Caloric Restriction for Insulin Resistance
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byKitt Petersen, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Academic
Recruiting
Sponsor: Yale University
Must be taking: Birth control
Disqualifiers: Diabetes, Eating disorders, Hypertriglyceridemia, others
No Placebo Group
Trial Summary
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.
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.
12345Is 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.
13678How 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.
134910Eligibility 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.
+4 more
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%.
+5 more
Trial 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
Participant Groups
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.
2Treatment groups
Experimental Treatment
Group I: Lifestyle InterventionExperimental Treatment1 Intervention
Caloric Restriction to reverse lipid-induced insulin resistance.
Group II: Baseline Assessment of Hepatic Mitochondrial Fat OxidationExperimental Treatment1 Intervention
Tracer study to assess hepatic mitochondrial fat oxidation (PINTA).
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Magnetic Resonance Research Center (MRRC)New Haven, CT
Yale Center for Clinical Investigation HRUNew Haven, CT
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Who Is Running the Clinical Trial?
Yale UniversityLead Sponsor
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Collaborator
References
Mild Caloric Restriction Decreases Insulin Requirements in Patients With Type 2 Diabetes and Severe Insulin Resistance. [2021]Type 2 diabetes (T2D) affects ~10% of the US population, a subset of whom have severe insulin resistance (SIR) (>200 units/d). Treatment of these patients with high-dose insulin presents logistical and compliance challenges. We hypothesized that mild caloric restriction would reduce insulin requirements in patients with T2D and SIR.This was a retrospective study at the National Institutes of Health Clinical Center. Inclusion criteria were as follows: T2D, and insulin dose >200 units/d or >2 units/kg/d. The intervention consisted of mild caloric restriction during a 3 to 6-day hospitalization. The major outcomes were change in insulin dose and blood glucose from admission to discharge.Ten patients met inclusion criteria. Baseline glycated hemoglobin A1c was 10.0 ± 1.6% and body mass index 38.8 ± 9.0 kg/m. Food intake was restricted from 2210 ± 371 kcal/d preadmission to 1810 ± 202 during the hospital stay (16.5% reduction). Insulin dose decreased from 486 ± 291 units/d preadmission to 223 ± 127 at discharge (44% reduction, P = 0.0025). Blood sugars decreased nonsignificantly in the fasting state (from 184 ± 85 to 141 ± 42, P = 0.20), before lunch (239 ± 68 to 180 ± 76, P = 0.057), and at bedtime (212 ± 95 to 176 ± 48, P = 0.19), and significantly decreased before dinner (222 ± 92 to 162 ± 70, P = 0.016).Mild caloric restriction, an accessible and affordable intervention, substantially reduced insulin doses in patients with T2D and SIR. Further studies are needed to determine if the intervention and results are sustainable outside of a hospital setting.
Caloric restriction per se is a significant factor in improvements in glycemic control and insulin sensitivity during weight loss in obese NIDDM patients. [2022]To examine the effects of caloric restriction, independent of differences in weight loss, on improvements in glycemic control, fasting insulin, and insulin sensitivity.
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]Limited evidence is available on the dose-dependent effects of calorie restriction in patients with type 2 diabetes.
Benefits of short-term dietary restriction in mammals. [2021]Dietary or calorie restriction (DR, CR), defined as reduced food intake without malnutrition, imparts many benefits in model organisms. Extended longevity is the most popularized benefit but the least clinically relevant due to the requirement for long-term food restriction. DR also promotes stress resistance and metabolic fitness. Emerging data in experimental models and in humans indicate that these benefits occur rapidly upon initiation of DR, suggesting potential clinical relevance. Here we review data on the ability of short-term DR to induce beneficial effects on clinically relevant endpoints including surgical stress, inflammation, chemotherapy and insulin resistance. The encouraging results obtained in these preclinical and clinical studies, and the general lack of mechanistic understanding, both strongly suggest the need for further research in this emerging area.
Very-low-calorie diet: a quick therapeutic tool to improve β cell function in morbidly obese patients with type 2 diabetes. [2023]Caloric restriction in obese diabetic patients quickly improves glucose control, independently from weight loss. However, the early effects of a very-low-calorie diet (VLCD) on insulin sensitivity and insulin secretion in morbidly obese patients with type 2 diabetes are still unclear.
Caloric restriction for treatment of geriatric obesity: Do the benefits outweigh the risks? [2022]Most evidence for the health benefits of prescribing caloric restriction (CR) for weight loss is derived from randomized, controlled trials (RCTs) in young/middle-aged adults; there are very few RCTs in older adults in which the isolated effects of CR can be deciphered. The purpose of this review is to summarize the RCT evidence of the benefits (and potential risks) of CR for the treatment of obesity in older adults. We identified only 19 published papers from 10 RCTs ranging from 3 to 18 months that met the criteria of independent effects of a CR component and were conducted in adults with a mean age ≥65 yrs. Overall, the results show a beneficial treatment effect for improving some metabolic, functional and body composition outcomes with few documented risks. However, all outcomes were assessed immediately after treatment cessation. Thus, until additional scientifically rigorous evidence with long-term follow-up is available, the risk-to-benefit ratio of CR for the treatment of obesity in older adults remains unclear.
Caloric Restriction Paradoxically Increases Adiposity in Mice With Genetically Reduced Insulin. [2018]Antiadiposity effects of caloric restriction (CR) are associated with reduced insulin/IGF-1 signaling, but it is unclear whether the effects of CR would be additive to genetically reducing circulating insulin. To address this question, we examined female Ins1(+/-):Ins2(-/-) mice and Ins1(+/+):Ins2(-/-) littermate controls on either an ad libitum or 60% CR diet. Although Igf1 levels declined as expected, CR was unable to reduce plasma insulin levels in either genotype below their ad libitum-fed littermate controls. In fact, 53-week-old Ins1(+/-):Ins2(-/-) mice exhibited a paradoxical increase in circulating insulin in the CR group compared with the ad libitum-fed Ins1(+/-):Ins2(-/-) mice. Regardless of insulin gene dosage, CR mice had lower fasting glucose and improved glucose tolerance. Although body mass and lean mass predictably fell after CR initiation, we observed a significant and unexpected increase in fat mass in the CR Ins1(+/-):Ins2(-/-) mice. Specifically, inguinal fat was significantly increased by CR at 66 weeks and 106 weeks. By 106 weeks, brown adipose tissue mass was also significantly increased by CR in both Ins1(+/-):Ins2(-/-) and Ins1(+/+):Ins2(-/-) mice. Interestingly, we observed a clear whitening of brown adipose tissue in the CR groups. Mice in the CR group had altered daily energy expenditure and respiratory exchange ratio circadian rhythms in both genotypes. Multiplexed analysis of circulating hormones revealed that CR was associated with increased fasting and fed levels of the obesogenic hormone, glucose-dependent insulinotropic polypeptide. Collectively these data demonstrate CR has paradoxical effects on adipose tissue growth in the context of genetically reduced insulin.
Effects of Intermittent Fasting or Calorie Restriction on Markers of Lipid Metabolism in Human Skeletal Muscle. [2021]Impaired lipid metabolism is linked with obesity-associated insulin resistance, which may be reversed by caloric restriction (CR).
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]Intermittent fasting appears an equivalent alternative to calorie restriction (CR) to improve health in humans. However, few trials have considered applying meal timing during the 'fasting' day, which may be a limitation. We developed a novel intermittent fasting plus early time-restricted eating (iTRE) approach. Adults (N = 209, 58 ± 10 years, 34.8 ± 4.7 kg m-2) at increased risk of developing type 2 diabetes were randomized to one of three groups (2:2:1): iTRE (30% energy requirements between 0800 and 1200 hours and followed by a 20-h fasting period on three nonconsecutive days per week, and ad libitum eating on other days); CR (70% of energy requirements daily, without time prescription); or standard care (weight loss booklet). This open-label, parallel group, three-arm randomized controlled trial provided nutritional support to participants in the iTRE and CR arms for 6 months, with an additional 12-month follow-up. The primary outcome was change in glucose area under the curve in response to a mixed-meal tolerance test at month 6 in iTRE versus CR. Glucose tolerance was improved to a greater extent in iTRE compared with CR (-10.10 (95% confidence interval -14.08, -6.11) versus -3.57 (95% confidence interval -7.72, 0.57) mg dl-1 min-1; P = 0.03) at month 6, but these differences were lost at month 18. Adverse events were transient and generally mild. Reports of fatigue were higher in iTRE versus CR and standard care, whereas reports of constipation and headache were higher in iTRE and CR versus standard care. In conclusion, incorporating advice for meal timing with prolonged fasting led to greater improvements in postprandial glucose metabolism in adults at increased risk of developing type 2 diabetes. ClinicalTrials.gov identifier NCT03689608 .
Metabolic and physical function are improved with lifelong 15% calorie restriction in aging male mice. [2023]Chronic calorie restriction (CR) results in lengthened lifespan and reduced disease risk. Many previous studies have implemented 30-40% calorie restriction to investigate these benefits. The goal of our study was to investigate the effects of calorie restriction, beginning at 4 months of age, on metabolic and physical changes induced by aging. Male C57BL/6NCrl calorie restricted and ad libitum fed control mice were obtained from the National Institute on Aging (NIA) and studied at 10, 18, 26, and 28 months of age to better understand the metabolic changes that occur in response to CR in middle age and advanced age. Food intake was measured in ad libitum fed controls to assess the true degree of CR (15%) in these mice. We found that 15% CR decreased body mass and liver triglyceride content, improved oral glucose clearance, and increased all limb grip strength in 10- and 18-month-old mice. Glucose clearance in ad libitum fed 26- and 28-month-old mice is enhanced relative to younger mice but was not further improved by CR. CR decreased basal insulin concentrations in all age groups and improved insulin sensitivity and rotarod time to fall in 28-month-old mice. The results of our study demonstrate that even a modest reduction (15%) in caloric intake may improve metabolic and physical health. Thus, moderate calorie restriction may be a dietary intervention to promote healthy aging with improved likelihood for adherence in human populations.