Caloric Restriction for Insulin Resistance

Recruiting at 1 trial location

Overseen By Kitt Petersen, MD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Yale University

Must be taking: Birth control

Disqualifiers: Diabetes, Eating disorders, Hypertriglyceridemia, others

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

Compensation: Varies

Number of Visits: 1

250 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines whether weight loss can reduce fat in muscles and the liver while improving insulin handling in people with insulin resistance and a family history of type 2 diabetes. Participants may receive an ACC inhibitor (a type of drug) or try a lifestyle change involving caloric restriction. It is ideal for healthy adults who are sedentary, non-smokers, do not have diabetes or other major diseases, and are not on medications (except birth control). As an unphased trial, this study offers a unique opportunity to contribute to groundbreaking research that could lead to new insights and treatments for insulin resistance.

Will I have to stop taking my current medications?

Yes, you will need to stop taking your current medications, except for birth control pills, to participate in this trial.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research shows that eating fewer calories is generally safe and can improve insulin use in the body. Studies have found that this can lead to significant weight loss, which benefits individuals whose cells don't respond well to insulin. However, the long-term safety of all calorie-cutting diets remains uncertain.

Specific safety information for the ACC inhibitor is not available. If a trial tests this treatment without mentioning a specific phase, it is likely still under study for safety and effectiveness. If the FDA has approved the ACC inhibitor for another condition, it might be somewhat safe, but its use in each trial should be carefully considered.

Before joining a trial, discussing potential risks with the study team is crucial. They can provide the most relevant information for your situation. Understanding the possible side effects and benefits is essential before deciding to participate. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about this trial because it explores new ways to tackle insulin resistance, a common issue in conditions like type 2 diabetes. Most treatments focus on medications that increase insulin sensitivity or reduce glucose production. However, this trial looks at how caloric restriction and a novel ACC inhibitor can reverse lipid-induced insulin resistance. The ACC inhibitor works by targeting a specific enzyme to enhance fat oxidation in the liver, which could offer a fresh angle on managing insulin resistance. Additionally, understanding how caloric restriction affects insulin resistance could lead to non-pharmaceutical lifestyle interventions, providing a holistic approach to treatment.

What evidence suggests that this trial's treatments could be effective for insulin resistance?

Research has shown that eating fewer calories, as participants in the Lifestyle Intervention arm of this trial may experience, can improve insulin use and lower blood sugar levels, both crucial for managing insulin resistance. Studies have also found that reducing calorie intake can decrease belly fat, leading to long-term health benefits. One study found that various methods of cutting calories can aid weight loss and reduce body fat, both beneficial for insulin resistance. These findings suggest that consuming fewer calories might lower fat in the liver and muscles, potentially enhancing insulin use, especially in individuals with a family history of type 2 diabetes. ^{2 3 4 5 6}

Who Is on the Research Team?

Kitt Petersen, MD

Principal Investigator

Yale University

Are You a Good Fit for This Trial?

This trial is for healthy, non-smoking adults who are sedentary, not on medications (except birth control), and have a family history of type 2 diabetes but do not have it themselves. They should be free from systemic diseases, eating disorders, and regular exercise routines. Women must use contraception and can participate at certain times based on their menstrual cycle or contraceptive use.

Inclusion Criteria

Your physical activity level will be measured using a questionnaire, and you need to have an activity index score of at least 2.3.

I do not have diabetes or any other systemic or organ disease.

I am on birth control pills or have had a hysterectomy.

Exclusion Criteria

Your blood tests show any unusual counts or clotting issues.

Your blood has high levels of triglycerides (over 100 mg/dL).

Your hematocrit level is lower than 35%.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Baseline Assessment

Baseline assessment of hepatic mitochondrial fat oxidation using tracer study

1 day

1 visit (in-person)

Lifestyle Intervention

Caloric restriction to reverse lipid-induced insulin resistance

up to 6 months

Follow-up

Participants are monitored for improvements in insulin sensitivity after intervention

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• ACC Inhibitor
• Caloric Restriction
• Dietary consultations

Trial Overview

The study is testing if losing weight through caloric restriction can reduce fat in the liver and muscles and improve insulin sensitivity in people with insulin resistance. It involves detailed assessments including a triple tracer study to measure hepatic mitochondrial oxidation.

