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Dietary Ketosis: Fatty Acids Activate AMPK Energy Circuits Modulating Global Methylation

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ClinicalTrials.gov Identifier: NCT03319173
Recruitment Status : Recruiting
First Posted : October 24, 2017
Last Update Posted : October 24, 2017
Sponsor:
Collaborator:
University of Minnesota - Clinical and Translational Science Institute
Information provided by (Responsible Party):
Bristlecone Health, Inc.

Brief Summary:
The study explores whether selective memory complaints (SMC), mild cognitive impairment (MCI) and the comorbidity of Metabolic Syndrome symptomatic of peripheral and cerebral hypo-metabolism with corresponding epigenetic shifts in global DNA (deoxyribonucleic acid) methylation (away from nutrient availability and toward biosynthesis) are initiated by chronic metabolic inflexibility, over-activation of the mTOR (mammalian target of rapamycin) pathway, and the deregulation of neural oxidative phosphorylation.

Condition or disease Intervention/treatment Phase
Mild Cognitive Impairment Metabolic Syndrome Behavioral: Dietary intervention Not Applicable

Detailed Description:

Nutritional epigenetics denotes gene-diet interactions and highlights the modulatory role of nutrition in aging and age-related diseases such as cancer, CVD (cardiovascular disease), diabetes and neurodegenerative disorders. Nutrients are a source of epigenetic modification; they are able to regulate the placement of histone modifiers distinguishing phenotype from genotype. The energy status of the cells (fed or fasted) modulates the regulation of global DNA methylation via the S-adenosylmethionine (SAM), the methyltransferase inhibitor, S-adenosylhomocysteine (SAH) axis and whole blood histamine levels. Insulin resistance and hyperinsulinemia dysregulate cellular signals leading to metabolic inflexibility. Chronic elevations in insulin with long-standing impairments in glucose delivery are associated with profound changes in epigenetic patterns due to over-activation of the mTOR kinase pathway and repression of AMPK (adenosine monophosphate-activated protein kinase). Dietary ketosis is known to change the metabolic status of the cells by increasing the AMP/ATP (adenosine monophosphate/adenosine tri-phosphate) ratio. AMPK activation adapts rRNA (ribosomal ribonucleic acid) synthesis away from growth/biosynthesis and toward ATP availability and utilization, thereby, attenuating the progression of hypo-metabolic diseases in the body and the brain at the level of the genome.

The study will explore whether early stage memory loss (SMC & MCI) and the comorbidity of Metabolic Syndrome are symptomatic of peripheral and cerebral cellular hypo-metabolism induced by chronic insulin resistance. We will attempt to show that consequential to systemic hyperinsulinemia, aberrant crosstalk between the mitochondria and nuclear genome results in the dysregulation of the regulatory kinases mediating metabolic state and intracellular/extracellular signaling: mTOR and AMPK. The suppression of AMPK signals with chronic overexpression of mTOR signaling will adapt rRNA synthesis away from nutrient availability and toward ATP consuming processes: the biosynthesis of cholesterol, triglycerides, glycogen with inhibition of fatty acid oxidation, histone acetylation with a down-regulation of NAD+ (nicotinamide adenine dinucleotide coenzyme) and SAHH (S-adenosylhomocysteine hydrolase) cofactors leading to global DNA hypo-methylation and local hyper-methylation, suppression of the SAM/SAH ratio, the inhibition of SIRT (sirtuin) expression and normalized whole blood histamine levels. These epigenetic shifts mediate global metabolic inflexibility by channeling fuel substrates toward cytosolic, substrate level phosphorylation (SLP) via over expression of the glycolytic enzymes including PDK (pyruvate dehydrogenase kinase) and away from mitochondrial oxidation mediated by the suppression of PDC (pyruvate dehydrogenase complex), the major regulatory gateway of metabolism between glycolysis and citric acid cycle. We will attempt to show that activation of the AMPK pathway via induced and controlled dietary ketosis will inhibit mTOR signaling away from the biosynthesis of energy and SLP toward the generation of ATP by increasing the cellular AMP/ATP ratio, thus regulating oxidative metabolic signals and attenuating global, cellular hypo-metabolism evidenced by marked reductions in lipid synthesis and LP-IR score (particle concentration and size), HgA1c (hemoglobin A1c), fasting insulin/HOMA-IR (homeostatic model assessment of insulin resistance), blood ketones, fasting triglycerides together with epigenetic regulation of DNA methylation status including normalized whole blood histamine levels and homocysteine regulation. Improvement in cerebral glucose metabolism and corresponding diagnosis of SMC/MCI will be assessed by the objective changes in the outcome measures of MoCA (Montreal Cognitive Assessment), MMSE (Mini-Mental State Exam) and BVMT-R (Brief Visuospatial Memory Test-Revised) administered at baseline and week 12.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 80 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: To assess differences between the control and experimental groups, a mixed model will be fit for each variable separately using both baseline (week 0) and post program (week 12) values for each subject. Models will include week, group, and their interaction as fixed effects, gender as a covariate, and subject as a random effect. To assess significant differences, we will use the difference at week 12 adjusted for the baseline difference, and will report p-values, least squares means, and 95% confidence intervals. Further analysis of treatment effects over time will be examined by comparing the within-group differences over time.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Dietary Ketosis a Metabolic Sister to Calorie Restriction (CR): Fatty Acids Activate AMPK Energy Circuits Modulating Global Methylation Via the SAM/SAH Axis
Actual Study Start Date : October 15, 2017
Estimated Primary Completion Date : May 15, 2018
Estimated Study Completion Date : May 15, 2018

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Experimental group

Dietary interventions for subjects in the experimental group include clinically regulated meal plans designed to facilitate prolonged benign dietary ketosis (BDK) in order to regulate glucose with restored insulin sensitivity focused at reversing the impaired capacity to switch between fat and carbohydrate oxidation. Subjects will consume 3 meals per day with the following approximate macronutrient breakdown per meal: 65% fat, 25% protein, 10% carbohydrate.

