High Fructose Diet for Obesity

Overseen By Ryan Walker

Age: 18 - 65

Sex: Any

Trial Phase: Academic

Sponsor: Icahn School of Medicine at Mount Sinai

Must not be taking: Probiotics, Antibiotics, others

Disqualifiers: Diabetes, Eating disorders, others

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

Compensation: Varies

Number of Visits: Unknown

30 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial excludes participants who are on chronic medications that affect body weight, insulin resistance, or lipid profiles. If you are taking such medications, you may need to stop them to participate in the trial.

Is a high fructose diet safe for humans?

Research suggests that consuming high amounts of fructose can lead to health issues like liver damage, increased body fat, and insulin resistance, which are linked to conditions like diabetes and heart disease. However, normal levels of fructose intake do not seem to cause significant weight gain or changes in blood fats in overweight or obese individuals. ^{1 2 3 4 5}

How does the High Fructose Diet treatment for obesity differ from other treatments?

The High Fructose Diet treatment for obesity is unique because it involves the consumption of a diet high in fructose, which is typically considered a cause of obesity, rather than a solution. This approach contrasts with other treatments that often focus on reducing sugar intake, including fructose, to manage weight and metabolic health. ^{3 6 7 8 9}

What is the purpose of this trial?

Americans commonly consume excess amounts of dietary fructose. Added fructose has been shown to have an adverse impact on metabolic health, including increased insulin resistance and type 2 diabetes (T2D) risk. However, the mechanisms that link dietary fructose and metabolic health are poorly understood. Malabsorption or incomplete metabolism of fructose in the small intestine is common in the population. Excess fructose reaches the colon where it may change the structure and function of the gut microbiome, alter bacterial metabolites and trigger inflammatory responses impacting T2D risk. To elucidate whether commonly consumed levels of dietary fructose influence metabolic outcomes through altering the gut microbiome, the research team will randomize 30 participants to a controlled cross-over dietary intervention, in which the participants will consume 12-day isocaloric, added fructose or glucose diets (25% of total calories) separated by a 10-day controlled diet washout period. The research team aims to: 1. Determine the relationships between high fructose consumption, the gut microbiome and metabolic risk. 2. Characterize the causal role(s) that fructose-induced alterations to the gut microbiome have on metabolic risk using a germ-free mouse model. The research team will measure 1) microbiota community structure and function via metagenomic sequencing of stool, 2) fecal metabolites via targeted and untargeted metabolomics, 3) anthropometrics, 4) insulin resistance, serum markers of T2D risk and inflammatory cytokines, 5) fecal microbial carbohydrate oxidation capacity and 6) liver fat via MRI elastography. The research team will use novel statistical approaches, including Distributed Lag Modeling, to understand the complex relationships between diet, the microbiome, metabolites and health outcomes. The research team will then conduct controlled dietary interventions and fecal microbiome transplantation studies in germ-free mice. Donor fecal samples from human participants in both the glucose and fructose arms of the clinical intervention will be transplanted into germ-free and colonized mice to establish a causal relationship between fructose-induced changes to the gut microbiome, liver fat and metabolic and inflammatory changes known to increase risk for T2D. The research team aims to comprehensively assess the structural and functional changes to the gut microbiome brought about by a high fructose diet. Determining the impact of excess fructose on the microbiome will help identify novel means by which fructose contributes to metabolic disease risk. In addition to identifying strategies to improve metabolic health in adults, data from this proposal could help inform targeted approaches to mitigate future disease risk in vulnerable populations that consume high levels of fructose, such as children.

Research Team

Ryan Walker

Principal Investigator

Icahn School of Medicine at Mount Sinai

Eligibility Criteria

This trial is for adults with Type 2 Diabetes, Mesenteric Artery Stenosis, or Obesity. Participants will be tested on how a high fructose diet versus a glucose diet affects their gut microbiome and metabolic health. They should not have conditions that interfere with the study's dietary requirements.

Inclusion Criteria

Participants must be determined to be a fructose malabsorber via hydrogen breath test

Exclusion Criteria

Consumption of > 1 sugar sweetened beverage per day

Use of probiotic/prebiotic/synbiotic supplements

Vegetarian, vegan or other restrictive dietary habits

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Dietary Intervention

Participants consume a 12-day isocaloric high fructose diet followed by a 12-day isocaloric high glucose diet, with a 10-day washout period in between

34 days

Follow-up

Participants are monitored for safety and effectiveness after the dietary intervention

4 weeks

Treatment Details

Interventions

• High Fructose Diet

Trial Overview The study tests the effects of a controlled high fructose diet compared to a glucose diet on participants' gut bacteria and metabolism. It involves consuming specific diets for 12 days, followed by a washout period, then switching diets. The impact on liver fat and diabetes risk markers will also be studied using advanced techniques like MRI elastography.

Participant Groups

Group I: Glucose Dietary then Fructose Dietary Experimental Treatment 2 Interventions

Participants that will be randomized to the 12-day isocaloric weight-maintaining high glucose diet, then will change to the12-day isocaloric weight-maintaining high fructose diet after a 10-day washout period.

Group II: Fructose Dietary then Glucose Dietary Experimental Treatment 2 Interventions

Participants that will be randomized to the 12-day isocaloric weight-maintaining high fructose diet, then will change to the 12-day isocaloric weight-maintaining high glucose diet after a 10-day washout period.

Who Is Running the Clinical Trial?

Icahn School of Medicine at Mount Sinai

Lead Sponsor

Trials

933

Recruited

579,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Metabolic Solutions Inc.

Industry Sponsor

Trials

5

Recruited

180+

Findings from Research

In a study involving 17 monkeys on a high-fructose diet for up to 7 years, those allowed to eat freely developed hepatic steatosis (HS) and increased diabetes incidence, indicating that long-term fructose consumption can lead to significant liver fat accumulation and metabolic issues.

Even without weight gain, monkeys on a controlled high-fructose diet for 6 weeks showed liver damage and increased markers of endotoxemia and microbial translocation, suggesting that fructose can harm liver health rapidly through mechanisms unrelated to obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. Kavanagh, K., Wylie, AT., Tucker, KL., et al.[2023]

Fructose consumption is linked to obesity and metabolic syndrome, which can increase the risk of developing diabetes, highlighting its potential negative health impacts.

The review discusses how fructose contributes to fatty liver, obesity, and insulin resistance, emphasizing the metabolic changes induced by high fructose corn syrup and dietary fructose.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mini review on fructose metabolism. Akram, M., Hamid, A.[2013]

A systematic review found no evidence that normal dietary intake of fructose leads to increased triglycerides or body weight in overweight or obese individuals.

Previous studies linking fructose consumption to hyperlipidemia or obesity may not apply to overweight or obese populations due to their unique metabolic conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evidence-based review on the effect of normal dietary consumption of fructose on blood lipids and body weight of overweight and obese individuals. Dolan, LC., Potter, SM., Burdock, GA.[2019]

Excessive consumption of fructose, particularly from added sugars, is linked to negative health outcomes such as increased visceral fat, lipid dysregulation, and reduced insulin sensitivity, raising the risk for cardiovascular disease and type 2 diabetes.

Current dietary guidelines recommend limiting sugar intake, but more research is needed to understand the specific adverse effects of fructose compared to other sugars like glucose, especially through dose-response studies in both normal and overweight individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fructose consumption: recent results and their potential implications. Stanhope, KL., Havel, PJ.[2021]

In a study involving mice fed a high-fructose diet for 6 weeks, protodioscin significantly improved glucose intolerance and reduced harmful serum levels of uric acid, blood urea nitrogen, creatinine, total cholesterol, and triglycerides.

Protodioscin also showed protective effects on kidney health by reducing inflammation markers and improving kidney tissue damage, suggesting it could be a promising treatment for metabolic syndrome and renal injury caused by high fructose intake.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Protodioscin ameliorates fructose-induced renal injury via inhibition of the mitogen activated protein kinase pathway. Shen, J., Yang, X., Meng, Z., et al.[2018]

In a study of 131 obese patients over 6 weeks, a moderate natural fructose diet led to greater weight loss (4.19 kg) compared to a low-fructose diet (2.83 kg), suggesting that not all fructose is equally harmful.

Both diets resulted in significant improvements in metabolic syndrome parameters, indicating that reducing energy and added fructose intake can be an effective strategy for combating obesity and diabetes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: a randomized controlled trial. Madero, M., Arriaga, JC., Jalal, D., et al.[2017]

In a review of 31 isocaloric trials with 637 participants, fructose did not significantly affect body weight when substituted for other carbohydrates in diets with the same calorie content.

However, in 10 hypercaloric trials with 119 participants, high doses of fructose (providing excess calories) led to modest weight gain, suggesting that the increase in weight may be due to the extra calories rather than fructose itself.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis. Sievenpiper, JL., de Souza, RJ., Mirrahimi, A., et al.[2022]

Excessive consumption of fructose, particularly in amounts that exceed 25-40% of total caloric intake, is linked to weight gain, increased triglyceride levels, and fatty liver disease, as shown in meta-analyses of studies lasting from one to ten weeks.

The effects of high fructose intake cannot be separated from overall excessive caloric intake, indicating that more high-quality randomized controlled trials are needed to understand fructose's specific metabolic impacts, especially in children who are particularly vulnerable to high sugar consumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fructose Consumption-Free Sugars and Their Health Effects. Stricker, S., Rudloff, S., Geier, A., et al.[2021]

Chronic consumption of a high-fructose diet in Sprague-Dawley rats led to leptin resistance, which means that the rats' bodies became less responsive to leptin, a hormone that helps regulate hunger and energy balance.

This leptin resistance occurred before any significant weight gain or changes in fat levels, and when these fructose-fed rats were later given a high-fat diet, they gained significantly more weight compared to rats that had not been exposed to fructose, highlighting a potential mechanism linking fructose intake to obesity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. Shapiro, A., Mu, W., Roncal, C., et al.[2021]

References

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

Dietary fructose induces endotoxemia and hepatic injury in calorically controlled primates. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Mini review on fructose metabolism. [2013]

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

Evidence-based review on the effect of normal dietary consumption of fructose on blood lipids and body weight of overweight and obese individuals. [2019]

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

Fructose consumption: recent results and their potential implications. [2021]

5. Germany pubmed.ncbi.nlm.nih.gov

Protodioscin ameliorates fructose-induced renal injury via inhibition of the mitogen activated protein kinase pathway. [2018]

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

The effect of two energy-restricted diets, a low-fructose diet versus a moderate natural fructose diet, on weight loss and metabolic syndrome parameters: a randomized controlled trial. [2017]

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

Effect of fructose on body weight in controlled feeding trials: a systematic review and meta-analysis. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Fructose Consumption-Free Sugars and Their Health Effects. [2021]

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

Fructose-induced leptin resistance exacerbates weight gain in response to subsequent high-fat feeding. [2021]