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

Trial Summary

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.

What data supports the effectiveness of the treatment involving caloric restriction for insulin resistance?

Research shows that mild caloric restriction can significantly reduce insulin requirements in patients with type 2 diabetes and severe insulin resistance, with a study reporting a 44% reduction in insulin doses. Additionally, caloric restriction has been found to improve glycemic control and insulin sensitivity, which are important for managing insulin resistance. ^{1 2 3 4 5}

Is caloric restriction generally safe for humans?

Caloric restriction has shown benefits in improving metabolic and body composition outcomes with few documented risks in older adults, but the long-term safety is still unclear. In a study with patients with type 2 diabetes, mild caloric restriction was well-tolerated and reduced insulin requirements, suggesting it is generally safe in the short term. ^{1 3 6 7 8}

How does the ACC Inhibitor treatment differ from other treatments for insulin resistance?

The ACC Inhibitor treatment is unique because it targets a specific enzyme involved in fat metabolism, potentially reducing insulin resistance by altering how the body processes fats. This mechanism is different from other treatments that primarily focus on increasing insulin sensitivity or reducing blood sugar levels directly. ^{1 3 4 9 10}

What is the purpose of this trial?

This trial is investigating if losing a small amount of weight can help people who are at risk for diabetes because of their family history. The study focuses on lean individuals who have trouble using insulin properly. By reducing fat in their muscles and liver, the researchers hope to improve their body's response to insulin and better manage blood sugar levels.

Research Team

Kitt Petersen, MD

Principal Investigator

Yale University

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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 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]

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]

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]

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]

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]

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]

References

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

Mild Caloric Restriction Decreases Insulin Requirements in Patients With Type 2 Diabetes and Severe Insulin Resistance. [2021]

2. United States 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. [2022]

3. United States 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. [2023]

4. England pubmed.ncbi.nlm.nih.gov

Benefits of short-term dietary restriction in mammals. [2021]

5. United States 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. [2023]

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

Caloric restriction for treatment of geriatric obesity: Do the benefits outweigh the risks? [2022]

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

Caloric Restriction Paradoxically Increases Adiposity in Mice With Genetically Reduced Insulin. [2018]

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

Effects of Intermittent Fasting or Calorie Restriction on Markers of Lipid Metabolism in Human Skeletal Muscle. [2021]

9. United States 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. [2023]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice. [2023]