The Impact of the Physiological Response to Sugar on Brain Activity and Behavior

Prior studies in humans indicate that while energy expenditure response is similar after consumption of equal amounts of fructose, glucose, and sucrose (a dimer of glucose + fructose), carbohydrate oxidation and blood glucose responses differ. Elevated carbohydrate oxidation responses appear to be driven by the presence of fructose, and elevated blood glucose responses appear to be driven by the presence of glucose. Prior work also suggests that post-ingestive signals of glucose availability, measure specifically as blood glucose levels, intestinal glucose transporter activity, and carbohydrate oxidation rate, are all associated with elevated brain response to calorie-predictive flavor cues and reward learning of these flavor cues. However, in animal models, glucose has been shown to repeatedly and reliably condition these calorie-predictive learning responses, but fructose does not. Human work has indicated that oxidation of glucose is critical for these responses. Thus, it is unclear what roles fructose and glucose each play in conditioning reward responses and flavor-calorie learning. We hypothesize that fructose plays a synergistic role in enhancing flavor-calorie learning without itself conditioning the reward response.

• Sucrose drink (Other), also known as Flavored beverage solution with 110 calories of sucrose: Participants will consume flavored beverage solutions containing 110 calories of sucrose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.
• Glucose drink (Other), also known as Flavored beverage solution with 110 calories of glucose: Participants will consume flavored beverage solutions containing 110 calories of glucose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.
• Fructose drink (Other), also known as Flavored beverage solution with 110 calories of fructose: Participants will consume flavored beverage solutions containing 110 calories of fructose in 6 exposure sessions within 1 week. One exposure session will include pre- and post-consumption blood draws and indirect calorimetry measurements inside a metabolic chamber over a 2-hour period. The other 5 exposure sessions will occur at specified times outside the laboratory sessions. Subjective ratings of internal state (i.e., hunger, fullness, and thirst) will be collected throughout each exposure. Subjective ratings of liking and wanting of each beverage will also be assessed.

Primary outcomes

• Change in Preference- Subjective Liking Ratings for Each Beverage on a Scale [Immediately after informed consent and in the post-test session approximately 5 weeks later]: Subjective ratings of liking of flavors used in the intervention will be assessed at baseline and after the intervention. The generalized Labeled Magnitude Scale will be used. The scale is anchored by descriptors of "Most Disliked Sensation Imaginable" and "Most Liked Sensation Imaginable" at the lower and upper ends, respectively. The score is determined by the place on the scale participants select (range of scale is 0-100). An increase in score from baseline to post-intervention indicates an increase in liking.

Secondary outcomes

• Post-Test Measure of Preference- Subjective Wanting Ratings for Each Beverage on a Scale [At the end of study; approximately 5 weeks after first session]: Subjective ratings of liking of flavors used in the intervention will be assessed at baseline and after the intervention. A Visual Analog Scale will be used. Participants select a place on the line that corresponds with their subjective rating, and the score is determined by the place selected (range of scores is 0-100). The line is anchored by polar opposite descriptors ("Do not want at all" and "Want very much"). An increase in score from baseline to post-intervention indicates and increase in wanting.
• Post-Test Measure of Preference - Wanting (ad Libitum Intake): The Amount Consumed of Each Beverage is Reported as the Outcome [At the end of study; approximately 5 weeks after first session]: Ad libitum intake will be used as a measure of wanting in a post-test session. Participants will be provided each beverage used during the intervention and asked to drink as much or as little of them as they would like over a 30-minute period.
• Post-Test Measure of Preference- Wanting (Forced Choice): Number of Participants Who Chose Each Indicated Beverage [At the end of study; approximately 5 weeks after first session]: Forced choice will be used as a measure of wanting in a post-test session. Participants will be provided each of the beverages used during the intervention and asked to choose 1 to take home with them.
• Blood Oxygen Level-dependent (BOLD) Response to Beverages [At the end of study; approximately 5 weeks after first session]: In a post-test session, functional magnetic resonance imaging (fMRI) scans were performed while beverages (without calories) used during the intervention and a tasteless solution are delivered through a custom manifold fitted to a head coil and connected to a pump system that allows precisely timed and measured delivery of liquids. Participants receive the glucose, sucrose, fructose, and tasteless (control) solutions 18 times each over the course of 2 runs. Contrasts of interest are the blood oxygen level-dependent (BOLD) response of glucose+>tasteless solution, sucrose>tasteless solution, and fructose>tasteless deliveries. Parameter estimates for these contrasts are extracted and reported. A positive outcome reflects greater whole-brain BOLD response for the sugar condition compared with a tasteless solution.
• Blood Glucose Response to Beverages [Each week for 3 weeks during the study]: Blood glucose will be assessed at baseline and at set time points for 2 hours after consumption of intervention beverages (baseline, 5-, 20-, 40-, 60-, 90-, and 120-minutes after drink consumption)in one exposure session. Area under the curve is calculated using these time points and reported as the outcome measure.
• Energy Expenditure in Response to Beverages [Each week for 3 weeks during the study]: Indirect calorimetry will be used to determine energy expenditure at baseline and for 120 minutes after consumption of condition beverages in an exposure session. Area under the curve is calculated as a change from baseline energy expenditure using minute-by-minute resolution across 120 minutes and reported as the outcome measure.

