Nutritive and Non-Nutritive Sweeteners

NNNS: High Fructose Corn Syrup (HFCS) (2010)


Melanson KJ, Zukley L, Lowndes J, Nguyen V, Angelopoulos TJ, Rippe JM. Effects of high-fructose corn syrup and sucrose consumption on circulating glucose, insulin, leptin, and ghrelin and on appetite in normal-weight women. Nutrition. 2007 Feb; 23 (2): 103-112.

PubMed ID: 17234503
Study Design:
Randomized Controlled Trial
A - Click here for explanation of classification scheme.
Quality Rating:
Positive POSITIVE: See Quality Criteria Checklist below.
Research Purpose:

To investigate whether high fructose corn syrup may have more deleterious effects on measured indicators of energy balance control as compared to sucrose.

Inclusion Criteria:
  • Female
  • Non-smokers
  • Age 20-60
  • Body Mass Index of 19-25kg/m2.
Exclusion Criteria:
  • Male
  • Smoker
  • Age less than 20 or greater than 60
  • Body Mass Index of less than 19 or greater than 25
  • Prescription medications
  • Consumption of more than two carbonated soft drinks per day
  • Enrollment in weight-loss programs during the previous month
  • Greater than five-pound weight loss during past three months
  • Surgical procedure for weight loss at any time
  • Major surgery within three months of enrollment
  • History of thyroid diseases
  • Diabetes
  • Glucose intolerance (standard two-hour glucose tolerance test given)
  • Cardiovascular diseases
  • Uncontrolled hypertension
  • Gastrointestinal disorders
  • Cancer
  • Eating disorders
  • Pregnancy/lactation
  • Dietary restrictions or allergies that would limit the ability to adhere to dietary requirements of the study
  • Consumption of greater than 14 alcoholic drinks per week
  • Caffeine dependency.
Description of Study Protocol:


  • Each subject underwent two experimental visits in randomized order, one month apart
  • Visits included either consumption of high fructose corn syrup beverage or sucrose beverage
  • Visits included two nights and two days in a clinical metabolic unit
  • Two days prior to the visits, subjects had to follow a standardized diet and limit physical activity to less than one hour per day
  • Day one of visit dietary intake was controlled with subjective appetite monitoring. This was after an overnight fast
  • Day one controlled diet (three meals per day) was accompanied by beverages sweetened with high fructose corn syrup or sucrose as 30 percent of energy intake. Meals were ingested entirety within 15 minutes.
  • The next 12 hours (Day two), subjects ate ad libitum three meals per day. All portions were served in excess. Beverages included: Decaffeinated coffee or tea, fruit juice, milk and water.
  • Subjects had to consume greater than one liter of water each day
  • Blood sampling was taken over a 24-hour period (Day one through morning of Day two) with insertion of intravenous catheter
  • Study was conducted during mid-follicular phase of each subject's menstrual cycle.

Blinding used

Subjects and investigators were both blinded to the identity of the high fructose corn syrup or sucrose beverages.

Statistical Analysis

Two-way analysis of variance with repeated measures (time and trial) was performed to assess differences in the fluctuations of:

  • Glucose
  • Insulin
  • Leptin
  • Ghrelin
  • Appetite ratings with respect to the two trials.

Dietary intake was analyzed with paired sample T-tests for differences between trials on day two.

Data Collection Summary:

Timing of Measurements

  • Blood sample drawn from each subject during Day one for 30-minute intervals until 1 p.m. then hourly until morning of Day two of each trial 
  • Subjective appetite rating assessed after each meal of Day one and Day two.

Dependent Variables

  • Blood glucose, insulin, leptin, and ghrelin (measured through blood draw)
  • Dietary intake (three-day recall prior for baseline, subjects met with dietitian to assess two-day intake prior to the two-day study, study diets measured by observation and analysis)
  • Appetite rating (Palatibility measured by subjective appetite rating by subjects or 10 centimeter visual analog scales).

Independent Variables

Consumption of high fructose corn syrup beverage or sucrose beverage during Day one of each trial phase.

Control Variables

  • Day one diet (other than sweetened beverages)
  • Physical activity prior to and during trial periods.
Description of Actual Data Sample:
  • Initial N: 30 females
  • Attrition (final N): 30 females
  • Age: 33±10.6
  • Anthropometrics: Body Mass Index 22.4±1.7
  • Location: Clinical Metabolic Unit was located at the Florida Hospital Celebration Health.


Summary of Results:

Key Findings


  • No differences in day of menstrual cycle between the two experimental visits
  • Body weight did not differ between experimental visits
  • No difference between the two experimental visits with: fasting glucose, insulin, leptin and ghrelin (P>0.05)
  • No between-trial differences in within-day variation for the two experimental visits for any of the four labs
  • Nocturnal peaks of leptin and ghrelin did not differ between treatments
  • No difference in the change from fasted to postprandial values at 30 to 60 minutes after any of the three meals
  • Ghrelin was suppressed similarly by high fructose corn syrup and sucrose.

