We analyzed 2298 adults from CODING (Complex Diseases in the New found land Population: Environment and Genetics) study. Intake of dietary fructose was evaluated from the Willett food frequency questionnaire. Fat distribution was estimated by dual-energy x-ray absorptiometry. Partial correlation analysis was used to determine the correlations of dietary fructose intake with fat distribution adjusted for major confounding factors. RESULTS Daily dietary fructose intake was negatively associated with arm fat in postmenopausal women (r = -0.080, P < 0.05), but positively associated with arm fat in premenopausal women after adjusting for age, total calorie intake, and physical activity levels (r = 0.079, P < 0.05). Dietary fructose intake was negatively correlated with both arm fat (r = -0.131, P < 0.05) and visceral fat (r = -0.124 measured in mass, r = -0.124 measured in volume respectively; P < 0.05) in men <45 y of age, not in men ≥45 y. CONCLUSION This study demonstrated that dietary fructose intake is significantly correlated with arm fat in both women and men, and visceral fat in men in the Newfoundland free-living population. The correlations are sex- and menopause-status dependent.
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Villaño D, Masoodi H, Marhuenda J, García-Viguera C, Zafrilla P. Stevia, sucralose and sucrose added to a maqui-Citrus beverage and their effects on glycemic response in overweight subjects: A randomized clinical trial. Lebensm Wiss Technol 2021. [DOI: 10.1016/j.lwt.2021.111173] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
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17
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Fattore E, Botta F, Bosetti C. Effect of fructose instead of glucose or sucrose on cardiometabolic markers: a systematic review and meta-analysis of isoenergetic intervention trials. Nutr Rev 2021; 79:209-226. [PMID: 33029629 DOI: 10.1093/nutrit/nuaa077] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 06/05/2020] [Accepted: 06/28/2020] [Indexed: 12/25/2022] Open
Abstract
CONTEXT Free, or added, sugars are considered important determinants in the pandemics of obesity and associated chronic diseases, and fructose has emerged as the sugar of main concern. OBJECTIVE The aim of this review was to assess the evidence of the effects of isoenergetic replacement of fructose or high-fructose corn syrup (HFCS) for glucose or sucrose on cardiometabolic markers in controlled dietary intervention trials. DATA SOURCES The electronic databases PubMed/MEDLINE, the Cochrane Library, and Embase were searched from 1980 to May 5, 2020. STUDY SELECTION Studies were eligible if they measured at least one of the following outcomes: total cholesterol, low- and high-density lipoprotein cholesterol, triacylglycerols, apolipoprotein A1, apolipoprotein B, systolic blood pressure, diastolic blood pressure, fasting glucose, and body weight. DATA EXTRACTION For each outcome, the mean values and the corresponding measure of dispersion were extracted after the intervention or control diet. DATA ANALYSIS Fixed-effects and random-effects models were used to pool study-specific estimates. Between-study heterogeneity was assessed by the χ2 test and the I2 statistic and publication bias by the Egger test and funnel plots. RESULTS Twenty-five studies involving 1744 volunteers were identified. No significant effects were found when fructose or HFCS was substituted for glucose, except for a slight decrease in diastolic blood pressure when fructose was substituted for glucose. Similarly, no effects were found when fructose or HFCS was substituted for sucrose, except for a small increase, of uncertain clinical significance, of apolipoprotein B when HFCS was substituted for sucrose. CONCLUSIONS Isoenergetic substitution of fructose or HFCS for glucose or sucrose has no significant effect on most of the cardiometabolic markers investigated; however, some results were affected by residual between-study heterogeneity and studies with high or unclear risk of bias. SYSTEMATIC REVIEW REGISTRATION PROSPERO registration number CRD42016042930.
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Affiliation(s)
- Elena Fattore
- Department of Environmental Health Sciences, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
| | - Francesca Botta
- Department of Statistics and Quantitative Methods, Università degli Studi di Milano-Bicocca, Milan, Italy, and with 1MED SA, Agno, Switzerland
| | - Cristina Bosetti
- Department of Oncology, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy
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Zafar MI, Frese M, Mills KE. Chronic Fructose Substitution for Glucose or Sucrose in Food or Beverages and Metabolic Outcomes: An Updated Systematic Review and Meta-Analysis. Front Nutr 2021; 8:647600. [PMID: 33996873 PMCID: PMC8113762 DOI: 10.3389/fnut.2021.647600] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/26/2021] [Indexed: 12/14/2022] Open
Abstract
Despite the publication of several of meta-analyses in recent years, the effects of fructose on human health remains a topic of debate. We previously undertook two meta-analyses on post-prandial and chronic responses to isoenergetic replacement of fructose for sucrose or glucose in food or beverages (Evans et al. 2017, AJCN 106:506–518 & 519–529). Here we report on the results of an updated search with a complete re-extraction of previously identified studies and a new and more detailed subgroup-analysis and meta-regression. We identified two studies that were published after our previous analyses, which slightly altered effect sizes and conclusions. Overall, the isoenergetic substitution of fructose for glucose resulted in a statistically significant but clinically irrelevant reduction in fasting blood glucose, insulin, and triglyceride concentrations. A subgroup analysis by diabetes status revealed much larger reductions in fasting blood glucose in people with impaired glucose tolerance and type 2 diabetes. However, each of these subgroups contained only a single study. In people with a healthy body mass index, fructose consumption was associated with statistically significant, but clinically irrelevant reductions in fasting blood glucose and fasting blood insulin. Meta-regression of the outcomes by a number of pre-identified and post-hoc covariates revealed some sources of heterogeneity, such as year of publication, age of the participants at baseline, and participants' sex. However, the small number of studies and the large number of potential covariates precluded detailed investigations of effect sizes in different subpopulations. For example, well-controlled, high quality studies in people with impaired glucose tolerance and type 2 diabetes are still lacking. Taken together, the available data suggest that chronic consumption of fructose is neither more beneficial, nor more harmful than equivalent doses of sucrose or glucose for glycemic and other metabolic outcomes.
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Affiliation(s)
- Mohammad Ishraq Zafar
- Institute of Reproductive Health/Center of Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Michael Frese
- Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia
| | - Kerry E Mills
- Faculty of Science and Technology, University of Canberra, Canberra, ACT, Australia
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Maj M, Harbottle B, Thomas PA, Hernandez GV, Smith VA, Edwards MS, Fanter RK, Glanz HS, Immoos C, Burrin DG, Santiago-Rodriguez TM, La Frano MR, Manjarín R. Consumption of High-Fructose Corn Syrup Compared with Sucrose Promotes Adiposity and Increased Triglyceridemia but Comparable NAFLD Severity in Juvenile Iberian Pigs. J Nutr 2021; 151:1139-1149. [PMID: 33693900 PMCID: PMC8112773 DOI: 10.1093/jn/nxaa441] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/11/2020] [Accepted: 12/16/2020] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Fructose consumption has been linked to nonalcoholic fatty liver disease (NAFLD) in children. However, the effect of high-fructose corn syrup (HFCS) compared with sucrose in pediatric NAFLD has not been investigated. OBJECTIVES We tested whether the isocaloric substitution of dietary sucrose by HFCS would increase the severity of NAFLD in juvenile pigs, and whether this effect would be associated with changes in gut histology, SCFA production, and microbial diversity. METHODS Iberian pigs, 53-d-old and pair-housed in pens balanced for weight and sex, were randomly assigned to receive a mash diet top-dressed with increasing amounts of sucrose (SUC; n = 3 pens; 281.6-486.8 g/kg diet) or HFCS (n = 4; 444.3-724.8 g/kg diet) during 16 wk. Diets exceeded the animal's energy requirements by providing sugars in excess, but met the requirements for all other nutrients. Animals were killed at 165 d of age after blood sampling, and liver, muscle, and gut were collected for histology, metabolome, and microbiome analyses. Data were analyzed by multivariate and univariate statistics. RESULTS Compared with SUC, HFCS increased subcutaneous fat, triacylglycerides in plasma, and butyrate in colon (P ≤ 0.05). In addition, HFCS decreased UMP and short-chain acyl carnitines in liver, and urea nitrogen and creatinine in serum (P ≤ 0.05). Microbiome analysis showed a 24.8% average dissimilarity between HFCS and SUC associated with changes in SCFA-producing bacteria. Body weight gain, intramuscular fat, histological and serum markers of liver injury, and circulating hormones, glucose, and proinflammatory cytokines did not differ between diets. CONCLUSIONS Fructose consumption derived from HFCS promoted butyrate synthesis, triglyceridemia, and subcutaneous lipid deposition in juvenile Iberian pigs, but did not increase serum and histological markers of NAFLD compared with a sucrose-enriched diet. Longer studies could be needed to observe differences in liver injury among sugar types.