Both groups will play the Advanced PEAK brain training games on iPhone, iPad or Android devices for 75 minutes per week.

Behavioral: Dietary intervention

Subjects in the experimental group will receive clinically regulated meal plans designed to facilitate prolonged benign dietary ketosis (BDK) in order to regulate glucose with restored insulin sensitivity focused at reversing the impaired capacity to switch between fat and carbohydrate oxidation.

Subjects in the control group will follow the their current dietary protocol (Standard American Diet-SAD).


Active Comparator: Control group

Dietary interventions for subjects in the control group include the subjects' current dietary protocol (Standard American Diet-SAD). Subjects will consume 4-6 small meals per day with the following approximate macronutrient breakdown per meal: 50% carbohydrate, 35% protein, 15% fat.

Both groups will play the Advanced PEAK brain training games on iPhone, iPad or Android devices for 75 minutes per week.

Behavioral: Dietary intervention

Subjects in the experimental group will receive clinically regulated meal plans designed to facilitate prolonged benign dietary ketosis (BDK) in order to regulate glucose with restored insulin sensitivity focused at reversing the impaired capacity to switch between fat and carbohydrate oxidation.

Subjects in the control group will follow the their current dietary protocol (Standard American Diet-SAD).





Primary Outcome Measures :
  1. MoCA (Montreal Cognitive Assessment) [ Time Frame: 12 weeks ]
    Measures changes in cognitive function over time. Score: 30 points (maximum), 0 points (minimum). Score >25 = normal cognitive function. Score 17-25 = mild cognitive impairment (MCI). Score <17 = increased likelihood of Alzheimer's Disease or dementia.


Secondary Outcome Measures :
  1. Whole blood histamine [ Time Frame: 12 weeks ]
    Assessment of changes in global methylation status over time. Ranges: 0.3-1.0 ng/mL. Normal methylation = 0.6-0.7 ng/mL. Under-methylation = 0.8-1.0 ng/mL. Over-methylation = 0.3-0.5 ng/mL.

  2. NMR lipoprofile particle size - LDL particle size [ Time Frame: 12 weeks ]
    Assessment of changes in LDL particle size from small particle size 'B' to large particle size 'A' over time. LDL-P (total LDL particle production) Range: 1000-2000 nmol/L. Small LDL-P (total small Pattern B) Range: <=527 nmol/L.

  3. NMR lipoprofile particle size - LP-IR score [ Time Frame: 12 weeks ]
    Assessment of changes insulin resistance and diabetes risk. Range: <=46

  4. MMSE (Mini-Mental State Examination) [ Time Frame: 12 weeks ]
    Measures cognitive function over time. Score: 30 points (maximum), 0 points (minimum). Score >24 = normal cognitive function. Score 19-24 = mild cognitive impairment (MCI). Score <19 = increased likelihood of Alzheimer's Disease or dementia.

  5. Brief Visuospatial Memory Test - Revised (BVMT-R) [ Time Frame: 12 weeks ]
    Assessment of changes in visuospatial memory over time. Score: 12 points. Participant views a stimulus page of six geometric figures for 10 seconds. Participants asked to draw as many of the figures as possible, without looking, in their correct location. Participants are given three opportunities to complete the task. Two points are awarded for each figure that is drawn correctly and in the correct location.

  6. Blood ketones [ Time Frame: 12 weeks ]
    Assessment of changes in blood ketones over time. Ranges: 0.5-2.0 ng/mL

  7. Fasting triglycerides [ Time Frame: 12 weeks ]
    Assessment of changes in fasting triglycerides over time. Ranges: < 150 mg/dL



Information from the National Library of Medicine

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Ages Eligible for Study:   35 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male or Female (age 35-80)
  • Previously diagnosed with MetS and/or T2DM as measured by possessing at least 2 of the following physiological measures: type II diabetes, BMI >30, HgA1c > 5.7, waist/height ratio >.6, fasting glucose > 125
  • Subjective Memory Complaints (SCM) - Subjects score > 3 'yes' answers on the Subjective Memory --Complaints Questionnaire
  • Previously diagnosed with Mild Cognitive Impairment (MCI)

Exclusion Criteria:

  • Previously diagnosed with Alzheimer's disease (AD), dementia or Parkinson's disease

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): NCT03319173


Contacts
Contact: Julie A Gomer, Doctorate 763-913-4600 julie@bristleconefitness.com

Locations
United States, Minnesota
Bristlecone Health, Inc. Recruiting
Maple Grove, Minnesota, United States, 55311
Contact: Julie A Gomer, Doctorate    763-913-4600    julie@bristleconefitness.com   
Sponsors and Collaborators
Bristlecone Health, Inc.
University of Minnesota - Clinical and Translational Science Institute
Investigators
Principal Investigator: Kelly J Gibas, Doctorate Bristlecone Health, Inc.

Responsible Party: Bristlecone Health, Inc.
ClinicalTrials.gov Identifier: NCT03319173     History of Changes
Other Study ID Numbers: Bristlecone-001
First Posted: October 24, 2017    Key Record Dates
Last Update Posted: October 24, 2017
Last Verified: October 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Bristlecone Health, Inc.:
Mild Cognitive Impairment
AMPK activation
DNA global hypo-methylation
Metabolic Syndrome
Ketogenic diet

Additional relevant MeSH terms:
Metabolic Syndrome X
Cognitive Dysfunction
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders