Clinical trial NCT02460783: Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function
Official title: Intermittent Calorie Restriction, Insulin Resistance, and Biomarkers of Brain Function
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Alzheimer's Disease
Obesity
Diabetes Mellitus
Keywords: Biomarkers
Diabetes
Obesity
Dementia of the Alzheimer Type
Functional Magnetic Resonance Imaging (fMRI)
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2015-06-02
Enrollment: 129
Sex: ALL
Minimum age (years): 55
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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.

Primary outcomes:
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine312-insulin Receptor Substrate-1 (pS312-IRS-1)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) P-pan-Tyrosine-IRS-1 (pY-IRS-1)
timeFrame: Week 0, Week 4, Week 8
Secondary outcomes:
measure: Mean Change in Body Weight
timeFrame: Week 0, Week 8
measure: Mean Change in Body Mass Index (BMI)
timeFrame: Week 0, Week 8
measure: Mean Change in Waist Circumference
timeFrame: Week 0, Week 8
measure: Mean Change in Fasting Glucose
timeFrame: Week 0, Week 8
measure: Mean Change in Fasting Insulin
timeFrame: Week 0, Week 8
measure: Mean Change in Homeostatic Model Assessment of Insulin Resistance 2 (HOMA2-IR)
timeFrame: Week 0, Week 8
measure: Mean Change in Glycosylated Hemoglobin (HbA1c)
timeFrame: Week 0, Week 8
measure: Mean Change in White Blood Cells (WBCs)
timeFrame: Week 0, Week 8
measure: Mean Change in Red Blood Cells (RBCs)
timeFrame: Week 0, Week 8
measure: Mean Change in Platelets
timeFrame: Week 0, Week 8
measure: Mean Change in Hemoglobin
timeFrame: Week 0, Week 8
measure: Mean Change in Hematocrit
timeFrame: Week 0, Week 8
measure: Mean Change in International Normalized Ratio (INR)
timeFrame: Week 0, Week 8
measure: Mean Change in Serum Beta-Hydroxybutyrate (bHB)
timeFrame: Week 0, Week 8
measure: Mean Change in Serum Acetoacetate (AcAc)
timeFrame: Week 0, Week 8
measure: Mean Change in Serum Non-Esterified Fatty Acids (NEFA)
timeFrame: Week 0, Week 8
measure: Mean Change in Serum Cortisol
timeFrame: Week 0, Week 8
measure: Mean Change in Creatinine
timeFrame: Week 0, Week 8
measure: Mean Change in Blood Urea Nitrogen (BUN)
timeFrame: Week 0, Week 8
measure: Mean Change in Alanine Aminotransferase (ALT)
timeFrame: Week 0, Week 8
measure: Mean Change in Aspartate Aminotransferase (AST)
timeFrame: Week 0, Week 8
measure: Mean Change in Total Cholesterol
timeFrame: Week 0, Week 8
measure: Mean Change in HDL Cholesterol
timeFrame: Week 0, Week 8
measure: Mean Change in LDL Cholesterol
timeFrame: Week 0, Week 8
measure: Mean Change in Triglycerides
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) Amyloid Beta 42
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) Amyloid Beta 40
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) Amyloid Beta 42 / Amyloid Beta 40 Ratio
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) Total Tau
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) p181-Tau
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) Neurogranin
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) Light Chain Neurofilaments (Nf-L)
timeFrame: Week 0, Week 8
measure: Mean Change in Cerebrospinal Fluid (CSF) Glial Fibrillary Acidic Protein (GFAP)
timeFrame: Week 0, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 42
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 40
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Amyloid Beta 42 / Amyloid Beta 40 Ratio
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Total Tau
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) p181-Tau
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) p231-Tau
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Akt
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine473-Akt (pS473-Akt)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Serine473-Akt (pS473-Akt) / Akt Ratio
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated Extracellular Signal-regulated Kinase 1/2 (pERK1/2)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated c-Jun N-terminal Kinase (pJNK)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Phosphorylated p38 (pp38)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) proBDNF
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) BDNF
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Neurogranin
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Heavy Chain Neurofilaments (Nf-H)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) A-synuclein
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) TAR DNA-binding Protein 43 (TDP-43)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Monocarboxylate Transporter 1 (MCT1)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Monocarboxylate Transporter 2 (MCT2)
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Mitochondrial Complex IV Quantity
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Neuron-Derived Extracellular Vesicle (NDEV) Mitochondrial Complex V Quantity
timeFrame: Week 0, Week 4, Week 8
measure: Mean Change in Glucose by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in N-acetyl-aspartate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Lactate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Glutamate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Gamma-Aminobutyric Acid (GABA) by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Glutamine by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Glutathione by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Myo-Inositol by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in N-acetyl-aspartyl-glutamate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Ascorbate by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Alanine by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Scyllo-Inositol by Proton J-PRESS MRS of Posteromedial Cortex (PMC)
timeFrame: Week 0, Week 8
measure: Mean Change in Glucose by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Lactate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Glutamate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Glutamine by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Glutathione by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Myo-Inositol by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in N-acetyl-aspartyl-glutamate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Ascorbate by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Alanine by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Scyllo-Inositol by Proton J-PRESS MRS of Medial Prefrontal Cortex (MPFC)
timeFrame: Week 0, Week 8
measure: Mean Change in Executive Function Composite
timeFrame: Week 0, Week 8
measure: Mean Change in California Verbal Learning Test (CVLT)
timeFrame: Week 0, Week 8
measure: Mean Change in Logical Memory (LM) Test
timeFrame: Week 0, Week 8
measure: Change in the Positive and Negative Affect Schedule (PANAS)
timeFrame: Week 0, Week 8
measure: Mean Change in the Short Form 36-item Health Survey (SF-36)
timeFrame: Week 0, Week 8
measure: Mean Change in Total Energy Expenditure
timeFrame: Week 0, Week 8
measure: Mean Change in Daily Energy Expenditure
timeFrame: Week 0, Week 8
measure: Mean Change in Hourly Energy Expenditure
timeFrame: Week 0, Week 8
measure: Mean Change in Metabolic Rate
timeFrame: Week 0, Week 8
measure: Mean Change in Time in Activity
timeFrame: Week 0, Week 8
measure: Mean Change in Total Steps
timeFrame: Week 0, Week 8
measure: Mean Change in Steps Per Minute
timeFrame: Week 0, Week 8
measure: Mean Change in Total Sedentary Bouts
timeFrame: Week 0, Week 8
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: National Institute of Aging, Clinical Research Unit
state: Maryland
Study officials:
affiliation: National Institute on Aging (NIA)
name: Dimitrios I Kapogiannis, M.D.
role: PRINCIPAL_INVESTIGATOR
References: