Sugar and fructose

What it is

Table sugar, or sucrose, is made of glucose and fructose in equal parts ¹. Glucose–fructose syrup, called high-fructose corn syrup in the United States, is made from starch and mostly contains 42% or 55% free fructose ². Free sugars include sugars added to foods and those in honey, syrups and fruit juices ².

In the body

The liver takes up most dietary fructose and breaks it down by a route bypassing the main control point of glucose breakdown ¹².

Ketohexokinase C, aldolase B and triokinase convert fructose to triose phosphates, which enter glycolysis below phosphofructokinase, the step inhibited by ATP and citrate, and yield fatty acids ¹².

Hepatic fructose metabolism and de novo lipogenesisHepatocyte cytosol; pyruvate dehydrogenase in mitochondria

Fructose
Ketohexokinase C (KHK)ATP to ADPKm 0.8 mM; not restrained by cellular energy status
Fructose 1-phosphate
Aldolase B (ALDOB)Deficient in hereditary fructose intolerance
Dihydroxyacetone phosphate + glyceraldehyde
Triokinase and FMN cyclase (TKFC)ATP to ADPTriose phosphates enter glycolysis below phosphofructokinase-1
Dihydroxyacetone phosphate + glyceraldehyde 3-phosphate
several stepsNAD+ to NADH, ADP to ATPTriose phosphates also yield glucose, glycogen, lactate and glycerol
Pyruvate
Pyruvate dehydrogenase complex, mitochondrialCoA, NAD+ to NADHReleases CO2
Acetyl-CoA
Acetyl-CoA carboxylase 1 (ACACA)ATP, HCO3−, BiotinAcetyl-CoA reaches the cytosol as citrate (ACLY); malonyl-CoA inhibits CPT1A
Malonyl-CoA
Fatty acid synthase (FASN)Acetyl-CoA, 14 NADPHSeven malonyl-CoA per palmitate; ChREBP and SREBP-1c induce the enzymes
Palmitate

Large fructose loads transiently lower hepatic ATP and phosphate; falling phosphate activates AMP deaminase, and AMP is degraded to uric acid ¹².

Uric acid formation after a fructose loadHepatocyte cytosol

ATP
Ketohexokinase C (KHK)Fructose to fructose 1-phosphateRapid phosphorylation of large loads lowers ATP and free phosphate
ADP
Adenylate kinaseADP to ATP2 ADP ⇌ ATP + AMP
AMP
AMP deaminase (AMPD)H2OReleases NH4+; activated as free phosphate falls
IMP
Cytosolic purine 5′-nucleotidase (NT5C2)H2OReleases phosphate
Inosine
Purine nucleoside phosphorylase (PNP)PhosphateReleases ribose 1-phosphate
Hypoxanthine
Xanthine oxidoreductase (XDH)NAD+ to NADH or O2 to H2O2, Mo-molybdopterin, FAD, 2 [2Fe-2S]AllopurinolFebuxostat
Xanthine
Xanthine oxidoreductase (XDH)NAD+ to NADH or O2 to H2O2, Mo-molybdopterin, FAD, 2 [2Fe-2S]AllopurinolFebuxostatEnd product of purine metabolism in humans
Uric acid

Loss of ketohexokinase causes benign essential fructosuria, and loss of aldolase B hereditary fructose intolerance ¹³.

What studies show

In a double-blind trial in 641 Dutch children, a daily sugar-free drink led to less weight gain over 18 months than one with 26 g sucrose ⁴.

Weight rose by 6.35 kg and 7.37 kg (difference −1.01 kg, 95% CI −1.54 to −0.48) ⁴. In 224 overweight or obese adolescents, a 1-year intervention including home delivery of non-caloric drinks reduced weight gain at 1 year by 1.9 kg; BMI change at 2 years, the primary outcome, did not differ (P = 0.46) ⁵.

In 32 overweight or obese adults given drinks supplying 25% of energy requirements as fructose or glucose for 10 weeks, weight rose similarly, but only fructose raised postprandial fractional hepatic de novo lipogenesis (11.4% to 16.9%), intra-abdominal fat (+14.0%) and fasting apoB (+27.2%) ⁶. Groups were matched, and the US National Institutes of Health funded the study ⁶. In a randomised trial in 94 young men, 80 g a day of fructose or sucrose in drinks for 7 weeks doubled the fractional secretion rate of newly synthesised VLDL palmitate (median 19.7 and 20.8 against 9.1%/day without drinks); glucose did not (11.0%/day) ⁷.

The Sugar Research Foundation funded a review in 1965, set its objective and received drafts; in the review, published in 1967 without disclosure of this role, studies linking sucrose to coronary heart disease were discounted ⁸. Evidence linking sugary drinks to weight gain was judged insufficient in 5 of 6 conclusions of systematic reviews with food-industry conflicts of interest and in 2 of 12 without (relative risk 5.0, 95% CI 1.3 to 19.3) ⁹.

References

Independent research
Hannou SA, Haslam DE, McKeown NM, Herman MA. Fructose metabolism and metabolic disease Journal of Clinical Investigation, 2018.
doi:10.1172/JCI96702 PubMed 29388924
Funding and finding
Funding
This work is supported by American Heart Association 16CSA28590003 (to MAH and NMM), NIH R01DK100425 (to MAH), NIH 5T32HL069772-15 (to DEH), and US Department of Agriculture Agricultural Research Service agreement 58-1950-4-003 (to NMM).
Finding
Narrative review. Sucrose is composed of equal portions of glucose and fructose. GLUT5 (SLC2A5) absorbs fructose with a Km of 6 mM; healthy adults absorb from less than 5 g to more than 50 g of free fructose. The liver extracts about 70% of an oral fructose load and 15% to 30% of an oral glucose load; the intestine metabolises up to 30% of an oral fructose load. KHK phosphorylates fructose to fructose 1-phosphate; the C isoform (liver, kidney, intestine) has a Km of 0.8 mM, the A isoform 8 mM. ALDOB cleaves fructose 1-phosphate to dihydroxyacetone phosphate and glyceraldehyde, which TKFC phosphorylates to glyceraldehyde 3-phosphate, so fructose carbon enters below phosphofructokinase. Fructose activates ChREBP and SREBP1c; malonyl-CoA inhibits CPT1A. Falling intracellular phosphate activates AMP deaminase and AMP is catabolised to uric acid; Mendelian randomisation studies do not strongly support a causal role for circulating uric acid in cardiometabolic disease. KHK loss of function causes essential fructosuria with no documented adverse effects. Large long-term randomised trials of added sugars on cardiometabolic risk are lacking.
Regulator
EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA), Turck D, Bohn T, Castenmiller J, de Henauw S, Hirsch-Ernst KI, et al. Tolerable upper intake level for dietary sugars EFSA Journal, 2022.
doi:10.2903/j.efsa.2022.7074 PubMed 35251356
Funding and finding
Funding
European Food Safety Authority. Requestor: European Commission, following a request from the national food competent authorities of Denmark, Finland, Iceland, Norway and Sweden (question EFSA-Q-2016-00414).
Finding
Systematic reviews of 49 RCTs and 66 cohorts on metabolic endpoints. Added sugars are mono- and disaccharides added during processing or preparation or at the table; free sugars are added sugars plus sugars naturally present in honey, syrups, fruit juices and juice concentrates. Sucrase-isomaltase hydrolyses sucrose; glucose enters enterocytes by SGLT1, fructose by facilitated diffusion through GLUT5, incompletely and enhanced by co-ingested glucose; GLUT2 moves all three monosaccharides into portal blood. Hepatic glycolysis is restrained at phosphofructokinase by ATP and citrate, fructolysis is not; almost all fructose entering hepatocytes becomes triose phosphates, from which lactate, glucose, glycogen, glycerol and fatty acids are formed. Large fructose loads transiently deplete hepatic ATP, with AMP formation and purine degradation. Dietary sugars are a well-established hazard for dental caries: plaque bacteria convert sugars to organic acids that demineralise enamel and dentine, and about 30% of plaque is matrix largely of glucans made from sucrose by bacterial glucosyltransferases. Certainty of a causal relationship for added and free sugars (RCTs on surrogate endpoints): moderate for obesity and dyslipidaemia, low for NAFLD and type 2 diabetes, very low for hypertension; too few RCTs below 10% of energy. Cohorts did not support a relationship of dietary sugars in isocaloric exchange with chronic metabolic disease. In RCTs, free fructose and free glucose had similar effects on body weight, liver fat, glucose tolerance, blood lipids and blood pressure, while free fructose increased hepatic insulin resistance and uric acid more; certainty for fructose and gout moderate (cohorts). Sugar-sweetened beverages: high certainty for obesity, type 2 diabetes, hypertension and cardiovascular disease, moderate for gout. Glucose-fructose syrups are made by hydrolysing starch to glucose and converting about half enzymatically to fructose; most contain 42% fructose (processed foods) or 55% (sugar-sweetened beverages), as free monosaccharides; called high-fructose corn syrup in the United States and isoglucose in the EU. No tolerable upper intake level could be set; intake of added and free sugars should be as low as possible in a nutritionally adequate diet.
Textbook or database
Gaughan S, Ayres L, Baker PR II. Hereditary Fructose Intolerance GeneReviews, University of Washington, Seattle, 2021.
PubMed 26677512
Funding and finding
Funding
not stated
Finding
Initial posting 17 December 2015; last update 18 February 2021. Autosomal recessive; biallelic pathogenic ALDOB variants. Prevalence estimated from carrier testing: 1 in 18,000 (United Kingdom), 1 in 26,000 (Germany), 1 in 31,000 (Poland), 1 in 60,000 (United States). p.Ala150Pro (legacy Ala149Pro) is the most common variant in all studies. Accumulated fructose 1-phosphate inhibits gluconeogenesis and glycogenolysis, causes overuse and reduced regeneration of ATP, and impairs protein glycosylation. After fructose, sucrose or sorbitol, untreated patients develop hypoglycaemia, vomiting and metabolic disturbances, and may progress to hepatic and renal failure; with early dietary restriction of fructose, sucrose, sorbitol and sucralose, quality of life and life expectancy are normal.
Independent research
de Ruyter JC, Olthof MR, Seidell JC, Katan MB. A trial of sugar-free or sugar-sweetened beverages and body weight in children New England Journal of Medicine, 2012.
doi:10.1056/NEJMoa1203034 PubMed 22998340
Funding and finding
Registration
NCT00893529
Participants
641
Follow-up
18 months
Funding
Supported by grants from the Netherlands Organization for Health Research and Development (120520010), the Netherlands Heart Foundation (2008B096), and the Royal Netherlands Academy of Arts and Sciences (ISK/741/PAH). The investigators hired Refresco Benelux to produce the beverages; the manufacturer had no role in the design of the study, the accrual or analysis of the data, or the preparation of the manuscript.
Finding
Double-blind; one 250 ml can per day of a sugar-free drink (34 mg sucralose, 12 mg acesulfame potassium) or a matching drink with 26 g sucrose (104 kcal). With imputation for the 26% who stopped drinking the beverages, BMI z score rose by 0.02 SD in the sugar-free group and 0.15 SD in the sugar group (95% CI of the difference -0.21 to -0.05); weight rose by 6.35 kg and 7.37 kg (difference 1.01 kg; 95% CI -1.54 to -0.48).
Independent research
Ebbeling CB, Feldman HA, Chomitz VR, Antonelli TA, Gortmaker SL, Osganian SK, et al. A randomized trial of sugar-sweetened beverages and adolescent body weight New England Journal of Medicine, 2012.
doi:10.1056/NEJMoa1203388 PubMed 22998339
Funding and finding
Registration
NCT00381160
Participants
224
Follow-up
2 years: 1-year intervention, then 1 year without intervention
Funding
Supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK073025 and K24DK082730, to Dr. Ludwig) and from the National Center for Research Resources to the Boston Children's Hospital General Clinical Research Center (M01RR02172), the Harvard Catalyst Clinical and Translational Science Center (UL1RR025758), and the New Balance Foundation. Beverages for the intervention group were purchased from an online delivery service.
Finding
Home delivery of noncaloric beverages, telephone calls with parents and check-in visits for 1 year. Change in experimental minus control group: at 1 year, BMI -0.57 (P=0.045) and weight -1.9 kg (+1.6 against +3.5 kg; P=0.04); at 2 years, the primary outcome, BMI -0.30 (P=0.46) and weight -0.8 kg (+4.3 against +5.1 kg; P=0.55). Retention 97% at 1 year and 93% at 2 years.
Independent research
Stanhope KL, Schwarz JM, Keim NL, Griffen SC, Bremer AA, Graham JL, et al. Consuming fructose-sweetened, not glucose-sweetened, beverages increases visceral adiposity and lipids and decreases insulin sensitivity in overweight/obese humans Journal of Clinical Investigation, 2009.
doi:10.1172/JCI37385 PubMed 19381015
Funding and finding
Participants
39
Follow-up
10 weeks of sugar-sweetened beverages: 8 weeks outpatient with ad libitum diet, then 2 weeks inpatient with energy-balanced diet
Funding
This research was supported with funding from NIH grant R01 HL-075675 and grant UL1 RR024146 from the National Center for Research Resources, a component of the NIH, and the NIH Roadmap for Medical Research. P.J. Havel's laboratory also receives support from NIH grants HL-091333, AT-002599, AT-002993 and AT-003545 and the American Diabetes Association; N.L. Keim's research is supported by intramural USDA-ARS CRIS 5306-51530-016-00D.
In-kind support
Postheparin total and hepatic lipase activity was assayed by Asahi Kasei Pharma; payment terms are not stated.
Finding
Beverages provided 25% of energy requirements as fructose (17 completers) or glucose (15 completers). Change at 10 weeks, fructose against glucose: body weight +1.4% and +1.8%; intra-abdominal fat volume +14.0% (P<0.01) and +3.2% (not significant); fasting LDL cholesterol +13.9% and +3.6%; fasting apoB +27.2% and +3.0%; fasting triglyceride +3.9% and +9.7%; insulin sensitivity index -17.3% and +1.1%. Postprandial fractional hepatic de novo lipogenesis rose from 11.4% to 16.9% with fructose (P=0.021) and from 13.4% to 14.2% with glucose (P=0.31); the 16-hour DNL AUC increased more with fructose (P=0.016) in the 18 participants with isotope data.
Independent research
Geidl-Flueck B, Hochuli M, Németh Á, Eberl A, Derron N, Köfeler HC, et al. Fructose- and sucrose- but not glucose-sweetened beverages promote hepatic de novo lipogenesis: A randomized controlled trial Journal of Hepatology, 2021.
doi:10.1016/j.jhep.2021.02.027 PubMed 33684506
Funding and finding
Registration
NCT01733563
Participants
126
Follow-up
7 weeks
Funding
This study was funded by the Swiss National Science Foundation (No. 144204), Vontobel Foundation, Rhyner Bangerter Foundation, Promedica Foundation, Uniscientia Foundation, Prof. Otto Beisheim-Foundation, Jubiläumsstiftung Swiss Life, Philhuman Foundation and the Austrian Federal Ministry of Education (No. BMWFW-10.420/0005-WF/V/3c/2017).
In-kind support
Molkerei Biedermann AG provided the beverages in coded containers; the Swiss technology testing service, Dietikon, performed quality control; payment terms are not stated.
Finding
Described as double-blind; the control group abstained from sugar-sweetened beverages and received no placebo. 80 g per day of fructose, sucrose or glucose in three 200 ml beverages for 7 weeks. Median basal hepatic fractional secretion rate of newly synthesised VLDL palmitate (%/day): fructose 19.7 (P=0.013), sucrose 20.8 (P=0.0015), glucose 11.0 (P=0.16), control 9.1. Total energy intake did not change; fasting triglyceride, glucose and insulin did not change; liver fat was not measured.
Independent research
Kearns CE, Schmidt LA, Glantz SA. Sugar Industry and Coronary Heart Disease Research: A Historical Analysis of Internal Industry Documents JAMA Internal Medicine, 2016.
doi:10.1001/jamainternmed.2016.5394 PubMed 27617709
Funding and finding
Funding
This work was supported by the UCSF Philip R. Lee Institute for Health Policy Studies, a donation by the Hellmann Family Fund to the UCSF Center for Tobacco Control Research and Education, the UCSF School of Dentistry Department of Orofacial Sciences and Global Oral Health Program, National Institute of Dental and Craniofacial Research grant DE-007306 and National Cancer Institute Grant CA-087472. The funders had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.
Finding
In 1965 the Sugar Research Foundation approved Project 226, a literature review by Hegsted and McGandy overseen by Stare, and paid $6500 ($48,900 in 2016 dollars). The foundation set the review's objective, contributed articles for inclusion and received drafts. The two-part review, published in the New England Journal of Medicine in 1967, discounted studies linking sucrose to coronary heart disease and concluded that reducing dietary cholesterol and substituting polyunsaturated for saturated fat was the only dietary intervention needed; the foundation's funding and role were not disclosed. The authors state that evidence of industry influence on the review's conclusions is circumstantial. In 1971 the industry influenced the National Caries Program of the National Institute of Dental Research to shift its emphasis to interventions other than restricting sucrose.
Independent research
Bes-Rastrollo M, Schulze MB, Ruiz-Canela M, Martinez-Gonzalez MA. Financial conflicts of interest and reporting bias regarding the association between sugar-sweetened beverages and weight gain: a systematic review of systematic reviews PLoS Medicine, 2013.
doi:10.1371/journal.pmed.1001578 PubMed 24391479
Funding and finding
Funding
No funding was received for this work.
Finding
17 systematic reviews with 18 conclusions on sugar-sweetened beverages and weight gain or obesity. Five of 6 conclusions (83.3%) from reviews disclosing a financial conflict of interest with the food industry found insufficient evidence of a positive association; 10 of 12 conclusions (83.3%) from reviews reporting no such conflict found a potential risk. Relative risk of a conclusion of no positive association 5.0 (95% CI 1.3 to 19.3).
Industry-funded
Choi HK, Curhan G. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study BMJ, 2008.
doi:10.1136/bmj.39449.819271.BE PubMed 18244959
Funding and finding
Participants
46,393
Follow-up
12 years
Funding
This work was supported in part by grants from the National Institutes of Health (DK58573, AA11181, HL35464, and CA55075) and TAP Pharmaceuticals. The funding sources had no role in the design, conduct, or reporting of the study or in the decision to submit the manuscript for publication.
Finding
755 incident cases of gout. Sugar-sweetened soft drinks, 2 or more servings per day against less than 1 per month: multivariate relative risk 1.85 (95% CI 1.08 to 3.16); 16 cases in 7392 person-years against 279 cases in 158,891 person-years. Highest against lowest fifth of free fructose intake: 2.02 (1.49 to 2.75). Diet soft drinks were not associated with gout (P for trend 0.99).
Expert consensus
World Health Organization. Guideline: Sugars Intake for Adults and Children World Health Organization, Geneva, 2015.
PubMed 25905159
Funding and finding
Funding
WHO expresses special appreciation to the following for providing financial support for the guideline development work: the Ministry of Health, Labour and Welfare of the Government of Japan; the Korean Food and Drug Administration, through grants to the Korea Health Industry Development Institute; Zhejiang University in Hangzhou, China; and the WHO Regional Office for Europe.
Finding
WHO recommends a reduced intake of free sugars throughout the lifecourse (strong recommendation) and, in adults and children, reducing free sugars to less than 10% of total energy intake (strong recommendation); WHO suggests a further reduction to below 5% (conditional recommendation). The 10% limit rests on moderate-quality evidence from observational studies of dental caries and the 5% limit on very-low-quality evidence from ecological studies. The excess body weight associated with free sugars results from excess energy intake.

Updated 2026-10-21