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Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function

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ClinicalTrials.gov Identifier: NCT02460783
Recruitment Status : Recruiting
First Posted : June 2, 2015
Last Update Posted : December 31, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) )

Brief Summary:

Background:

- Insulin removes sugar from the blood to use for energy. Insulin resistance means that cells may not respond to insulin normally. It can lead to serious diseases. Researchers want to see how diet affects insulin resistance, weight, and brain chemicals related to Alzheimer s disease.

Objectives:

- To compare two forms of diet and their effects on insulin resistance and the brain.

Eligibility:

- Women ages 55 70 with insulin resistance.

Design:

  • This study requires 6 clinic visits over 9 12 weeks. Participants must fast before visits.
  • Visit 1, screening:
  • Medical history, physical exam, and blood and urine tests.
  • Participants will get a wrist device to wear for 4 days.
  • Visit 2:
  • Weight and waist measurement.
  • Blood drawn.
  • Questionnaires and thinking tests.
  • Lumbar puncture. Skin will be numbed and a needle inserted between bones in the back will remove <TAB>fluid.
  • Participants will drink a nutrition shake. Blood will be taken 12 times over 4 <TAB>hours through a thin tube in <TAB>the arm.
  • Brain MRI. Participants will lie on a table that slides in and out of a cylinder in a strong magnetic field. <TAB>They will have a coil on their head and may do tasks.
  • Participants will get advice about healthy eating and be randomly put in one of 2 groups. One group will get <TAB>nutrition shakes to drink.
  • Visits 3 5:
  • Weight and waist measurements, vital signs, blood draw, and questionnaires.
  • Between visits, participants will get a call or email to check how they are doing.
  • Visit 6: Repeat of visit 1.
  • Participants will wear the wrist device for 4 more days, have a follow-up contact, then the study is finished.

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Obesity Diabetes Mellitus Dietary Supplement: Boost A Behavioral: Healthy Living Diet Phase 2

Detailed Description:
Being overweight or obese can cause insulin resistance (IR), which is defined as reduced responsiveness to insulin by the cells of various tissues or organs. IR at midlife increases the risk of developing Alzheimer s disease (AD). We recently discovered novel biomarkers of brain IR (altered Tyr and Ser phosphorylated forms of insulin receptor substrate 1; IRS-1) in plasma exosomes enriched for neuronal origin. Moreover, IR is associated with AD biomarkers including deficits in resting state brain activity and cognitive performance. Calorie restriction is defined as consuming fewer calories than what is considered normal without a lack of nutrients. A certain type of calorie restriction, in which one consumes 500-600 calories a day for two consecutive days, followed by non-restricted eating for 5 days (5-2 CR), has been shown to lower peripheral insulin resistance effectively. Effects of CR and lowering peripheral IR on brain IR and cognition are unknown. The goal of this exploratory pilot study is to provide proof-of-concept that 5-2 CR at midlife can reverse brain IR, lower peripheral IR, improve cognitive performance, and increase brain activation at rest and during tasks. Specifically, we will study the effects of 8 weeks of 5-2 CR versus a control dietary intervention on brain and peripheral IR, memory and executive function, resting state default mode network activity, brain metabolism, and AD biomarkers. Forty overweight to obese women and men (between 55 and 70 years of age) will be randomized 1:1 into 5-2 CR and control groups. In the 5-2 CR group, participants will be offered healthy living dietary counseling at baseline, which they will be instructed to implement for five days/week. For each of the other two consecutive days/week, they will consume two shakes (Boost , CWI Medical), providing a total of 480 Kcal/day. In the control group, participants will be offered healthy living dietary counseling at baseline, which they will be asked to implement for every day of the week. Participants will undergo screening including a history and physical examination, calculation of Body Mass Index (BMI, which must be greater than or equal to 27) and a blood draw for insulin and glucose to determine whether they have insulin resistance. If participants meet eligibility criteria, they will continue with a baseline visit involving anthropometric measures, questionnaires, tests of cognitive function, brain MRI, blood draws for plasma and peripheral blood mononuclear cells, and lumbar puncture for cerebrospinal fluid biomarkers of AD. After 8 weeks, we will collect the same measures. To assess and reinforce compliance with their respective diet, participants will come into the clinic every 2 weeks to discuss compliance, measure their body weight and perform blood draws for measurement of ketones to objectively confirm energy restriction for the 5-2 CR group. We will also contact participants every week to further ensure compliance. To assess the effects of the diets on physical activity, participants will be asked to wear an accelerometer for 96 hours before and after they are on the diet.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function
Study Start Date : May 30, 2015
Estimated Primary Completion Date : July 1, 2019
Estimated Study Completion Date : July 1, 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 5-2 CR
Healthy living diet for 5 days/week;
Dietary Supplement: Boost A
Supplement providing 530 Kcal/Bottle

Active Comparator: Healthy Living
Healthy living diet for 7 days/week
Behavioral: Healthy Living Diet
Counseling and educational material on diet portion, consistency




Primary Outcome Measures :
  1. Exosomal p-S312-IRS-1/p-panY-IRS-1 ratio (index of brain insulin resistance) [ Time Frame: 0, 8 weeks ]