Sex: All, ages: 18 Years to 45 Years, accepts healthy volunteers

Inclusion Criteria:

1. BMI between 18.5-25 kg/m2
2. Not pregnant or planning to become pregnant during study participation
3. Residing in the Roanoke area and/or willing/able to attend sessions at the Fralin Biomedical Research Institute (FBRI) at Virginia Tech Carilion
4. Weigh at least 110 lbs

Exclusion Criteria:

1. Current inhaled nicotine use
2. History of alcohol dependence.
3. Current or past diagnosis of cardiometabolic disease or problems, including diabetes, endocrine, heart, or thyroid problems, that may influence study outcomes
4. Hemoglobin A1C >5.7%
5. Taking medications known to influence study measures (including attention-deficit/hyperactivity disorder (ADHD), allergy, antidepressant, antipsychotic, anxiolytic, birth control, blood pressure, blood glucose, cholesterol, thyroid, sleep, or weight loss medications)
6. Active medical or neurologic disorder, including cardiometabolic conditions or gastrointestinal conditions that may influence study outcomes
7. Recent change in body weight (gain or loss of > 5 lbs within the past 3 months)
8. Current shift work (typical pattern of work/activity overnight)
9. Previous weight loss surgery
10. Adherence to a special diet within the past 3 months (e.g., low-carb or ketogenic diet, exclusion of food groups/specific macronutrients, intermittent fasting, etc.)
11. Allergy to any food or ingredient included in the study diets, meals, or beverages
12. Currently pregnant or planning to become pregnant during study participation
13. Claustrophobia
14. Contraindications for MRI, including pacemaker, aneurysm clips, neurostimulators, cochlear or other implants, metal in eyes, regular work with steel, etc. (Note: This is an fMRI-specific exclusion criterion. Participants may be allowed to participate in all other study sessions and measures that do not involve fMRI.)
15. Contraindications for bioelectrical impedance analysis, specifically implanted devices
16. Use of substances (or combinations of substances) in doses and frequencies that could influence neural outcomes of study.

Participant flow

Outcome results

• Change in Preference- Subjective Liking Ratings for Each Beverage on a Scale (Primary), Mean, units on a scale: Glucose Drink -12.8 +/- 26.3; Fructose Drink -12.0 +/- 26.2; Sucrose Drink -12.6 +/- 26.3
• Post-Test Measure of Preference- Subjective Wanting Ratings for Each Beverage on a Scale (Secondary), Mean, units on a scale: Glucose Drink 42 +/- 12.7; Sucrose Drink 54.8 +/- 12.5; Fructose Drink 46.9 +/- 14.5
• Post-Test Measure of Preference - Wanting (ad Libitum Intake): The Amount Consumed of Each Beverage is Reported as the Outcome (Secondary), Mean, ml consumed: Glucose Drink 67.8 +/- 98.1; Fructose Drink 66.0 +/- 99.1; Sucrose Drink 66.3 +/- 98.5
• Post-Test Measure of Preference- Wanting (Forced Choice): Number of Participants Who Chose Each Indicated Beverage (Secondary), Count of participants, Participants: Glucose Drink 1; Fructose Drink 3; Sucrose Drink 2
• Blood Oxygen Level-dependent (BOLD) Response to Beverages (Secondary), Mean, arbitrary units: Glucose Drink 0.005 +/- 0.085; Fructose Drink 0.109 +/- 0.186; Sucrose Drink 0.050 +/- 0.210
• Blood Glucose Response to Beverages (Secondary), Mean, mg/dl*min: Glucose Drink 16821.25 +/- 4861.348755; Fructose Drink 11484.58334 +/- 1468.61789; Sucrose Drink 13760.66666 +/- 3813.485448
• Energy Expenditure in Response to Beverages (Secondary), Mean, kcal/min*min: Glucose Drink -0.89 +/- 6.63; Fructose Drink 0.940 +/- 6.14; Sucrose Drink 1.89 +/- 3.86

Adverse events

Time frame: 5 weeks

• Study Protocol and Statistical Analysis Plan (PDF, 2024-04-12)