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Affiliation(s)
- Magdalena Maj
- Biological Sciences Department, California Polytechnic State University, San Luis Obispo, CA, USA,Center for Applications in Biotechnology, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Brooke Harbottle
- Animal Science Department, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Payton A Thomas
- Animal Science Department, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Gabriella V Hernandez
- Animal Science Department, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Victoria A Smith
- Animal Science Department, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Mark S Edwards
- Animal Science Department, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Rob K Fanter
- College of Agriculture, Food and Environmental Sciences, California Polytechnic State University, San Luis Obispo, CA, USA,Center for Health Research, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Hunter S Glanz
- Statistics Department, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Chad Immoos
- Chemistry and Biochemistry Department, California Polytechnic State University, San Luis Obispo, CA, USA
| | - Douglas G Burrin
- United States Department of Agriculture-Agricultural Research Services, Children's Nutrition Research Center, Section of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA
| | | | - Michael R La Frano
- Center for Health Research, California Polytechnic State University, San Luis Obispo, CA, USA,Food Science and Nutrition Department, California Polytechnic State University, San Luis Obispo, CA, USA
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Hydes T, Alam U, Cuthbertson DJ. The Impact of Macronutrient Intake on Non-alcoholic Fatty Liver Disease (NAFLD): Too Much Fat, Too Much Carbohydrate, or Just Too Many Calories? Front Nutr 2021; 8:640557. [PMID: 33665203 PMCID: PMC7921724 DOI: 10.3389/fnut.2021.640557] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 01/27/2021] [Indexed: 12/13/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a growing epidemic, in parallel with the obesity crisis, rapidly becoming one of the commonest causes of chronic liver disease worldwide. Diet and physical activity are important determinants of liver fat accumulation related to insulin resistance, dysfunctional adipose tissue, and secondary impaired lipid storage and/or increased lipolysis. While it is evident that a hypercaloric diet (an overconsumption of calories) promotes liver fat accumulation, it is also clear that the macronutrient composition can modulate this risk. A number of other baseline factors modify the overfeeding response, which may be genetic or environmental. Although it is difficult to disentangle the effects of excess calories vs. specifically the individual effects of excessive carbohydrates and/or fats, isocaloric, and hypercaloric dietary intervention studies have been implemented to provide insight into the effects of different macronutrients, sub-types and their relative balance, on the regulation of liver fat. What has emerged is that different types of fat and carbohydrates differentially influence liver fat accumulation, even when diets are isocaloric. Furthermore, distinct molecular and metabolic pathways mediate the effects of carbohydrates and fat intake on hepatic steatosis. Fat accumulation appears to act through impairments in lipid storage and/or increased lipolysis, whereas carbohydrate consumption has been shown to promote liver fat accumulation through de novo lipogenesis. Effects differ dependent upon carbohydrate and fat type. Saturated fat and fructose induce the greatest increase in intrahepatic triglycerides (IHTG), insulin resistance, and harmful ceramides compared with unsaturated fats, which have been found to be protective. Decreased intake of saturated fats and avoidance of added sugars are therefore the two most important dietary interventions that can lead to a reduction in IHTG and potentially the associated risk of developing type 2 diabetes. A healthy and balanced diet and regular physical activity must remain the cornerstones of effective lifestyle intervention to prevent the development and progression of NAFLD. Considering the sub-type of each macronutrient, in addition to the quantity, are critical determinants of liver health.
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Affiliation(s)
- Theresa Hydes
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Uazman Alam
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
| | - Daniel J Cuthbertson
- Department of Metabolic and Cardiovascular Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.,Liverpool University Hospitals NHS Foundation Trust, Liverpool, United Kingdom
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21
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Park JY, Jang MG, Oh JM, Ko HC, Hur SP, Kim JW, Baek S, Kim SJ. Sasa quelpaertensis Leaf Extract Ameliorates Dyslipidemia, Insulin Resistance, and Hepatic Lipid Accumulation in High-Fructose-Diet-Fed Rats. Nutrients 2020; 12:nu12123762. [PMID: 33297496 PMCID: PMC7762336 DOI: 10.3390/nu12123762] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 12/01/2020] [Accepted: 12/01/2020] [Indexed: 12/13/2022] Open
Abstract
Background: Increased dietary fructose consumption is closely associated with lipid and glucose metabolic disorders. Sasa quelpaertensis Nakai possesses various health-promoting properties, but there has been no research on its protective effect against fructose-induced metabolic dysfunction. In this study, we investigated the effects of S. quelpaertensis leaf extract (SQE) on metabolic dysfunction in high-fructose-diet-fed rats. Methods: Animals were fed a 46% carbohydrate diet, a 60% high-fructose diet, or a 60% high-fructose diet with SQE (500 mg/kg of body weight (BW)/day) in drinking water for 16 weeks. Serum biochemical parameters were measured and the effects of SQE on hepatic histology, protein expression, and transcriptome profiles were investigated. Results: SQE improved dyslipidemia and insulin resistance induced in high-fructose-diet-fed rats. SQE ameliorated the lipid accumulation and inflammatory response in liver tissues by modulating the expressions of key proteins related to lipid metabolism and antioxidant response. SQE significantly enriched the genes related to the metabolic pathway, namely, the tumor necrosis factor (TNF) signaling pathway and the PI3K-Akt signaling pathway. Conclusions: SQE could effectively prevent dyslipidemia, insulin resistance, and hepatic lipid accumulation by regulation of metabolism-related gene expressions, suggesting its role as a functional ingredient to prevent lifestyle-related metabolic disorders.
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Affiliation(s)
- Jeong Yong Park
- Department of Biology, Jeju National University, Jeju 63243, Korea; (J.Y.P.); (M.G.J.); (J.M.O.)
| | - Mi Gyeong Jang
- Department of Biology, Jeju National University, Jeju 63243, Korea; (J.Y.P.); (M.G.J.); (J.M.O.)
| | - Jung Min Oh
- Department of Biology, Jeju National University, Jeju 63243, Korea; (J.Y.P.); (M.G.J.); (J.M.O.)
| | - Hee Chul Ko
- Biotech Regional Innovation Center, Jeju Nation University, Jeju 63423, Korea; (H.C.K.); (J.-W.K.); (S.B.)
| | - Sung-Pyo Hur
- Jeju International Marine Science Research & Logistics Center, Korea Institute of Ocean Science & Technology, Gujwa, Jeju 63349, Korea;
| | - Jae-Won Kim
- Biotech Regional Innovation Center, Jeju Nation University, Jeju 63423, Korea; (H.C.K.); (J.-W.K.); (S.B.)
| | - Songyee Baek
- Biotech Regional Innovation Center, Jeju Nation University, Jeju 63423, Korea; (H.C.K.); (J.-W.K.); (S.B.)
| | - Se-Jae Kim
- Department of Biology, Jeju National University, Jeju 63243, Korea; (J.Y.P.); (M.G.J.); (J.M.O.)
- Biotech Regional Innovation Center, Jeju Nation University, Jeju 63423, Korea; (H.C.K.); (J.-W.K.); (S.B.)
- Correspondence: ; Tel.: +82-64-754-3529
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Zhang S, Guo F, Yu M, Yang X, Yao Z, Li Q, Wei Z, Feng K, Zeng P, Zhao D, Li X, Zhu Y, Miao QR, Iwakiri Y, Chen Y, Han J, Duan Y. Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity. J Hepatol 2020; 73:1482-1495. [PMID: 32738448 DOI: 10.1016/j.jhep.2020.07.034] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 06/26/2020] [Accepted: 07/21/2020] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Chronic overconsumption of a high-carbohydrate diet leads to steatosis and its associated metabolic disorder and, eventually, to non-alcoholic fatty liver disease. Carbohydrate-responsive element binding protein (ChREBP) and insulin regulate de novo lipogenesis from glucose. Herein, we studied the effect of reticulon-4 (Nogo) expression on diet-induced metabolic disorders in mice. METHODS Nogo-deficient (Nogo-/-) and littermate control [wild-type (WT)] mice were fed a high-glucose or high-fructose diet (HGD/HFrD) to induce metabolic disorders. The effects of Nogo small interfering (si) RNA (siRNA) on HFrD-induced metabolic disorders were investigated in C57BL/6J mice. RESULTS HGD/HFrD induced steatosis and its associated metabolic disorders in WT mice by activating ChREBP and impairing insulin sensitivity. They also activated Nogo-B expression, which in turn inhibited insulin activity. In response to HGD/HFrD feeding, Nogo deficiency enhanced insulin sensitivity and energy metabolism to reduce the expression of ChREBP and lipogenic molecules, activated AMP-activated catalytic subunit α, peroxisome proliferator activated receptor α and fibroblast growth factor 21, and reduced endoplasmic reticulum (ER) stress and inflammation, thereby blocking HGD/HFrD-induced hepatic lipid accumulation, insulin resistance and other metabolic disorders. Injection of Nogo siRNA protected C57BL/6J mice against HFrD-induced metabolic disorders by ameliorating insulin sensitivity, ChREBP activity, ER stress and inflammation. CONCLUSIONS Our study identified Nogo as an important mediator of insulin sensitivity and ChREBP activity. Reduction of Nogo expression is a potential strategy for the treatment of high-carbohydrate diet-induced metabolic complications. LAY SUMMARY Nogo deficiency blocks high-carbohydrate diet-induced glucose intolerance and insulin resistance, while increasing glucose/lipid utilisation and energy expenditure. Thus, reduction of Nogo expression protects against high-carbohydrate diet-induced body-weight gain, hepatic lipid accumulation and the associated metabolic disorders, indicating that approaches inhibiting Nogo expression can be applied for the treatment of diseases associated with metabolic disorders.
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Affiliation(s)
- Shuang Zhang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Fangling Guo
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Miao Yu
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoxiao Yang
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China
| | - Zhi Yao
- Tianjin Medical University, Tianjin, China
| | - Qi Li
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Zhuo Wei
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Ke Feng
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Peng Zeng
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Dan Zhao
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Xiaoju Li
- College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China
| | - Yan Zhu
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qing Robert Miao
- Winthrop Hospital Diabetes and Obesity Research Center, New York University, New York, NY, USA
| | - Yasuko Iwakiri
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, USA
| | - Yuanli Chen
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
| | - Jihong Han
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China; College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
| | - Yajun Duan
- Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, College of Food and Biological Engineering, Hefei University of Technology, Hefei, China.
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Bray GA, Bouchard C. The biology of human overfeeding: A systematic review. Obes Rev 2020; 21:e13040. [PMID: 32515127 DOI: 10.1111/obr.13040] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 03/18/2020] [Accepted: 04/09/2020] [Indexed: 12/21/2022]
Abstract
This systematic review has examined more than 300 original papers dealing with the biology of overfeeding. Studies have varied from 1 day to 6 months. Overfeeding produced weight gain in adolescents, adult men and women and in older men. In longer term studies, there was a clear and highly significant relationship between energy ingested and weight gain and fat storage with limited individual differences. There is some evidence for a contribution of a genetic component to this response variability. The response to overfeeding was affected by the baseline state of the groups being compared: those with insulin resistance versus insulin sensitivity; those prone to obesity versus those resistant to obesity; and those with metabolically abnormal obesity versus those with metabolically normal obesity. Dietary components, such as total fat, polyunsaturated fat and carbohydrate influenced the patterns of adipose tissue distribution as did the history of low or normal birth weight. Overfeeding affected the endocrine system with increased circulating concentrations of insulin and triiodothyronine frequently present. Growth hormone, in contrast, was rapidly suppressed. Changes in plasma lipids were influenced by diet, exercise and the magnitude of weight gain. Adipose tissue and skeletal muscle morphology and metabolism are substantially altered by chronic overfeeding.
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Affiliation(s)
- George A Bray
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA
| | - Claude Bouchard
- Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana, USA
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Steenson S, Shojaee-Moradie F, B. Whyte M, G. Jackson K, Lovegrove JA, A. Fielding B, Umpleby AM. The Effect of Fructose Feeding on Intestinal Triacylglycerol Production and De Novo Fatty Acid Synthesis in Humans. Nutrients 2020; 12:nu12061781. [PMID: 32549314 PMCID: PMC7353183 DOI: 10.3390/nu12061781] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2020] [Revised: 06/11/2020] [Accepted: 06/12/2020] [Indexed: 01/12/2023] Open
Abstract
A high fructose intake exacerbates postprandial plasma triacylglycerol (TAG) concentration, an independent risk factor for cardiovascular disease, although it is unclear whether this is due to increased production or impaired clearance of triacylglycerol (TAG)-rich lipoproteins. We determined the in vivo acute effect of fructose on postprandial intestinal and hepatic lipoprotein TAG kinetics and de novo lipogenesis (DNL). Five overweight men were studied twice, 4 weeks apart. They consumed hourly mixed-nutrient drinks that were high-fructose (30% energy) or low-fructose (<2% energy) for 11 h. Oral 2H2O was administered to measure fasting and postprandial DNL. Postprandial chylomicron (CM)-TAG and very low-density lipoprotein (VLDL)-TAG kinetics were measured with an intravenous bolus of [2H5]-glycerol. CM and VLDL were separated by their apolipoprotein B content using antibodies. Plasma TAG (p < 0.005) and VLDL-TAG (p = 0.003) were greater, and CM-TAG production rate (PR, p = 0.046) and CM-TAG fractional catabolic rate (FCR, p = 0.073) lower when high-fructose was consumed, with no differences in VLDL-TAG kinetics. Insulin was lower (p = 0.005) and apoB48 (p = 0.039), apoB100 (p = 0.013) and non-esterified fatty acids (NEFA) (p = 0.013) were higher after high-fructose. Postprandial hepatic fractional DNL was higher than intestinal fractional DNL with high-fructose (p = 0.043) and low-fructose (p = 0.043). Fructose consumption had no effect on the rate of intestinal or hepatic DNL. We provide the first measurement of the rate of intestinal DNL in humans. Lower CM-TAG PR and CM-TAG FCR with high-fructose consumption suggests lower clearance of CM, rather than elevated production, may contribute to elevated plasma TAG, possibly due to lower insulin-mediated stimulation of lipoprotein lipase.
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Affiliation(s)
- Simon Steenson
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK; (S.S.); (F.S.-M.); (M.B.W.); (B.A.F.)
- Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6AP, UK; (K.G.J.); (J.A.L.)
| | - Fariba Shojaee-Moradie
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK; (S.S.); (F.S.-M.); (M.B.W.); (B.A.F.)
| | - Martin B. Whyte
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK; (S.S.); (F.S.-M.); (M.B.W.); (B.A.F.)
| | - Kim G. Jackson
- Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6AP, UK; (K.G.J.); (J.A.L.)
| | - Julie A. Lovegrove
- Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6AP, UK; (K.G.J.); (J.A.L.)
| | - Barbara A. Fielding
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK; (S.S.); (F.S.-M.); (M.B.W.); (B.A.F.)
| | - A. Margot Umpleby
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK; (S.S.); (F.S.-M.); (M.B.W.); (B.A.F.)
- Correspondence: ; Tel.: +44-148-368-6737
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Smajis S, Gajdošík M, Pfleger L, Traussnigg S, Kienbacher C, Halilbasic E, Ranzenberger-Haider T, Stangl A, Beiglböck H, Wolf P, Lamp T, Hofer A, Gastaldelli A, Barbieri C, Luger A, Trattnig S, Kautzky-Willer A, Krššák M, Trauner M, Krebs M. Metabolic effects of a prolonged, very-high-dose dietary fructose challenge in healthy subjects. Am J Clin Nutr 2020; 111:369-377. [PMID: 31796953 DOI: 10.1093/ajcn/nqz271] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Accepted: 10/08/2019] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Increased fructose intake has been associated with metabolic consequences such as impaired hepatic lipid metabolism and development of nonalcoholic fatty liver disease (NAFLD). OBJECTIVES The aim of this study was to investigate the role of fructose in glucose and lipid metabolism in the liver, heart, skeletal muscle, and adipose tissue. METHODS Ten healthy subjects (age: 28 ± 19 y; BMI: 22.2 ± 0.7 kg/m2) underwent comprehensive metabolic phenotyping prior to and 8 wk following a high-fructose diet (150 g daily). Eleven patients with NAFLD (age: 39.4 ± 3.95 y; BMI: 28.4 ± 1.25) were characterized as "positive controls." Insulin sensitivity was analyzed by a 2-step hyperinsulinemic euglycemic clamp, and postprandial interorgan crosstalk of lipid and glucose metabolism was evaluated, by determining postprandial hepatic and intra-myocellular lipid and glycogen accumulation, employing magnetic resonance spectroscopy (MRS) at 7 T. Myocardial lipid content and myocardial function were assessed by 1H MRS imaging and MRI at 3 T. RESULTS High fructose intake resulted in lower intake of other dietary sugars and did not increase total daily energy intake. Ectopic lipid deposition and postprandial glycogen storage in the liver and skeletal muscle were not altered. Postprandial changes in hepatic lipids were measured [Δhepatocellular lipid (HCL)_healthy_baseline: -15.9 ± 10.7 compared with ± ΔHCL_healthy_follow-up: -6.9 ± 4.6; P = 0.17] and hepatic glycogen (Δglycogen_baseline: 64.4 ± 14.1 compared with Δglycogen_follow-up: 51.1 ± 9.8; P = 0.42). Myocardial function and myocardial mass remained stable. As expected, impaired hepatic glycogen storage and increased ectopic lipid storage in the liver and skeletal muscle were observed in insulin-resistant patients with NAFLD. CONCLUSIONS Ingestion of a high dose of fructose for 8 wk was not associated with relevant metabolic consequences in the presence of a stable energy intake, slightly lower body weight, and potentially incomplete absorption of the orally administered fructose load. This indicated that young, metabolically healthy subjects can at least temporarily compensate for increased fructose intake. This trial was registered at www.clinicaltrials.gov as NCT02075164.
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Affiliation(s)
- Sabina Smajis
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Martin Gajdošík
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria.,High Field MR Center, Department for Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Lorenz Pfleger
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria.,High Field MR Center, Department for Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Stefan Traussnigg
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Christian Kienbacher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | | | - Anna Stangl
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Hannes Beiglböck
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Peter Wolf
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Tanja Lamp
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Astrid Hofer
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | | | - Chiara Barbieri
- National Research Council Institute of Clinical Physiology, Pisa, Italy
| | - Anton Luger
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Siegfried Trattnig
- High Field MR Center, Department for Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria
| | | | - Martin Krššák
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria.,High Field MR Center, Department for Biomedical Imaging and Image Guided Therapy, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Krebs
- Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
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Schwingshackl L, Neuenschwander M, Hoffmann G, Buyken AE, Schlesinger S. Dietary sugars and cardiometabolic risk factors: a network meta-analysis on isocaloric substitution interventions. Am J Clin Nutr 2020; 111:187-196. [PMID: 31711109 DOI: 10.1093/ajcn/nqz273] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 10/09/2019] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND There is controversy on the relevance of dietary sugar intake for cardiometabolic health. OBJECTIVE The aim of this network meta-analysis (NMA) was to assess how isocaloric substitutions of dietary sugar with other carbohydrates affect cardiometabolic risk factors, comparing different intervention studies. METHODS We included randomized controlled trials (RCTs) investigating the isocaloric effect of substituting dietary sugars (fructose, glucose, sucrose) with other sugars or starch on cardiometabolic risk markers, including LDL cholesterol, triacylglycerol (TG), fasting glucose (FG), glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR), uric acid, C-reactive protein (CRP), alanine transaminase (ALT), aspartate transaminase (AST), and liver fat content. To identify the most beneficial intervention for each outcome, random-effects NMA was conducted by calculating pooled mean differences (MDs) with 95% CIs, and by ranking the surface under the cumulative ranking curves (SUCRAs). The certainty of evidence was evaluated using the Confidence In Network Meta-Analysis tool. RESULTS Thirty-eight RCTs, including 1383 participants, were identified. A reduction in LDL-cholesterol concentrations was shown for the exchange of sucrose with starch (MD: -0.23 mmol/L; 95% CI: -0.38, -0.07 mmol/L) or fructose with starch (MD: -0.22 mmol/L; 95% CI: -0.39, -0.05 mmol/L; SUCRAstarch: 98%). FG concentrations were also lower for the exchange of sucrose with starch (MD: -0.14 mmol/L; 95% CI: -0.29, 0.01 mmol/L; SUCRAstarch: 91%). Replacing fructose with an equivalent energy amount of glucose reduced HOMA-IR (MD: -0.36; 95% CI: -0.71, -0.02; SUCRAglucose: 74%) and uric acid (MD: -23.77 µmol/L; 95% CI: -44.21, -3.32 µmol/L; SUCRAglucose: 93%). The certainty of evidence was rated very low to moderate. No significant effects were observed for TG, HbA1c, CRP, ALT, and AST. CONCLUSIONS Our findings indicate that substitution of sucrose and fructose with starch yielded lower LDL cholesterol. Insulin resistance and uric acid concentrations were beneficially affected by replacement of fructose with glucose. Our findings are limited by the very low to moderate certainty of evidence. This review was registered at www.crd.york.ac.uk/prospero as CRD42018080297.
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Affiliation(s)
- Lukas Schwingshackl
- Institute for Evidence in Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany
| | - Manuela Neuenschwander
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Georg Hoffmann
- Department of Nutritional Sciences, University of Vienna, Vienna, Austria
| | - Anette E Buyken
- Institute of Nutrition, Consumption, and Health, Faculty of Natural Sciences, University of Paderborn, Paderborn, Germany
| | - Sabrina Schlesinger
- Institute for Biometrics and Epidemiology, German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
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Merino B, Fernández-Díaz CM, Cózar-Castellano I, Perdomo G. Intestinal Fructose and Glucose Metabolism in Health and Disease. Nutrients 2019; 12:E94. [PMID: 31905727 PMCID: PMC7019254 DOI: 10.3390/nu12010094] [Citation(s) in RCA: 71] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Revised: 12/26/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023] Open
Abstract
The worldwide epidemics of obesity and diabetes have been linked to increased sugar consumption in humans. Here, we review fructose and glucose metabolism, as well as potential molecular mechanisms by which excessive sugar consumption is associated to metabolic diseases and insulin resistance in humans. To this end, we focus on understanding molecular and cellular mechanisms of fructose and glucose transport and sensing in the intestine, the intracellular signaling effects of dietary sugar metabolism, and its impact on glucose homeostasis in health and disease. Finally, the peripheral and central effects of dietary sugars on the gut-brain axis will be reviewed.