How Is the Trial Designed?

Group I: Lifestyle Intervention Experimental Treatment 1 Intervention

Caloric Restriction to reverse lipid-induced insulin resistance.

Group II: Baseline Assessment of Hepatic Mitochondrial Fat Oxidation Experimental Treatment 1 Intervention

Tracer study to assess hepatic mitochondrial fat oxidation (PINTA).

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

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

Collaborator

Trials

2,513

Recruited

4,366,000+

Published Research Related to This Trial

A novel intermittent fasting approach called iTRE, which involves eating during a specific time window, showed greater improvements in glucose tolerance compared to traditional calorie restriction (CR) after 6 months in a study of 209 adults at risk for type 2 diabetes.

While iTRE led to better glucose metabolism initially, these benefits diminished by the 18-month follow-up, and participants reported more fatigue and some mild adverse effects compared to those on CR or standard care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial. Teong, XT., Liu, K., Vincent, AD., et al.[2023]

Short-term dietary restriction (DR) can quickly induce beneficial effects on important health factors such as surgical stress, inflammation, chemotherapy response, and insulin resistance, making it clinically relevant.

While extended longevity is a well-known benefit of DR, the immediate improvements in metabolic fitness and stress resistance highlight the potential for DR to be used in clinical settings, warranting further research into its mechanisms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benefits of short-term dietary restriction in mammals. Robertson, LT., Mitchell, JR.[2021]

A 15% calorie restriction starting at 4 months of age in male mice led to significant health benefits, including reduced body mass, lower liver triglyceride levels, and improved glucose clearance and grip strength in younger mice (10 and 18 months).

Even in older mice (26 and 28 months), calorie restriction improved insulin sensitivity and physical performance, suggesting that moderate calorie restriction can promote healthier aging and may be a more sustainable dietary approach for humans.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice. Peters, EC., Safayan, L., Marx, TJ., et al.[2023]

In a study of 10 patients with type 2 diabetes and severe insulin resistance, mild caloric restriction during a 3 to 6-day hospitalization led to a significant 44% reduction in insulin requirements, from an average of 486 units per day to 223 units.

The intervention also resulted in notable decreases in blood sugar levels before dinner, suggesting that mild caloric restriction could be an effective and accessible strategy for managing insulin needs in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Mild Caloric Restriction Decreases Insulin Requirements in Patients With Type 2 Diabetes and Severe Insulin Resistance. Meehan, CA., Cochran, E., Mattingly, M., et al.[2021]

Calorie-restricted diets can significantly increase the remission rates of type 2 diabetes, with a 38% increase at 6 months and a 13% increase at 12 months compared to usual diets, based on a systematic review of 28 trials involving 6281 participants.

A reduction of 500 calories per day led to substantial weight loss (average -6.33 kg) and lower HbA1c levels (average -0.82%) at 6 months, indicating that calorie restriction can effectively improve key health markers in diabetes management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of calorie restriction in comparison to usual diet or usual care on remission of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Jayedi, A., Zeraattalab-Motlagh, S., Shahinfar, H., et al.[2023]

A review of 10 randomized controlled trials involving older adults (mean age ≥65 years) found that caloric restriction (CR) can improve metabolic, functional, and body composition outcomes with minimal documented risks.

However, all benefits were assessed immediately after treatment ended, highlighting the need for more long-term studies to better understand the safety and effectiveness of CR for obesity in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caloric restriction for treatment of geriatric obesity: Do the benefits outweigh the risks? Normandin, E., Houston, DK., Nicklas, BJ.[2022]

In a study of 76 women over 8 weeks, intermittent fasting (IF) led to greater weight and fat loss compared to caloric restriction (CR), particularly in the IF70 group, which also showed reduced nonesterified fatty acids (NEFAs).