Dietary Intake

No difference observed in between-trial dietary components during ad libitum feedings (P >0.05)

Appetite Ratings

The within-trial variation in hunger, desire to eat, and thirst ratings were similar between trials for Day one and Day two (P>0.05).

Treatment Order

  • 16 subjects consumed high fructose corn syrup on their first visit and 14 consumed sucrose on their first visit
  • No difference in treatment by treatment order interaction (P>0.05).


Author Conclusion:
  • In 30 non-obese women, high fructose corn syrup and sucrose resulted in similar circulating glucose, insulin, leptin and ghrelin levels and appetite over a day when fed as 30% of energy with meals under controlled conditions 
  • On the day after sweetener consumption, ad libitum energy and macronutrient intakes and most appetite ratings were similar
  • Longer-term investigations of the effect of high fructose corn syrup on energy balance control systems are needed to further understand the potential effect of this sweetener on body weight.
Funding Source:
Food Company:
Reviewer Comments:
Quality Criteria Checklist: Primary Research
Relevance Questions
  1. Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies) Yes
  2. Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about? Yes
  3. Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice? Yes
  4. Is the intervention or procedure feasible? (NA for some epidemiological studies) Yes
Validity Questions
1. Was the research question clearly stated? Yes
  1.1. Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified? Yes
  1.2. Was (were) the outcome(s) [dependent variable(s)] clearly indicated? Yes
  1.3. Were the target population and setting specified? Yes
2. Was the selection of study subjects/patients free from bias? Yes
  2.1. Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study? Yes
  2.2. Were criteria applied equally to all study groups? Yes
  2.3. Were health, demographics, and other characteristics of subjects described? Yes
  2.4. Were the subjects/patients a representative sample of the relevant population? Yes
3. Were study groups comparable? Yes
  3.1. Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT) No
  3.2. Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline? Yes
  3.3. Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.) Yes
  3.4. If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis? N/A
  3.5. If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.) N/A
  3.6. If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")? N/A
4. Was method of handling withdrawals described? Yes
  4.1. Were follow-up methods described and the same for all groups? Yes
  4.2. Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.) No
  4.3. Were all enrolled subjects/patients (in the original sample) accounted for? Yes
  4.4. Were reasons for withdrawals similar across groups? ???
  4.5. If diagnostic test, was decision to perform reference test not dependent on results of test under study? N/A
5. Was blinding used to prevent introduction of bias? Yes
  5.1. In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate? Yes
  5.2. Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.) ???
  5.3. In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded? N/A
  5.4. In case control study, was case definition explicit and case ascertainment not influenced by exposure status? N/A
  5.5. In diagnostic study, were test results blinded to patient history and other test results? N/A
6. Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described? Yes
  6.1. In RCT or other intervention trial, were protocols described for all regimens studied? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  6.3. Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect? Yes
  6.4. Was the amount of exposure and, if relevant, subject/patient compliance measured? Yes
  6.5. Were co-interventions (e.g., ancillary treatments, other therapies) described? Yes
  6.6. Were extra or unplanned treatments described? N/A
  6.7. Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups? Yes
  6.8. In diagnostic study, were details of test administration and replication sufficient? N/A
7. Were outcomes clearly defined and the measurements valid and reliable? Yes
  7.1. Were primary and secondary endpoints described and relevant to the question? Yes
  7.2. Were nutrition measures appropriate to question and outcomes of concern? Yes
  7.3. Was the period of follow-up long enough for important outcome(s) to occur? Yes
  7.4. Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures? Yes
  7.5. Was the measurement of effect at an appropriate level of precision? Yes
  7.6. Were other factors accounted for (measured) that could affect outcomes? Yes
  7.7. Were the measurements conducted consistently across groups? Yes
8. Was the statistical analysis appropriate for the study design and type of outcome indicators? Yes
  8.1. Were statistical analyses adequately described and the results reported appropriately? Yes
  8.2. Were correct statistical tests used and assumptions of test not violated? Yes
  8.3. Were statistics reported with levels of significance and/or confidence intervals? Yes
  8.4. Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)? Yes
  8.5. Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)? Yes
  8.6. Was clinical significance as well as statistical significance reported? Yes
  8.7. If negative findings, was a power calculation reported to address type 2 error? N/A
9. Are conclusions supported by results with biases and limitations taken into consideration? Yes
  9.1. Is there a discussion of findings? Yes
  9.2. Are biases and study limitations identified and discussed? Yes
10. Is bias due to study's funding or sponsorship unlikely? No
  10.1. Were sources of funding and investigators' affiliations described? Yes
  10.2. Was the study free from apparent conflict of interest? No