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Affiliation(s)
- Beatriz Merino
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Cristina M. Fernández-Díaz
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
| | - Irene Cózar-Castellano
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid 28029, Spain
| | - German Perdomo
- Instituto de Biología y Genética Molecular-IBGM (CSIC-Universidad de Valladolid), Valladolid 47003, Spain; (B.M.); (C.M.F.-D.); (G.P.)
- Departamento de Ciencias de la Salud, Universidad de Burgos, Burgos 09001, Spain
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Stokes CS, Lammert F, Krawczyk M. Short-term Dietary Interventions for the Management of Nonalcoholic Fatty Liver. Curr Med Chem 2019; 26:3483-3496. [PMID: 28482789 DOI: 10.2174/0929867324666170508144409] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2016] [Revised: 04/16/2017] [Accepted: 04/20/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) affects millions of individuals on a global scale and currently no gold standard treatment exists. The risk of developing NAFLD is considerably higher with increasing body mass index. Consequently, weight loss should be recommended to all overweight patients with fatty liver. However, lifestyle interventions, irrespective of weight status, may also influence the condition. The aim herein is to present examples of short-term interventions which assess direct effects of dietary-related components on hepatic steatosis. METHODS This review includes studies with short-term dietary-related interventions of up to 16 weeks that evaluate their efficacy in reducing intrahepatic lipid contents (hepatic steatosis). This review primarily focuses on the three main macronutrients: dietary carbohydrates, fats and proteins. RESULTS High saturated fat intake and high consumption of carbohydrates, particularly from simple sugars such as fructose are reported as risk factors for hepatic steatosis. Overall, shortterm hypocaloric diets have shown beneficial effects in reducing intrahepatic lipid contents. Macronutrient manipulations such as carbohydrate restriction as well as the consumption of unsaturated fatty acids are also reported to have efficacious effects. CONCLUSION This review highlights the different dietary interventions that can influence hepatic steatosis in the short term, illustrating both pro and anti-steatotic effects.
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Affiliation(s)
- Caroline S Stokes
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany
| | - Marcin Krawczyk
- Department of Medicine II, Saarland University Medical Center, Saarland University, Homburg, Germany.,Laboratory of Metabolic Liver Diseases, Center for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, Warsaw, Poland
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Simons N, Debray FG, Schaper NC, Kooi ME, Feskens EJM, Hollak CEM, Lindeboom L, Koek GH, Bons JAP, Lefeber DJ, Hodson L, Schalkwijk CG, Stehouwer CDA, Cassiman D, Brouwers MCGJ. Patients With Aldolase B Deficiency Are Characterized by Increased Intrahepatic Triglyceride Content. J Clin Endocrinol Metab 2019; 104:5056-5064. [PMID: 30901028 DOI: 10.1210/jc.2018-02795] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 03/18/2019] [Indexed: 02/09/2023]
Abstract
CONTEXT There is an ongoing debate about whether and how fructose is involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A recent experimental study showed an increased intrahepatic triglyceride (IHTG) content in mice deficient for aldolase B (aldo B-/-), the enzyme that converts fructose-1-phosphate to triose phosphates. OBJECTIVE To translate these experimental findings to the human situation. DESIGN Case-control study. SETTING Outpatient clinic for inborn errors of metabolism. PATIENTS OR OTHER PARTICIPANTS Patients with hereditary fructose intolerance, a rare inborn error of metabolism caused by a defect in aldolase B (n = 15), and healthy persons matched for age, sex, and body mass index (BMI) (n =15). MAIN OUTCOME MEASURE IHTG content, assessed by proton magnetic resonance spectroscopy. RESULTS IHTG content was higher in aldo B-/- patients than controls (2.5% vs 0.6%; P = 0.001) on a background of lean body mass (median BMI, 20.4 and 21.8 kg/m2, respectively). Glucose excursions during an oral glucose load were higher in aldo B-/- patients (P = 0.043). Hypoglycosylated transferrin, a surrogate marker for hepatic fructose-1-phosphate concentrations, was more abundant in aldo B-/- patients than in controls (P < 0.001). Finally, plasma β-hydroxybutyrate, a biomarker of hepatic β-oxidation, was lower in aldo B-/- patients than controls (P = 0.009). CONCLUSIONS This study extends previous experimental findings by demonstrating that aldolase B deficiency also results in IHTG accumulation in humans. It suggests that the accumulation of fructose-1-phosphate and impairment of β-oxidation are involved in the pathogenesis.
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Affiliation(s)
- Nynke Simons
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
| | | | - Nicolaas C Schaper
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
- School for Public Health and Primary Care (CAPHRI), Maastricht, Netherlands
| | - M Eline Kooi
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - Edith J M Feskens
- Division of Human Nutrition, Wageningen University, Wageningen, Netherlands
| | - Carla E M Hollak
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Academic Medical Center, Amsterdam, Netherlands
| | - Lucas Lindeboom
- Department of Radiology and Nuclear Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
- Department of Nutrition and Movement Sciences, Maastricht University Medical Center, Maastricht, Netherlands
| | - Ger H Koek
- School of Nutrition and Translational Research in Metabolism, Maastricht, Netherlands
- Department of Internal Medicine, Division of Gastroenterology & Hepatology, Maastricht University Medical Center, Maastricht, Netherlands
- Department of Surgery, Klinikum, Rheinisch-Westfälische Technische Hochschule, Aachen, Germany
| | - Judith A P Bons
- Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands
| | - Dirk J Lefeber
- Translational Metabolic Laboratory, Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Department of Neurology, Radboud University Medical Center, Nijmegen, Netherlands
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
| | - Casper G Schalkwijk
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
| | - Coen D A Stehouwer
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
- Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
| | - David Cassiman
- Department of Gastroenterology-Hepatology and Metabolic Center, University Hospital Leuven, Leuven, Belgium
| | - Martijn C G J Brouwers
- Division of Endocrinology, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- Laboratory for Metabolism and Vascular Medicine, Division of General Internal Medicine, Department of Internal Medicine, Maastricht University Medical Center, Maastricht, Netherlands
- CARIM School for Cardiovascular Diseases, Maastricht, Netherlands
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Suissa K, Benedetti A, Henderson M, Gray-Donald K, Paradis G. Effects of dietary glycemic index and load on children's cardiovascular risk factors. Ann Epidemiol 2019; 40:1-7.e3. [PMID: 31780200 DOI: 10.1016/j.annepidem.2019.10.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Revised: 10/12/2019] [Accepted: 10/17/2019] [Indexed: 02/08/2023]
Abstract
PURPOSE Consumption of foods high in glycemic index (GI) and glycemic load (GL) is associated with cardiovascular (CV) diseases in adulthood. We examined whether GI and GL predict CV risk factors in children after 2 years of follow-up. METHODS Three 24-hour recalls were administered at baseline, and individual average daily GI and GL scores were calculated in a cohort of 8-10 year-old children. CV risk factors included body mass index z-score (BMIz), percent fat mass, triglycerides (TGs), low-density lipoprotein and high-density lipoprotein (HDL) cholesterol, and systolic and diastolic blood pressure. Main analyses consisted of multiple linear regression adjusted for anthropometric, socioeconomic, and dietary factors. RESULTS After 2 years, the highest dietary GL tertile compared with the lowest was associated with increased BMIz (mean difference [MD], 1.1; 95% CI, 0.88-1.31), fat mass (MD, 10.8%; 95% CI, 8.62-13.0), TGs (MD, 0.17 mmol/L; 95% CI, 0.07-0.28), and decreased HDL (MD, -0.13 mmol/L; 95% CI, -0.19 to -0.07). The GL-TG and the GL-HDL associations were mediated by BMIz. CONCLUSIONS GL predicts increased BMIz, percent fat mass, and TGs and decreased HDL in young children after 2 years. Recommendations to decrease CV risk in children should include lowering foods high in GL.
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Affiliation(s)
- Karine Suissa
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Andrea Benedetti
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada; Department of Medicine, McGill University, Montreal, Quebec, Canada; Respiratory Epidemiology and Clinical Research Unit, McGill University Health Centre, Montreal, Quebec, Canada
| | - Mélanie Henderson
- Research Center, Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada; Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, Quebec, Canada
| | - Katherine Gray-Donald
- School of Human Nutrition, Faculty of Agricultural and Environmental Sciences, McGill University, Montreal, Quebec, Canada
| | - Gilles Paradis
- Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada.
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El-Agroudy NN, Kurzbach A, Rodionov RN, O'Sullivan J, Roden M, Birkenfeld AL, Pesta DH. Are Lifestyle Therapies Effective for NAFLD Treatment? Trends Endocrinol Metab 2019; 30:701-709. [PMID: 31422872 DOI: 10.1016/j.tem.2019.07.013] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 07/10/2019] [Accepted: 07/12/2019] [Indexed: 12/17/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is becoming the most common liver disorder worldwide. Specifically, nonalcoholic steatohepatitis (NASH) and fibrosis pose an enormous burden for patients and health-care systems. In the absence of approved pharmacological therapies, effective lifestyle interventions for NAFLD, such as dietary strategies and exercise training, are currently the therapeutic strategies of choice. This review covers the influence of macronutrient quality and quantity (i.e., low-carbohydrate and high-protein diets), for successful reduction of intrahepatocellular lipids (IHL). Moreover, we discuss the effectiveness of different modalities of physical exercising with and without weight loss. These lifestyle modifications not only provide strategies to reduce IHL but may also hold a still underestimated potential to induce improvement and/or even remission of NAFLD.
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Affiliation(s)
- Nermeen N El-Agroudy
- Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Anica Kurzbach
- Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Roman N Rodionov
- Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany
| | - John O'Sullivan
- Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany; Charles Perkins Centre, The University of Sydney, Sydney, New South Wales, Australia
| | - Michael Roden
- Division of Endocrinology and Diabetology, Medical Faculty, Heinrich-Heine University Düsseldorf, Germany; Institute for Clinical Diabetology and Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
| | - Andreas L Birkenfeld
- Medizinische Klinik III, Universitätsklinikum Carl Gustav Carus, TU Dresden, Dresden, Germany; German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany; Section of Diabetes and Nutritional Sciences, Rayne Institute, Denmark Hill Campus, King's College London, London, UK; Paul Langerhans Institute Dresden, Helmholtz Zentrum München at the TU Dresden, Dresden, Germany.
| | - Dominik H Pesta
- Institute for Clinical Diabetology and Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, German Diabetes Center, Düsseldorf, Germany; German Center for Diabetes Research (DZD e.V.), München-Neuherberg, Germany
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Zhao C, Liu L, Liu Q, Li F, Zhang L, Zhu F, Shao T, Barve S, Chen Y, Li X, McClain CJ, Feng W. Fibroblast growth factor 21 is required for the therapeutic effects of Lactobacillus rhamnosus GG against fructose-induced fatty liver in mice. Mol Metab 2019; 29:145-157. [PMID: 31668386 PMCID: PMC6812038 DOI: 10.1016/j.molmet.2019.08.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 08/24/2019] [Accepted: 08/29/2019] [Indexed: 02/07/2023] Open
Abstract
Objectives High fructose feeding changes fibroblast growth factor 21 (FGF21) regulation. Lactobacillus rhamnosus GG (LGG) supplementation reduces fructose-induced non-alcoholic fatty liver disease (NAFLD). The aim of this study was to determine the role of FGF21 and underlying mechanisms in the protective effects of LGG. Methods FGF21 knockout (KO) mice and C57BL/6 wild type (WT) mice were fed 30% fructose for 12 weeks. LGG was administered to the mice in the last 4 weeks during fructose feeding. FGF21-adiponectin (ADPN)-mediated hepatic lipogenesis and inflammation were investigated. Results FGF21 expression was robustly increased after 5-weeks of feeding and significantly decreased after 12-weeks of feeding in fructose-induced NAFLD mice. LGG administration reversed the depressed FGF21 expression, increased adipose production of ADPN, and reduced hepatic fat accumulation and inflammation in the WT mice but not in the KO mice. Hepatic nuclear carbohydrate responsive-element binding protein (ChREBP) was increased by fructose and reduced by LGG, resulting in a reduction in the expression of lipogenic genes. The methylated form of protein phosphatase 2A (PP2A) C, which dephosphorylates and activates ChREBP, was upregulated by fructose and normalized by LGG. Leucine carboxyl methyltransferase-1, which methylates PP2AC, was also increased by fructose and decreased by LGG. However, those beneficial effects of LGG were blunted in the KO mice. Hepatic dihydrosphingosine-1-phosphate, which inhibits PP2A, was markedly increased by LGG in the WT mice but attenuated in the KO mice. LGG decreased adipose hypertrophy and increased serum levels of ADPN, which regulates sphingosine metabolism. This beneficial effect was decreased in the KO mice. Conclusion LGG administration increases hepatic FGF21 expression and serum ADPN concentration, resulting in a reduced ChREBP activation through dihydrosphingosine-1-phosphate-mediated PP2A deactivation, and subsequently reversed fructose-induced NAFLD. Thus, our data suggest that FGF21 is required for the beneficial effects of LGG in reversal of fructose-induced NAFLD.
Lactobacillus rhamnosus GG (LGG) attenuates fructose-induced NAFLD. LGG increases FGF21 and adiponectin expression. LGG inhibits fructose-activated ChREBP and reduces hepatic lipogenesis. FGF21 is required for the therapeutic effects of LGG against fructose-induced NAFLD.
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Affiliation(s)
- Cuiqing Zhao
- College of Animal Science and Technology, Key Lab of Preventive Veterinary Medicine in Jilin Province, Jilin Agricultural Science and Technology University, Jilin, Jilin 132101, China; Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Institute of Virology, Wenzhou University, Wenzhou, Zhejiang 325035, China
| | - Liming Liu
- College of Animal Science and Technology, Key Lab of Preventive Veterinary Medicine in Jilin Province, Jilin Agricultural Science and Technology University, Jilin, Jilin 132101, China; Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Qi Liu
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Fengyuan Li
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Lihua Zhang
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Fenxia Zhu
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Key Laboratory of New Drug Delivery System of Chinese Materia Medica, Jiangsu Provincial Academy of Traditional Chinese Medicine, Nanjing, Jiangsu 210028, China
| | - Tuo Shao
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA
| | - Shirish Barve
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA; Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Yiping Chen
- Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325035, China
| | - Xiaokun Li
- Institute of Virology, Wenzhou University, Wenzhou, Zhejiang 325035, China
| | - Craig J McClain
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA; Robley Rex VA Medical Center, Louisville, KY 40206, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA; Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA
| | - Wenke Feng
- Department of Medicine, University of Louisville, Louisville, KY 40202, USA; Department of Pharmacology & Toxicology, University of Louisville, Louisville, KY 40202, USA; Hepatobiology & Toxicology Center, University of Louisville, Louisville, KY 40202, USA; Alcohol Research Center, University of Louisville, Louisville, KY 40202, USA.
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Taskinen MR, Packard CJ, Borén J. Dietary Fructose and the Metabolic Syndrome. Nutrients 2019; 11:nu11091987. [PMID: 31443567 PMCID: PMC6770027 DOI: 10.3390/nu11091987] [Citation(s) in RCA: 173] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2019] [Revised: 08/06/2019] [Accepted: 08/08/2019] [Indexed: 12/16/2022] Open
Abstract
Consumption of fructose, the sweetest of all naturally occurring carbohydrates, has increased dramatically in the last 40 years and is today commonly used commercially in soft drinks, juice, and baked goods. These products comprise a large proportion of the modern diet, in particular in children, adolescents, and young adults. A large body of evidence associate consumption of fructose and other sugar-sweetened beverages with insulin resistance, intrahepatic lipid accumulation, and hypertriglyceridemia. In the long term, these risk factors may contribute to the development of type 2 diabetes and cardiovascular diseases. Fructose is absorbed in the small intestine and metabolized in the liver where it stimulates fructolysis, glycolysis, lipogenesis, and glucose production. This may result in hypertriglyceridemia and fatty liver. Therefore, understanding the mechanisms underlying intestinal and hepatic fructose metabolism is important. Here we review recent evidence linking excessive fructose consumption to health risk markers and development of components of the Metabolic Syndrome.
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Affiliation(s)
- Marja-Riitta Taskinen
- Research Program for Clinical and Molecular Medicine Unit, Diabetes and Obesity, University of Helsinki, 00029 Helsinki, Finland
| | - Chris J Packard
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, 41345 Gothenburg, Sweden.
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Bergwall S, Ramne S, Sonestedt E, Acosta S. High versus low added sugar consumption for the primary prevention of cardiovascular disease. Hippokratia 2019. [DOI: 10.1002/14651858.cd013320] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Sara Bergwall
- Lund University; Department of Clinical Sciences Malmö, Vascular Diseases; Malmö Sweden
| | - Stina Ramne
- Lund University; Department of Clinical Sciences Malmö, Nutritional Epidemiology; Malmö Sweden
| | - Emily Sonestedt
- Lund University; Department of Clinical Sciences Malmö, Nutritional Epidemiology; Malmö Sweden
| | - Stefan Acosta
- Malmö University Hospital; Department of Vascular Diseases; Malmö Sweden S205 02
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Nier A, Brandt A, Rajcic D, Bruns T, Bergheim I. Short-Term Isocaloric Intake of a Fructose- but not Glucose-Rich Diet Affects Bacterial Endotoxin Concentrations and Markers of Metabolic Health in Normal Weight Healthy Subjects. Mol Nutr Food Res 2019; 63:e1800868. [PMID: 30570214 PMCID: PMC6590154 DOI: 10.1002/mnfr.201800868] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 12/06/2018] [Indexed: 12/18/2022]
Abstract
SCOPE Dietary pattern and impairments of intestinal barrier function are discussed to be critical in the development of metabolic impairments. Here, it is determined if an isocaloric exchange of complex carbohydrates with monosaccharides affects markers of intestinal permeability and metabolic health in healthy subjects. METHODS AND RESULTS After a dietary standardization for 4 days, all 12 subjects aged 21-33 years receive an isocaloric fructose- and glucose-enriched diet for 3 days separated by a wash-out phase. Anthropometry, blood pressure, markers of intestinal permeability and metabolic as well as inflammatory parameters are determined in blood samples or isolated peripheral blood mononuclear cells collected at baseline, after standardizations and the monosaccharide interventions, respectively. While anthropometric and inflammatory parameters are not changed, the intake of an isocaloric fructose- but not glucose-enriched diet is associated with a significant increase of bacterial endotoxin plasma levels and alanine aminotransferase activity in serum, while total plasma nitrate/nitrite concentrations are significantly decreased. In peripheral blood mononuclear cells, Toll like receptors 4, 2, and MYD88 mRNA expressions are significantly induced after the fructose-rich but not the glucose-rich diet. CONCLUSION In metabolically healthy subjects, even a short-term intake of a fructose-rich diet can elevate bacterial endotoxin levels and change markers of liver health and vascular endothelial function.