While IF did not enhance lipid metabolism markers in muscle compared to CR, it did reduce antioxidant enzyme expression and resulted in temporary insulin resistance, indicating a complex relationship between fasting, lipid storage, and metabolic health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Intermittent Fasting or Calorie Restriction on Markers of Lipid Metabolism in Human Skeletal Muscle. Liu, B., Hutchison, AT., Thompson, CH., et al.[2021]

In a study of 93 obese type II diabetic patients, those on a lower caloric restriction (400 kcal/day) showed better improvements in fasting glucose levels and insulin sensitivity compared to those on a higher caloric intake (1,000 kcal/day), despite both groups losing the same amount of weight (11% of initial body weight).

After 15 weeks on a higher caloric diet (1,000 kcal/day), participants who had previously been on the lower caloric restriction experienced worse glycemic control, indicating that both the degree of caloric restriction and the amount of weight lost independently affect glycemic control and insulin sensitivity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. Wing, RR., Blair, EH., Bononi, P., et al.[2022]

A very-low-calorie diet (VLCD) of 400 kcal/day for one week in 14 severely obese patients with type 2 diabetes led to significant improvements in glucose metabolism, primarily through enhanced insulin secretion rather than increased insulin sensitivity.

The study found a notable increase in the Disposition Index, indicating better glucose disposal capabilities, while insulin sensitivity remained unchanged, highlighting the importance of β cell function in managing glucose levels in these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Very-low-calorie diet: a quick therapeutic tool to improve β cell function in morbidly obese patients with type 2 diabetes. Malandrucco, I., Pasqualetti, P., Giordani, I., et al.[2023]

Caloric restriction (CR) in genetically modified mice did not lower plasma insulin levels as expected and even led to an increase in insulin levels in certain mice, despite improvements in glucose tolerance and lower fasting glucose.

CR resulted in unexpected increases in fat mass, particularly in inguinal fat and brown adipose tissue, suggesting that CR can have paradoxical effects on adipose tissue growth when insulin signaling is genetically reduced.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Caloric Restriction Paradoxically Increases Adiposity in Mice With Genetically Reduced Insulin. Dionne, DA., Skovsø, S., Templeman, NM., et al.[2018]

Citations

1.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC8071299/

Effects of Calorie Restriction on Health Span and Insulin ...

Fasting glucose was significantly reduced by CR at year 1, but not at year 2. CR improved insulin sensitivity: HOMA-IR reduced; insulin response increased (at 2 ...

2.

ijbnpa.biomedcentral.com

ijbnpa.biomedcentral.com/articles/10.1186/s12966-024-01657-9

Comparing caloric restriction regimens for effective weight ...

High-quality evidence demonstrates that the STF likely lead to the most pronounced decline in lean mass while reducing weight, consistent with ...

3.

nejm.org

nejm.org/doi/full/10.1056/NEJMoa2114833

Calorie Restriction with or without Time-Restricted Eating ...

In this 12-month trial, we found that the 8-hour time-restricted–eating regimen did not produce greater weight loss than the regimen of daily ...

4.

sciencedirect.com

sciencedirect.com/science/article/abs/pii/S1751991825000464

Intermittent fasting versus continuous caloric restriction for ...

IF improves short-term glycemic control, while CCR offers lasting metabolic benefits. · IF enhances fat oxidation, insulin sensitivity; CCR reduces visceral fat, ...

5.

nature.com

nature.com/articles/s41430-023-01311-w

Time-restricted eating with calorie restriction on weight loss ...

The pooled results showed that TRE with CR reduced the body weight, fat mass, and waist circumference significantly (WMD: −1.40, 95% CI: −1.81 ...

6.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC3014770/

Caloric Restriction in Humans: Impact on Physiological ...

While it is well established in obese humans that caloric restriction and weight loss improve insulin sensitivity (18, 58), the effects of caloric restriction ...