Secondary Outcome Measures :
  1. Hormones (GLP-1, insulin) during a mixed [ Time Frame: 0, 8 weeks ]
  2. Anthropometric measures (weight, waist) [ Time Frame: 0, 2, 4, 6, 8 weeks ]
  3. Measure: CSF, plasma BDNF [ Time Frame: 0, 8 weeks ]
  4. Cognitive performance (Examiner, Memory) [ Time Frame: 0, 8 weeks ]
  5. Mood, energy, concentration, etc. symptom [ Time Frame: 0, 2, 4, 6, 8 weeks ]
  6. Si and HOMA-IR (indices of peripheral insulin resistance) [ Time Frame: 0, 8 weeks ]
  7. Lipid panel, uric acid [ Time Frame: 0, 8 weeks ]
  8. MRS metabolites [ Time Frame: 0, 8 weeks ]
  9. fMRI activation to food preference task [ Time Frame: 0, 8 weeks ]
  10. fMRI activation to Stroop [ Time Frame: 0, 8 weeks ]
  11. CSF, plasma AD biomarkers (A(SqrRoot) <=42,p181Tau) [ Time Frame: 0, 8 weeks ]
  12. Cytokines: IL-6, IL-8, IL-12, IL-23 [ Time Frame: 0, 8 weeks ]
  13. Physical activity (Accelerometry) [ Time Frame: 0, 8 weeks ]
  14. DNA methylation [ Time Frame: 0, 2, 4, 6, 8 weeks ]
  15. Measure: Exosomal proteins and mRNA [ Time Frame: 0, 8 weeks ]
  16. ROS, AGES [ Time Frame: 0, 8 weeks ]
  17. Resting fMRI [ Time Frame: 0, 8 weeks ]
  18. Gene expression [ Time Frame: 0, 2, 4, 6, 8 weeks ]


Information from the National Library of Medicine

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Ages Eligible for Study:   55 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • BMI greater than or equal to 27; in addition, weight less than or equal to 350 lbs (weight limit for MRI scanner);
  • Age of 55-70 years;
  • HOMA-IR greater than or equal to 1.8;
  • MMSE greater than or equal to 26

EXCLUSION CRITEIRA:

  • History of clinically significant cardiovascular disease for the purpose of this study, such as chronic heart failure, coronary disease, cardiomyopathy, clinically significant cardiac valvular disease or clinically significant peripheral vascular disease. Cardiovascular conditions that are clinically non-significant for the purpose of this study, such as controlled hypertension, minor EKG abnormalities, mitral valve prolapse or benign murmurs are permissible;
  • History of clinically significant stroke or other neurological disease of the central nervous system;
  • History of substance abuse in the past 6 months or positive urine drug screen;
  • History of clinically significant endocrine disorders (common mild endocrine disorders, such as untreated subclinical hypothyroidism with TSH < 10 mU/l or successfully treated hypothyroidism may be allowed);
  • History of eating disorders, significant GI disorders or malabsorption disorders;
  • History of type 2 diabetes; and/or use of anti-diabetes medications or insulin; and/or type 2 diabetes diagnosed during the screening visit based on fasting glucose > 125 mg/dL;
  • History of hypoglycemia; and/or a fasting glucose < 70 mg/dL during the screening visit.
  • Current use of systemic corticosteroids;
  • Positive screening tests for HIV, HCV or HBV;
  • Hematocrit less than 35% or hemoglobin less than 11 mg/dL;
  • ALT or AST > 1.5 times the upper normal limit;
  • Contraindications for MRI (pacemakers, ferrous metal implants or shrapnel in or around the head, etc.).
  • Contraindications to LP, such as Coumadin, coagulopathy (international normalized ratio, or INR > 1.5; prothrombin time (PT), partial prothrombin time (PTT) > 1.5 x upper normal limit). Aspirin 81 mg qd is allowed. Aspirin up to 325 mg qd is allowed, if withheld for 7 days prior to the LP.
  • Pregnancy or nursing.
  • Refusal to consent to genetic testing for APOE.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02460783


Contacts
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Contact: Kristy L Kessler, R.N. (410) 350-7319 kristy.kessler@nih.gov
Contact: Dimitrios I Kapogiannis, M.D. (410) 350-3953 kapogiannisd@mail.nih.gov

Locations
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United States, Maryland
National Institute of Aging, Clinical Research Unit Recruiting
Baltimore, Maryland, United States, 21224
Sponsors and Collaborators
National Institute on Aging (NIA)
Investigators
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Principal Investigator: Dimitrios I Kapogiannis, M.D. National Institute on Aging (NIA)

Additional Information:
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Responsible Party: National Institute on Aging (NIA)
ClinicalTrials.gov Identifier: NCT02460783     History of Changes
Other Study ID Numbers: 150123
15-AG-0123
First Posted: June 2, 2015    Key Record Dates
Last Update Posted: December 31, 2018
Last Verified: December 17, 2018

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Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute on Aging (NIA) ):
Biomarkers
Diabetes
Obesity
Dementia of the Alzheimer Type
Functional Magnetic Resonance Imaging (fMRI)

Additional relevant MeSH terms:
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Diabetes Mellitus
Alzheimer Disease
Insulin Resistance
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Hyperinsulinism