Carbohydrate Consumption for Understanding Food Reward Mechanisms

(CARB Trial)

Overseen By Alexandra G DiFeliceantonio, PhD

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Virginia Polytechnic Institute and State University

Must not be taking: Antiglycemics, Thyroid, Sleep medications

Disqualifiers: Nicotine, Alcohol dependence, Diabetes, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 5 weeks

64 Participants Needed

Trial Summary

What is the purpose of this trial?

Dietary factors contributed to nearly 50% of all cardiometabolic deaths in the US in 2012, making it one of the leading causes of preventable death in the US, second only to tobacco use. Human diets and food choices can't help but be influenced by the ubiquitous availability of processed foods of high-energy density and low nutrient content, consumption of which can lead to obesity, type II diabetes, heart disease, and other types of metabolic dysfunction. Surprisingly, food reinforcement does not rely on perceived energy density. Rather food reinforcement is associated with actual energy density and therefore, on an implicit knowledge of caloric content. That implicit knowledge must have a neural signature and a mechanism by which the gut communicates nutritive value to the brain. There is evidence, at least for fat and carbohydrates, that these pathways are separable, but terminate in a common neural structure, the dorsal striatum or caudate. This could be one mechanism by which modern processed foods high in both fat and carbohydrate are so sought after and readily consumed, In fact, when experimentally tested, fat and carbohydrate combinations were more reinforcing calorie for calorie than fat or carbohydrates alone and the level of reinforcement correlated with activity in reward- related brain areas. Beyond simple reinforcing value, it is known from the literature on drugs of abuse that the faster a drug is arrives at the brain, the higher it's abuse potential, however, little is known about how the kinetics of nutrient excursion influence food preference, choice, and brain activity. This project aims to test this specifically for carbohydrate reward.

Will I have to stop taking my current medications?

The trial requires that you stop taking medications known to influence study measures, such as antiglycemic agents (medications that lower blood sugar), thyroid medications, and sleep medications.

What data supports the effectiveness of the drug used in the clinical trial titled 'Carbohydrate Consumption for Understanding Food Reward Mechanisms'?

Research shows that metformin, a component of the drug, can reduce food consumption by affecting appetite-regulating pathways in the brain. This suggests it may help in understanding food reward mechanisms by influencing how the brain responds to food. ^{1 2 3 4 5}

Is the treatment generally safe for humans?

The research articles provided do not contain specific safety data for the treatment or its various names, such as Glucophage or Metformin, in humans. ^{1 6 7 8 9}

How does the treatment in the 'Carbohydrate Consumption for Understanding Food Reward Mechanisms' trial differ from other treatments?

This treatment is unique because it focuses on understanding how carbohydrates, specifically glucose, influence food reward mechanisms by affecting brain activity and motivation to eat, unlike other treatments that may target satiety or metabolic effects without considering the direct impact on brain reward pathways. ^{8 10 11 12 13}

Eligibility Criteria

This trial is for English-speaking adults with a BMI of 18.5-30, living near Roanoke or able to visit the Fralin Biomedical Research Institute. It's not for those who are pregnant, have high blood sugar levels (Hemoglobin A1C >5.7%), work night shifts, had weight loss surgery, use inhaled nicotine, have metal implants that affect MRI scans, or have certain medical conditions like diabetes.

Inclusion Criteria

You are located in or able to travel to Roanoke for sessions at the Fralin Biomedical Research Institute.

Your body mass index (BMI) is between 18.5 and 30, which means you have a healthy weight for your height.

You are not expecting or planning a pregnancy during the study.

Exclusion Criteria

You have had a problem with alcohol addiction in the past.

I have been diagnosed with diabetes or thyroid issues.

I am currently taking medication that could affect the study's results.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intervention beverages and undergo various assessments including energy expenditure, substrate oxidation, and blood glucose response.

5 weeks

Weekly visits for assessments

Follow-up

Participants are monitored for changes in preference and physiological responses after the intervention.

4 weeks

Treatment Details

Interventions

• CS- Beverage
• CS+Fast
• CS+Slow

Trial Overview The study examines how different types of carbohydrate-rich beverages influence brain activity and food preferences. Participants will try three kinds: a control beverage (CS-), one that releases carbs slowly (CS+Slow), and another that releases them quickly (CS+Fast). The goal is to see if the speed at which carbs hit the system affects their rewarding properties.

Participant Groups

Group I: CS- First Experimental Treatment 3 Interventions

Participants who receive the conditional stimulus (CS) - first.