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Affiliation(s)
- Anika Nier
- Department of Nutritional SciencesMolecular Nutritional ScienceUniversity of Vienna1090ViennaAustria
- SD Model Systems of Molecular NutritionInstitute of NutritionFriedrich–Schiller University Jena07743JenaGermany
| | - Annette Brandt
- Department of Nutritional SciencesMolecular Nutritional ScienceUniversity of Vienna1090ViennaAustria
- SD Model Systems of Molecular NutritionInstitute of NutritionFriedrich–Schiller University Jena07743JenaGermany
| | - Dragana Rajcic
- Department of Nutritional SciencesMolecular Nutritional ScienceUniversity of Vienna1090ViennaAustria
| | - Tony Bruns
- Department of Internal Medicine IVUniversity Hospital Jena07743JenaGermany
| | - Ina Bergheim
- Department of Nutritional SciencesMolecular Nutritional ScienceUniversity of Vienna1090ViennaAustria
- SD Model Systems of Molecular NutritionInstitute of NutritionFriedrich–Schiller University Jena07743JenaGermany
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Macronutrients and the Adipose-Liver Axis in Obesity and Fatty Liver. Cell Mol Gastroenterol Hepatol 2019; 7:749-761. [PMID: 30763771 PMCID: PMC6463203 DOI: 10.1016/j.jcmgh.2019.02.001] [Citation(s) in RCA: 74] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2018] [Revised: 01/30/2019] [Accepted: 02/01/2019] [Indexed: 02/06/2023]
Abstract
Macronutrient metabolism is a highly orchestrated process, with adipose tissue and liver each playing central roles in nutrient uptake, processing, transport, and storage. These 2 tissues form an important metabolic circuit, particularly as it relates to lipids as the primary storage form of excess energy. The function of the circuit is influenced by many factors, including the quantity and type of nutrients consumed and their impact on the overall health of the tissues. In this review we begin with a brief summary of the homeostatic disposition of lipids between adipose tissue and liver and how these processes can become dysregulated in obesity. We then explore how specific dietary nutrients and nutrient combinations can exert unique influences on the liver-adipose tissue axis.
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Choo VL, Viguiliouk E, Blanco Mejia S, Cozma AI, Khan TA, Ha V, Wolever TMS, Leiter LA, Vuksan V, Kendall CWC, de Souza RJ, Jenkins DJA, Sievenpiper JL. Food sources of fructose-containing sugars and glycaemic control: systematic review and meta-analysis of controlled intervention studies. BMJ 2018; 363:k4644. [PMID: 30463844 PMCID: PMC6247175 DOI: 10.1136/bmj.k4644] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/28/2018] [Indexed: 12/16/2022]
Abstract
OBJECTIVE To assess the effect of different food sources of fructose-containing sugars on glycaemic control at different levels of energy control. DESIGN Systematic review and meta-analysis of controlled intervention studies. DATA SOURCES Medine, Embase, and the Cochrane Library up to 25 April 2018. ELIGIBILITY CRITERIA FOR SELECTING STUDIES Controlled intervention studies of at least seven days' duration and assessing the effect of different food sources of fructose-containing sugars on glycaemic control in people with and without diabetes were included. Four study designs were prespecified on the basis of energy control: substitution studies (sugars in energy matched comparisons with other macronutrients), addition studies (excess energy from sugars added to diets), subtraction studies (energy from sugars subtracted from diets), and ad libitum studies (sugars freely replaced by other macronutrients without control for energy). Outcomes were glycated haemoglobin (HbA1c), fasting blood glucose, and fasting blood glucose insulin. DATA EXTRACTION AND SYNTHESIS Four independent reviewers extracted relevant data and assessed risk of bias. Data were pooled by random effects models and overall certainty of the evidence assessed by the GRADE approach (grading of recommendations assessment, development, and evaluation). RESULTS 155 study comparisons (n=5086) were included. Total fructose-containing sugars had no harmful effect on any outcome in substitution or subtraction studies, with a decrease seen in HbA1c in substitution studies (mean difference -0.22% (95% confidence interval to -0.35% to -0.08%), -25.9 mmol/mol (-27.3 to -24.4)), but a harmful effect was seen on fasting insulin in addition studies (4.68 pmol/L (1.40 to 7.96)) and ad libitum studies (7.24 pmol/L (0.47 to 14.00)). There was interaction by food source, with specific food sources showing beneficial effects (fruit and fruit juice) or harmful effects (sweetened milk and mixed sources) in substitution studies and harmful effects (sugars-sweetened beverages and fruit juice) in addition studies on at least one outcome. Most of the evidence was low quality. CONCLUSIONS Energy control and food source appear to mediate the effect of fructose-containing sugars on glycaemic control. Although most food sources of these sugars (especially fruit) do not have a harmful effect in energy matched substitutions with other macronutrients, several food sources of fructose-containing sugars (especially sugars-sweetened beverages) adding excess energy to diets have harmful effects. However, certainty in these estimates is low, and more high quality randomised controlled trials are needed. STUDY REGISTRATION Clinicaltrials.gov (NCT02716870).
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Affiliation(s)
- Vivian L Choo
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Undergraduate Medical Education, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Effie Viguiliouk
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Sonia Blanco Mejia
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Adrian I Cozma
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Radiation Oncology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Tauseef A Khan
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
| | - Vanessa Ha
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Undergraduate Medical Education, School of Medicine, Queen's University, Kingston, ON, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - Thomas M S Wolever
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - Lawrence A Leiter
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - Vladimir Vuksan
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - Cyril W C Kendall
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| | - Russell J de Souza
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - David J A Jenkins
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
| | - John L Sievenpiper
- Toronto 3D (Diet, Digestive Tract, and Disease) Knowledge Synthesis and Clinical Trials Unit, Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, 61 Queen Street East, Toronto, ON, M5C 2T2, Canada
- Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, ON, Canada
- Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, ON, Canada
- Division of Endocrinology and Metabolism, Department of Medicine, St Michael's Hospital, Toronto, ON, Canada
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Carreño D, Corro N, Torres-Estay V, Véliz LP, Jaimovich R, Cisternas P, San Francisco IF, Sotomayor PC, Tanasova M, Inestrosa NC, Godoy AS. Fructose and prostate cancer: toward an integrated view of cancer cell metabolism. Prostate Cancer Prostatic Dis 2018; 22:49-58. [PMID: 30104655 DOI: 10.1038/s41391-018-0072-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Revised: 06/13/2018] [Accepted: 06/29/2018] [Indexed: 01/07/2023]
Abstract
Activation of glucose transporter-1 (Glut-1) gene expression is a molecular feature of cancer cells that increases glucose uptake and metabolism. Increased glucose uptake is the basis for the clinical localization of primary tumors using positron emission tomography (PET) and 2-deoxy-2-[18F]-fluoro-D-glucose (FDG) as a radiotracer. However, previous studies have demonstrated that a considerable number of cancers, which include prostate cancer (CaP), express low to undetectable levels of Glut-1 and that FDG-PET has limited clinical applicability in CaP. This observation could be explained by a low metabolic activity of CaP cells that may be overcome using different hexoses, such as fructose, as the preferred energy source. However, these hypotheses have not been examined critically in CaP. This review article summarizes what is currently known about transport and metabolism of hexoses, and more specifically fructose, in CaP and provides experimental evidences indicating that CaP cells may have increased capacity to transport and metabolize fructose in vitro and in vivo. Moreover, this review highlights recent findings that allow better understanding of how metabolism of fructose may regulate cancer cell proliferation and how fructose uptake and metabolism, through the de novo lipogenesis pathway, may provide new opportunities for CaP early diagnosis, staging, and treatment.
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Affiliation(s)
- Daniela Carreño
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Néstor Corro
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Loreto P Véliz
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Pedro Cisternas
- Centro de Envejecimiento y Regeneración (CARE), Department of Cell Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | | | - Paula C Sotomayor
- Center for Integrative Medicine and Innovative Science, Faculty of Medicine, Universidad Andres Bello, Santiago, Chile
| | - Marina Tanasova
- Department of Chemistry, Michigan Technological University, Houghton, MI, 49931, USA
| | - Nibaldo C Inestrosa
- Centro de Envejecimiento y Regeneración (CARE), Department of Cell Biology, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Alejandro S Godoy
- Department of Physiology, Pontificia Universidad Católica de Chile, Santiago, Chile. .,Department of Urology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
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39
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French Recommendations for Sugar Intake in Adults: A Novel Approach Chosen by ANSES. Nutrients 2018; 10:nu10080989. [PMID: 30060614 PMCID: PMC6115815 DOI: 10.3390/nu10080989] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 07/18/2018] [Accepted: 07/25/2018] [Indexed: 01/05/2023] Open
Abstract
This article presents a systematic review of the scientific evidence linking sugar consumption and health in the adult population performed by a group of experts, mandated by the French Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement, et du travail (ANSES). A literature search was performed by crossing search terms for overweight/obesity, diabetes/insulin resistance, dyslipidemia/cardiovascular diseases, non-alcoholic fatty liver diseases (NAFLD), and uric acid concentrations on one hand and for intake of sugars on the other. Controlled mechanistic studies, prospective cohort studies, and randomized clinical trials were extracted and assessed. A literature analysis supported links between sugar intake and both total energy intake and body weight gain, and between sugar intake and blood triglycerides independently of total energy intake. The effects of sugar on blood triglycerides were shown to be mediated by the fructose component of sucrose and were observed with an intake of fructose >50 g/day. In addition, prospective cohort studies showed associations between sugar intake and the risk of diabetes/insulin resistance, cardiovascular diseases, NAFLD, and hyperuricemia. Based on these observations, ANSES proposed to set a maximum limit to the intake of total sugars containing fructose (sucrose, glucose–fructose syrups, honey or other syrups, and natural concentrates, etc.) of 100 g/day.
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40
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Habitual Fructose Intake Relates to Insulin Sensitivity and Fatty Liver Index in Recent-Onset Type 2 Diabetes Patients and Individuals without Diabetes. Nutrients 2018; 10:nu10060774. [PMID: 29914103 PMCID: PMC6024554 DOI: 10.3390/nu10060774] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2018] [Revised: 06/07/2018] [Accepted: 06/13/2018] [Indexed: 12/16/2022] Open
Abstract
The association between the amount and sources of fructose intake with insulin sensitivity and liver fat needs further elucidation. This study aimed at examining whether habitual intake of sucrose plus non-sucrose bound as well as of non-sucrose bound fructose (total fructose, fruit-derived, juice-derived, sugar sweetened beverages (SSB)-derived fructose) is cross-sectionally associated with insulin sensitivity and fatty liver index (FLI). Fructose intake was estimated using the EPIC food frequency questionnaire from 161 participants with type 2 diabetes (T2D) in the ongoing German Diabetes Study (GDS) (age 53 ± 9 years; HbA1c 6.4 ± 0.9%) and 62 individuals without diabetes (CON) (47 ± 14 years; 5.3 ± 0.3%). Peripheral (M-value) and hepatic insulin resistance were assessed by hyperinsulinemic-euglycemic clamps with stable isotope dilution. FLI was calculated based on body mass index, waist circumference, triglyceride and gamma glutamyl transferase concentrations. Multivariable linear regression analyses were performed. A doubling of SSB-derived sucrose plus non-sucrose bound as well as of non-sucrose bound fructose intake was independently associated with a reduction of the M-value by −2.6% (−4.9; −0.2) and −2.7% (−5.2; −0.1) among T2D, respectively, with an increase in the odds of fatty liver by 16% and 17%, respectively among T2D (all p < 0.05). Doubling fruit-derived sucrose plus non-sucrose bound fructose intake independently related to a reduction in the odds of fatty liver by 13% (p = 0.033) among T2D. Moderate SSB-derived fructose intake may detrimentally affect peripheral insulin sensitivity, whereas fruit-derived fructose intake appeared beneficial for liver fat content.