Group II: CS+Slow First Experimental Treatment 3 Interventions

Participants who receive the CS+Slow First

Group III: CS+Fast First Experimental Treatment 3 Interventions

Participants who receive the CS+Fast First

Who Is Running the Clinical Trial?

Virginia Polytechnic Institute and State University

Lead Sponsor

Trials

162

Recruited

26,900+

Findings from Research

The novel GLP-1/Dexa conjugate significantly reduced food motivation and intake in obese mice, showing a sustained effect for up to 20 hours, which is longer than the 4-hour effect seen with GLP-1 alone.

Importantly, treatment with GLP-1/Dexa led to weight loss without negatively impacting mood or memory, suggesting it could be a safe and effective strategy for obesity management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

GLP-1/dexamethasone inhibits food reward without inducing mood and memory deficits in mice. Décarie-Spain, L., Fisette, A., Zhu, Z., et al.[2019]

In a study involving 18 subjects with type 2 diabetes, liraglutide significantly reduced appetite and energy intake compared to placebo, with participants reporting lower hunger ratings and higher fullness after treatment.

The estimated energy intake was 18% lower with liraglutide, suggesting that its appetite-suppressing effects may play a key role in promoting weight loss in individuals with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The once-daily human GLP-1 analogue liraglutide impacts appetite and energy intake in patients with type 2 diabetes after short-term treatment. Flint, A., Kapitza, C., Zdravkovic, M.[2015]

In a study involving 18 healthy individuals, dapagliflozin did not significantly affect overall energy intake or appetite ratings compared to a placebo, suggesting it may not influence eating behavior in this population.

Although not statistically significant, dapagliflozin trended towards increasing the desire for salty and sweet foods, which may relate to its effects on sodium and glucose excretion, indicating potential areas for further research, especially in individuals with type 2 diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects. Bertran, E., Berlie, HD., Nixon, A., et al.[2021]

Intracerebroventricular administration of metformin significantly reduced food intake in rats by blocking the appetite-stimulating effects of the peptide ghrelin, demonstrating a dose-dependent response.

Metformin's mechanism involves the inhibition of ghrelin-induced activation of hypothalamic AMPK signaling pathways and restoration of mTOR activity, which are crucial for regulating appetite.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracerebroventricular administration of metformin inhibits ghrelin-induced Hypothalamic AMP-kinase signalling and food intake. Stevanovic, D., Janjetovic, K., Misirkic, M., et al.[2013]

In a 24-week study involving 15 overweight/obese participants with type 1 diabetes, adding liraglutide to their insulin therapy led to a significant reduction in total food intake and fat consumption, while increasing carbohydrate intake.

Participants also experienced decreased appetite sensations, including reduced hunger and desire to eat, and an increased feeling of fullness after meals, indicating improved eating behaviors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of liraglutide on food consumption, appetite sensations and eating behaviours in overweight people with type 1 diabetes. Dubé, MC., D'Amours, M., Weisnagel, SJ.[2021]

Mice lacking the mGlu5 receptor weighed less than control mice despite similar food intake, indicating that mGlu5 plays a role in body weight regulation independent of food consumption.

The mGlu5 antagonist MTEP effectively reduced food intake and prevented weight gain in diet-induced obese rats, suggesting that targeting mGlu5 could be a potential strategy for managing obesity and enhancing energy expenditure.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabotropic glutamate receptor mGlu5 is a mediator of appetite and energy balance in rats and mice. Bradbury, MJ., Campbell, U., Giracello, D., et al.[2014]

In a study involving diet-induced obese mice treated with the mGluR5 negative allosteric modulator VU0409106 for 14 days, significant reductions in food intake, body weight, and inflammation in adipose tissue were observed, suggesting its potential as an obesity treatment.

VU0409106 also showed effectiveness in reducing binge-like eating behaviors, indicating that targeting mGluR5 could be beneficial not only for obesity but also for related eating disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior. Oliveira, TPD., Gonçalves, BDC., Oliveira, BS., et al.[2023]

Mild hypoglycemia increases the desire for high-calorie foods by activating specific brain regions, while normal glucose levels reduce interest in food stimuli, highlighting the role of glucose in food motivation.

Obese individuals show a lack of the normal brain response to higher glucose levels, suggesting that they may lose the ability to regulate their desire for high-calorie foods, which could contribute to overeating.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. Page, KA., Seo, D., Belfort-DeAguiar, R., et al.[2023]

In a study involving 68 adults with type 2 diabetes, empagliflozin (25 mg daily) combined with dietary energy restriction led to the most significant weight loss of 5.74 kg over 24 weeks, compared to other groups.

Despite the weight loss, the changes in appetite-regulating peptides like PYY and GLP-1 did not show significant differences between the treatment groups and the placebo, suggesting that these peptides may not explain the observed weight loss with empagliflozin therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial. Sargeant, JA., King, JA., Yates, T., et al.[2022]

Intraperitoneal injections of glucose significantly suppressed sham feeding by about 42%, indicating that postprandial glucose levels can reduce the motivation to eat based on taste, especially when glucose is administered alongside taste stimulation.

The effectiveness of glucose in inhibiting eating was enhanced when the gastric cannula was closed, suggesting that glucose works together with other signals from the stomach to signal fullness, rather than causing discomfort.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postabsorptive glucose decreases excitatory effects of taste on ingestion. Bédard, M., Weingarten, HP.[2017]

Intraperitoneal administration of gut hormones CCK, GLP-1, and PYY3-36 significantly reduced the consumption of a highly palatable sucrose solution in mice, indicating their potential to suppress hedonic-driven sugar intake.

The doses of these hormones did not cause conditioned taste aversion, suggesting that their effects on reducing sugar consumption are not associated with unpleasant side effects, making them a promising avenue for controlling excessive sugar intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systemic administration of anorexic gut peptide hormones impairs hedonic-driven sucrose consumption in mice. Yamaguchi, E., Yasoshima, Y., Shimura, T.[2018]

Glucose rapidly increases in the nucleus accumbens of rats after intravenous delivery, showing a strong dose-dependent response, while fructose only produces a minimal effect at high doses.

Rats demonstrate a significant preference for glucose over fructose, which develops over time with repeated exposure, suggesting that glucose's direct action in the brain plays a crucial role in its consumption and preference.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Experience-dependent escalation of glucose drinking and the development of glucose preference over fructose - association with glucose entry into the brain. Wakabayashi, KT., Spekterman, L., Kiyatkin, EA.[2023]

In a study of 13 obese participants with varying degrees of insulin resistance, those with higher insulin resistance showed a stronger preference for sugar-sweetened yogurts over monkfruit-sweetened options, indicating that insulin resistance may increase the desire for sugary foods.

The preference for sugar-sweetened yogurt was significantly correlated with measures of insulin resistance and blood glucose levels, suggesting that managing insulin resistance could be key in helping individuals make healthier dietary choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Insulin Resistance and Glycated Hemoglobin in Obesity Are Associated With Preference for Sugar-Sweetened Yogurt: A Pilot Study. Epstein, LH., Biondolillo, MJ., Rizwan, A., et al.[2023]

References

1. England pubmed.ncbi.nlm.nih.gov

GLP-1/dexamethasone inhibits food reward without inducing mood and memory deficits in mice. [2019]

2. England pubmed.ncbi.nlm.nih.gov

The once-daily human GLP-1 analogue liraglutide impacts appetite and energy intake in patients with type 2 diabetes after short-term treatment. [2015]

3. United States pubmed.ncbi.nlm.nih.gov

Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Intracerebroventricular administration of metformin inhibits ghrelin-induced Hypothalamic AMP-kinase signalling and food intake. [2013]

5. England pubmed.ncbi.nlm.nih.gov

Effect of liraglutide on food consumption, appetite sensations and eating behaviours in overweight people with type 1 diabetes. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Metabotropic glutamate receptor mGlu5 is a mediator of appetite and energy balance in rats and mice. [2014]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Negative Modulation of the Metabotropic Glutamate Receptor Type 5 as a Potential Therapeutic Strategy in Obesity and Binge-Like Eating Behavior. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Circulating glucose levels modulate neural control of desire for high-calorie foods in humans. [2023]

9. England pubmed.ncbi.nlm.nih.gov

The effects of empagliflozin, dietary energy restriction, or both on appetite-regulatory gut peptides in individuals with type 2 diabetes and overweight or obesity: The SEESAW randomized, double-blind, placebo-controlled trial. [2022]

10. United States pubmed.ncbi.nlm.nih.gov

Postabsorptive glucose decreases excitatory effects of taste on ingestion. [2017]

11. United States pubmed.ncbi.nlm.nih.gov

Systemic administration of anorexic gut peptide hormones impairs hedonic-driven sucrose consumption in mice. [2018]

12. France pubmed.ncbi.nlm.nih.gov

Experience-dependent escalation of glucose drinking and the development of glucose preference over fructose - association with glucose entry into the brain. [2023]

13. United States pubmed.ncbi.nlm.nih.gov

Insulin Resistance and Glycated Hemoglobin in Obesity Are Associated With Preference for Sugar-Sweetened Yogurt: A Pilot Study. [2023]