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41
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Jensen T, Abdelmalek MF, Sullivan S, Nadeau KJ, Green M, Roncal C, Nakagawa T, Kuwabara M, Sato Y, Kang DH, Tolan DR, Sanchez-Lozada LG, Rosen HR, Lanaspa MA, Diehl AM, Johnson RJ. Fructose and sugar: A major mediator of non-alcoholic fatty liver disease. J Hepatol 2018; 68:1063-1075. [PMID: 29408694 PMCID: PMC5893377 DOI: 10.1016/j.jhep.2018.01.019] [Citation(s) in RCA: 610] [Impact Index Per Article: 87.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 01/18/2018] [Accepted: 01/22/2018] [Indexed: 12/11/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome; its rising prevalence parallels the rise in obesity and diabetes. Historically thought to result from overnutrition and a sedentary lifestyle, recent evidence suggests that diets high in sugar (from sucrose and/or high-fructose corn syrup [HFCS]) not only increase the risk of NAFLD, but also non-alcoholic steatohepatitis (NASH). Herein, we review the experimental and clinical evidence that fructose precipitates fat accumulation in the liver, due to both increased lipogenesis and impaired fat oxidation. Recent evidence suggests that the predisposition to fatty liver is linked to the metabolism of fructose by fructokinase C, which results in ATP consumption, nucleotide turnover and uric acid generation that mediate fat accumulation. Alterations to gut permeability, the microbiome, and associated endotoxemia contribute to the risk of NAFLD and NASH. Early clinical studies suggest that reducing sugary beverages and total fructose intake, especially from added sugars, may have a significant benefit on reducing hepatic fat accumulation. We suggest larger, more definitive trials to determine if lowering sugar/HFCS intake, and/or blocking uric acid generation, may help reduce NAFLD and its downstream complications of cirrhosis and chronic liver disease.
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Affiliation(s)
- Thomas Jensen
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.
| | | | - Shelby Sullivan
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kristen J Nadeau
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Melanie Green
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Carlos Roncal
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Takahiko Nakagawa
- Division of Future Basic Medicine, Nara Medical University, Nara, Japan
| | - Masanari Kuwabara
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Yuka Sato
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Duk-Hee Kang
- Division of Nephrology, Department of Internal Medicine, Ewha Womans University College of Medicine, Seoul, Republic of Korea
| | - Dean R Tolan
- Dept of Biology, Boston University, Boston, MA, United States
| | | | - Hugo R Rosen
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Miguel A Lanaspa
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | | | - Richard J Johnson
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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42
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Rodrigues N, Peng M, Oey I, Venn BJ. Glycaemic, uricaemic and blood pressure response to beverages with partial fructose replacement of sucrose. Eur J Clin Nutr 2018; 72:1717-1723. [DOI: 10.1038/s41430-018-0134-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2017] [Revised: 01/29/2018] [Accepted: 02/09/2018] [Indexed: 01/09/2023]
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43
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Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals. Nutrients 2017; 9:nu9101065. [PMID: 28954437 PMCID: PMC5691682 DOI: 10.3390/nu9101065] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 08/28/2017] [Accepted: 09/21/2017] [Indexed: 02/07/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL) to non-alcoholic steatohepatitis (NASH), and it is the most frequent chronic liver disease in the industrialized world. Beyond liver related complications such as cirrhosis and hepatocellular carcinoma, NAFLD is also an emerging risk factor for type 2 diabetes and cardiovascular disease. Currently, lifestyle intervention including strategies to reduce body weight and to increase regular physical activity represents the mainstay of NAFLD management. Total caloric intake plays a very important role in both the development and the treatment of NAFLD; however, apart from the caloric restriction alone, modifying the quality of the diet and modulating either the macro- or micronutrient composition can also markedly affect the clinical evolution of NAFLD, offering a more realistic and feasible treatment alternative. The aim of the present review is to summarize currently available evidence from randomized controlled trials on the effects of different nutrients including carbohydrates, lipids, protein and other dietary components, in isocaloric conditions, on NAFLD in people at high cardiometabolic risk. We also describe the plausible mechanisms by which different dietary components could modulate liver fat content.
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44
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Parry SA, Hodson L. Influence of dietary macronutrients on liver fat accumulation and metabolism. J Investig Med 2017; 65:1102-1115. [PMID: 28947639 PMCID: PMC5749316 DOI: 10.1136/jim-2017-000524] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/08/2017] [Indexed: 02/07/2023]
Abstract
The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the available observational and intervention studies that have investigated the influence of dietary macronutrients on liver fat content. Findings from observational studies are conflicting with some reporting that relative to healthy controls, patients with NAFLD consume diets higher in total fat/saturated fatty acids, whilst others find they consume diets higher in carbohydrates/sugars. From the limited number of intervention studies that have been undertaken, a consistent finding is a hypercaloric diet, regardless of whether the excess calories have been provided either as fat, sugar, or both, increases liver fat content. In contrast, a hypocaloric diet decreases liver fat content. Findings from both hyper- and hypo-caloric feeding studies provide some suggestion that macronutrient composition may also play a role in regulating liver fat content and this is supported by data from isocaloric feeding studies; fatty acid composition and/or carbohydrate content/type appear to influence whether there is accrual of liver fat or not. The mechanisms by which specific macronutrients, when consumed as part of an isocaloric diet, cause a change in liver fat remain to be fully elucidated.
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Affiliation(s)
- Siôn A Parry
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
| | - Leanne Hodson
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK
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45
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Evans RA, Frese M, Romero J, Cunningham JH, Mills KE. Chronic fructose substitution for glucose or sucrose in food or beverages has little effect on fasting blood glucose, insulin, or triglycerides: a systematic review and meta-analysis. Am J Clin Nutr 2017; 106:519-529. [PMID: 28592603 DOI: 10.3945/ajcn.116.145169] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Accepted: 05/01/2017] [Indexed: 11/14/2022] Open
Abstract
Background: Conflicting evidence exists on the role of long-term fructose consumption on health. No systematic review has addressed the effect of isoenergetic fructose replacement of other sugars and its effect on glycated hemoglobin (HbA1c), fasting blood glucose, insulin, and triglycerides.Objective: The objective of this study was to review the evidence for a reduction in fasting glycemic and insulinemic markers after chronic, isoenergetic replacement of glucose or sucrose in foods or beverages by fructose. The target populations were persons without diabetes, those with impaired glucose tolerance, and those with type 2 diabetes.Design: We searched the Cochrane Library, MEDLINE, EMBASE, the WHO International Clinical Trials Registry Platform Search Portal, and clinicaltrials.gov The date of the last search was 26 April 2016. We included randomized controlled trials of isoenergetic replacement of glucose, sucrose, or both by fructose in adults or children with or without diabetes of ≥2 wk duration that measured fasting blood glucose. The main outcomes analyzed were fasting blood glucose and insulin as well as fasting triglycerides, blood lipoproteins, HbA1c, and body weight.Results: We included 14 comparison arms from 11 trials, including 277 patients. The studies varied in length from 2 to 10 wk (mean: 28 d) and included doses of fructose between 40 and 150 g/d (mean: 68 g/d). Fructose substitution in some subgroups resulted in significantly but only slightly lowered fasting blood glucose (-0.14 mmol/L; 95% CI: -0.24, -0.036 mmol/L), HbA1c [-10 g/L (95% CI: -12.90, -7.10 g/L; impaired glucose tolerance) and -6 g/L (95% CI: -8.47, -3.53 g/L; normoglycemia)], triglycerides (-0.08 mmol/L; 95% CI: -0.14, -0.02 mmol/L), and body weight (-1.40 kg; 95% CI: -2.07, -0.74 kg). There was no effect on fasting blood insulin or blood lipids.Conclusions: The evidence suggests that the substitution of fructose for glucose or sucrose in food or beverages may be of benefit to individuals, particularly those with impaired glucose tolerance or type 2 diabetes. However, additional high-quality studies in these populations are required.
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Affiliation(s)
| | - Michael Frese
- Health Research Institute.,Faculty of Education, Science, Technology, and Mathematics, and
| | - Julio Romero
- Department of Software Engineering and Artificial Intelligence, University of Canberra, Canberra, Australia; and
| | - Judy H Cunningham
- Formerly of Risk Assessment Chemical Safety and Nutrition, Food Standards Australia New Zealand, Canberra, Australia
| | - Kerry E Mills
- Health Research Institute, .,Faculty of Education, Science, Technology, and Mathematics, and
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46
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Arsenault BJ, Lamarche B, Després JP. Targeting Overconsumption of Sugar-Sweetened Beverages vs. Overall Poor Diet Quality for Cardiometabolic Diseases Risk Prevention: Place Your Bets! Nutrients 2017; 9:nu9060600. [PMID: 28608806 PMCID: PMC5490579 DOI: 10.3390/nu9060600] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 05/25/2017] [Accepted: 05/30/2017] [Indexed: 01/08/2023] Open
Abstract
Chronic overconsumption of sugar-sweetened beverages (SSBs) is amongst the dietary factors most consistently found to be associated with obesity, type 2 diabetes (T2D) and cardiovascular disease (CVD) risk in large epidemiological studies. Intervention studies have shown that SSB overconsumption increases intra-abdominal obesity and ectopic lipid deposition in the liver, and also exacerbates cardiometabolic risk. Similar to the prevalence of obesity and T2D, national surveys of food consumption have shown that chronic overconsumption of SSBs is skyrocketing in many parts of the world, yet with marked heterogeneity across countries. SSB overconsumption is also particularly worrisome among children and adolescents. Although the relationships between SSB overconsumption and obesity, T2D, and CVD are rather consistent in epidemiological studies, it has also been shown that SSB overconsumption is part of an overall poor dietary pattern and is particularly prevalent among subgroups of the population with low socioeconomic status, thereby questioning the major focus on SSBs to target/prevent cardiometabolic diseases. Public health initiatives aimed specifically at decreasing SSB overconsumption will most likely be successful in influencing SSB consumption per se. However, comprehensive strategies targeting poor dietary patterns and aiming at improving global dietary quality are likely to have much more impact in addressing the unprecedented public health challenges that we are currently facing.
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Affiliation(s)
- Benoit J Arsenault
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Y-2110, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Québec City, QC G1V 4G5, Canada.
- Department of Medicine, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada.
| | - Benoît Lamarche
- School of Nutrition, Université Laval, Québec City, QC G1V 0A6, Canada.
| | - Jean-Pierre Després
- Centre de recherche de l'Institut universitaire de cardiologie et de pneumologie de Québec, Y-2110, Pavillon Marguerite D'Youville, 2725 chemin Ste-Foy, Québec City, QC G1V 4G5, Canada.
- Department of Kinesiology, Faculty of Medicine, Université Laval, Québec City, QC G1V 0A6, Canada.
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47
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Matikainen N, Söderlund S, Björnson E, Bogl LH, Pietiläinen KH, Hakkarainen A, Lundbom N, Eliasson B, Räsänen SM, Rivellese A, Patti L, Prinster A, Riccardi G, Després JP, Alméras N, Holst JJ, Deacon CF, Borén J, Taskinen MR. Fructose intervention for 12 weeks does not impair glycemic control or incretin hormone responses during oral glucose or mixed meal tests in obese men. Nutr Metab Cardiovasc Dis 2017; 27:534-542. [PMID: 28428027 DOI: 10.1016/j.numecd.2017.03.003] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 02/28/2017] [Accepted: 03/09/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND AND AIMS Incretin hormones glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP) are affected early on in the pathogenesis of metabolic syndrome and type 2 diabetes. Epidemiologic studies consistently link high fructose consumption to insulin resistance but whether fructose consumption impairs the incretin response remains unknown. METHODS AND RESULTS As many as 66 obese (BMI 26-40 kg/m2) male subjects consumed fructose-sweetened beverages containing 75 g fructose/day for 12 weeks while continuing their usual lifestyle. Glucose, insulin, GLP-1 and GIP were measured during oral glucose tolerance test (OGTT) and triglycerides (TG), GLP-1, GIP and PYY during a mixed meal test before and after fructose intervention. Fructose intervention did not worsen glucose and insulin responses during OGTT, and GLP-1 and GIP responses during OGTT and fat-rich meal were unchanged. Postprandial TG response increased significantly, p = 0.004, and we observed small but significant increases in weight and liver fat content, but not in visceral or subcutaneous fat depots. However, even the subgroups who gained weight or liver fat during fructose intervention did not worsen their glucose, insulin, GLP-1 or PYY responses. A minor increase in GIP response during OGTT occurred in subjects who gained liver fat (p = 0.049). CONCLUSION In obese males with features of metabolic syndrome, 12 weeks fructose intervention 75 g/day did not change glucose, insulin, GLP-1 or GIP responses during OGTT or GLP-1, GIP or PYY responses during a mixed meal. Therefore, fructose intake, even accompanied with mild weight gain, increases in liver fat and worsening of postprandial TG profile, does not impair glucose tolerance or gut incretin response to oral glucose or mixed meal challenge.
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Affiliation(s)
- N Matikainen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Endocrinology, Abdominal Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland.
| | - S Söderlund
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - E Björnson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - L H Bogl
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Institute for Molecular Medicine FIMM, Helsinki, Finland; Department of Public Health, University of Helsinki, Helsinki, Finland
| | - K H Pietiläinen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki University Hospital, Helsinki, Finland; Endocrinology, Abdominal Center, Helsinki University Central Hospital, University of Helsinki, Helsinki, Finland
| | - A Hakkarainen
- Radiology, HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, Finland
| | - N Lundbom
- Radiology, HUS Medical Imaging Center, Helsinki University Hospital, University of Helsinki, Finland
| | - B Eliasson
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - S M Räsänen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - A Rivellese
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - L Patti
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - A Prinster
- Biostructure and Bioimaging Institute, National Research Council, Naples, Italy
| | - G Riccardi
- Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy
| | - J-P Després
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada
| | - N Alméras
- Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec City, Québec, Canada
| | - J J Holst
- NNF Centre for Basic Metabolic Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - C F Deacon
- NNF Centre for Basic Metabolic Research, Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - J Borén
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - M-R Taskinen
- Research Programs Unit, Diabetes and Obesity, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
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48
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Fructose Consumption in the Development of Obesity and the Effects of Different Protocols of Physical Exercise on the Hepatic Metabolism. Nutrients 2017; 9:nu9040405. [PMID: 28425939 PMCID: PMC5409744 DOI: 10.3390/nu9040405] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 04/03/2017] [Accepted: 04/06/2017] [Indexed: 02/07/2023] Open
Abstract
Fructose consumption has been growing exponentially and, concomitant with this, the increase in the incidence of obesity and associated complications has followed the same behavior. Studies indicate that fructose may be a carbohydrate with greater obesogenic potential than other sugars. In this context, the liver seems to be a key organ for understanding the deleterious health effects promoted by fructose consumption. Fructose promotes complications in glucose metabolism, accumulation of triacylglycerol in the hepatocytes, and alterations in the lipid profile, which, associated with an inflammatory response and alterations in the redox state, will imply a systemic picture of insulin resistance. However, physical exercise has been indicated for the treatment of several chronic diseases. In this review, we show how each exercise protocol (aerobic, strength, or a combination of both) promote improvements in the obesogenic state created by fructose consumption as an improvement in the serum and liver lipid profile (high-density lipoprotein (HDL) increase and decrease triglyceride (TG) and low-density lipoprotein (LDL) levels) and a reduction of markers of inflammation caused by an excess of fructose. Therefore, it is concluded that the practice of aerobic physical exercise, strength training, or a combination of both is essential for attenuating the complications developed by the consumption of fructose.
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49
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Steenson S, Umpleby AM, Lovegrove JA, Jackson KG, Fielding BA. Role of the Enterocyte in Fructose-Induced Hypertriglyceridaemia. Nutrients 2017; 9:nu9040349. [PMID: 28368310 PMCID: PMC5409688 DOI: 10.3390/nu9040349] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 03/21/2017] [Accepted: 03/31/2017] [Indexed: 01/12/2023] Open
Abstract
Dietary fructose has been linked to an increased post-prandial triglyceride (TG) level; which is an established independent risk factor for cardiovascular disease. Although much research has focused on the effects of fructose consumption on liver-derived very-low density lipoprotein (VLDL); emerging evidence also suggests that fructose may raise post-prandial TG levels by affecting the metabolism of enterocytes of the small intestine. Enterocytes have become well recognised for their ability to transiently store lipids following a meal and to thus control post-prandial TG levels according to the rate of chylomicron (CM) lipoprotein synthesis and secretion. The influence of fructose consumption on several aspects of enterocyte lipid metabolism are discussed; including de novo lipogenesis; apolipoprotein B48 and CM-TG production; based on the findings of animal and human isotopic tracer studies. Methodological issues affecting the interpretation of fructose studies conducted to date are highlighted; including the accurate separation of CM and VLDL. Although the available evidence to date is limited; disruption of enterocyte lipid metabolism may make a meaningful contribution to the hypertriglyceridaemia often associated with fructose consumption.
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Affiliation(s)
- Simon Steenson
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK.
- Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6AP, UK.
| | - A Margot Umpleby
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK.
| | - Julie A Lovegrove
- Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6AP, UK.
| | - Kim G Jackson
- Department of Food & Nutritional Sciences and Institute for Cardiovascular and Metabolic Research (ICMR), University of Reading, Reading RG6 6AP, UK.
| | - Barbara A Fielding
- Department of Nutritional Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7WG, UK.
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50
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Rippe JM, Sievenpiper JL, Lê KA, White JS, Clemens R, Angelopoulos TJ. What is the appropriate upper limit for added sugars consumption? Nutr Rev 2017; 75:18-36. [PMID: 27974597 PMCID: PMC5916235 DOI: 10.1093/nutrit/nuw046] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Dramatic increases in obesity and diabetes have occurred worldwide over the past 30 years. Some investigators have suggested that these increases may be due, in part, to increased added sugars consumption. Several scientific organizations, including the World Health Organization, the Scientific Advisory Council on Nutrition, the Dietary Guidelines Advisory Committee 2015, and the American Heart Association, have recommended significant restrictions on upper limits of sugars consumption. In this review, the scientific evidence related to sugars consumption and its putative link to various chronic conditions such as obesity, diabetes, heart disease, nonalcoholic fatty liver disease, and the metabolic syndrome is examined. While it appears prudent to avoid excessive calories from sugars, the scientific basis for restrictive guidelines is far from settled.
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Affiliation(s)
- James M Rippe
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA.
| | - John L Sievenpiper
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - Kim-Anne Lê
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - John S White
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - Roger Clemens
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
| | - Theodore J Angelopoulos
- J.M. Rippe is with the Rippe Lifestyle Institute, Shrewsbury, Massachusetts, USA; and the Department of Biomedical Sciences, University of Central Florida, Orlando, Florida, USA. J.L. Sievenpiper is with the Department of Nutritional Sciences, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada; and the Division of Endocrinology and Metabolism, St Michael's Hospital; the Li Ka Shing Knowledge Institute, St Michael's Hospital; the Toronto 3D Knowledge Synthesis and Clinical Trials Unit, St Michael's Hospital; and the Clinical Nutrition and Risk Factor Modification Centre, St Michael's Hospital, Toronto, Ontario, Canada. K.-A. Lê is with Nestec Ltd, Nestlé Research Center, Lausanne, Switzerland. J.S. White is with White Technical Research, Argenta, Illinois, USA. R. Clemens is with the Department of Pharmacology and Pharmaceutical Sciences, University of Southern California School of Pharmacy, University of Southern California; and the International Center for Regulatory Science, University of Southern California, Los Angeles, California, USA. T.J. Angelopoulos is with the School of Health Sciences, Emory and Henry College, Emory, Virginia, USA
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