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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03319173
Recruitment Status : Completed
First Posted : October 24, 2017
Results First Posted : November 12, 2019
Last Update Posted : November 12, 2019
Sponsor:
Collaborator:
University of Minnesota
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 cellular energy status in aging and age-related diseases like cancer, cardiovascular disease (CVD), diabetes and neurodegeneration. Nutrients are epigenetic modifiers; macro and micronutrients regulate the placement and distribution of DNA histone modifiers distinguishing phenotype from genotype. Cellular energy status (AMP/ATP) modulates the regulatory mechanics of DNA methylation via the SAM (S-adenosylmethionine) methlytransferase and the SAH (S-adenosyl homocysteine) methyltransferase inhibitor index. Whole blood histamine and homocysteine levels provide additional information on the status of methylation. Hyperinsulinemia and cellular insulin resistance dysregulate nutrient sensing pathways; perpetual fed-state signaling exacerbates systemic metabolic inflexibility. Chronic elevations in insulin with long-standing impairments in glucose delivery are associated with profound changes in epigenetic expression consequent of hyper-activation of mTOR and inhibition of AMPK kinase pathways. Dietary ketosis is known to govern adaptive mitonuclear energy availability by increasing cellular reduction potential via >AMP/ATP ratio. AMPK activation adapts rRNA synthesis away from fed-state growth/storage toward energy production/release, common to fasted-states. Research suggests that induced and controlled dietary ketogenesis, a fasting mimetic, transcriptionally modifies gene expression thereby attenuating metabolic diseases.

The study will explore whether early stage memory loss (SMC & MCI) and comorbidity of Metabolic Syndrome are symptomatic of peripheral and cerebral hypo-metabolism resultant of sustained cellular insulin resistance. The investigators will attempt to show that consequent to systemic hyperinsulinemia, mitonuclear crosstalk dysregulates the energy sensing kinases, mTOR/AMPK, thereby modifying the intra/extracellular nutrient signaling pathways. The suppression of AMPK, coupled with chronic fed-state signaling, adapts rRNA synthesis away from nutrient availability toward ATP consuming processes. Increased biosynthesis of proteins, lipids and cholesterol with concurrent inhibition of fat oxidation, energy cofactors (NAD+, SAHH) and programmed apoptosis results in the epigenetic drift of methylation toward global gene activation with region-specific silencing of key regulatory/longevity genes, SIRTs (sirtuins), FOX03 and Nrf2. This global shift in energy is marked by suppression of the SAM/SAH methylation index and correlative jumps in whole blood histamine and/or homocysteine. The study explores whether the aforementioned shift in nutrient sensing pathways modulates metabolic inflexibility via energy shunts toward cytosolic, substrate level phosphorylation via activation of PDK (pyruvate dehydrogenase kinase). An insulin resistant energy surplus (<AMP/ATP) fosters low cellular reduction potential, which triggers mitonuclear crosstalk inhibiting oxidative ATP via PDC (pyruvate dehydrogenase complex), the regulatory gateway between anaerobic glycolysis and oxidative mitochondrial respiration. The study will attempt to show that induced and controlled dietary ketosis initiates the spontaneous/favorable release of energy ( >AMP/ATP), activating the AMPK circuitry thereby inhibiting the synthesis/storage of protein, cholesterol and lipids. Thus, a shift in cellular energy from low reduction potential (ATP/NADH) to high reduction potential (AMP/NAD+) attenuates methylation drift evidenced by marked reductions in biosynthesis: fasting lipid profile (TRI., VLDL, LDL, HDL), LP-IR score (particle concentration/size), HgA1c, fasting insulin, HOMA-IR and epigenetic modification of DNA measured by improved methylation index (>SAM/SAH) with correlating reductions in whole blood histamine and/or homocysteine. The resultant change in cerebral glucose metabolism and correlative improvement in SMC/MCI will be assessed by valid clinical measures of cognition: Montreal Cognitive Assessment (MoCA), Brief Visual Memory Test-Revised (BVMT-R) and Rey Auditory Verbal Learning Task (RAVLT) administered at baseline and weeks 2/4/6/8/10/12.

Research Question: Are selective memory complaints (SMC), mild cognitive impairments (MCI) and comorbid Metabolic Syndrome symptomatic of peripheral/cerebral insulin resistance with a resultant epigenetic drift in methylation away from energy production toward anabolic synthesis/storage, initiated and sustained by metabolic inflexibility, aerobic glycolysis and PDK inhibition of oxidative phosphorylation?

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 98 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
Actual Primary Completion Date : September 30, 2018
Actual Study Completion Date : September 30, 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. NMR Lipoprofile Particle Size - Small LDL-P [ Time Frame: 12 weeks ]
    Assessment of changes in Small LDL-P (total small Pattern B)

  2. NMR Lipoprofile Particle Size - LP-IR Score (Lipoprotein Insulin Resistance) Ideal Range: <45 [ Time Frame: 12 weeks ]
    Lipoprotein insulin resistance (LP-IR) is an aggregate score of the 6 lipoprotein parameters range from 0 to 100, with higher scores indicating greater insulin resistance (IR).

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

  4. Triglyceride/HDL Ratio [ Time Frame: 12 weeks ]
    Assessment of changes in Triglyceride/HDL ratio over time.

  5. Fasting Insulin [ Time Frame: 12-weeks ]
    Assessment of changes in fasting insulin over time. Ranges: < 2.6-11.1 mU/L

  6. Fasting Glucose [ Time Frame: 12-weeks ]
    Assessment of changes in fasting glucose over time. Ranges: < 74-100 mg/dL

  7. HOMA-IR [ Time Frame: 12-weeks ]
    Assessment of changes in HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) over time. Ranges: < 1.0

  8. HgA1c [ Time Frame: 12-weeks ]
    Assessment of changes in HgA1c (Hemoglobin A1c) over time.

  9. Weight [ Time Frame: 12-weeks ]
    Assessment of changes in weight over time as measured in pounds.

  10. Body Fat Mass (BFM) [ Time Frame: 12-weeks ]
    Assessment of changes in body fat mass over time as measured in pounds.

  11. VLDL [ Time Frame: 12-weeks ]
    Assessment of changes in VLDL (very low density lipoprotein carrier) over time. Ranges: < 5-40 mg/dL

  12. SAM/SAH Ratio (S-adenosylmethionine/S-adenosylhomocysteine) [ Time Frame: 12-weeks ]
    Assessment of changes in SAM/SAH (S-adenosylmethionine/S-adenosylhomocysteine) ratio Range: >4.0

  13. SAM (S-adenosylmethionine) [ Time Frame: 12-weeks ]
    Assessment of changes in SAM (S-adenosylmethionine)

  14. SAH (S-adenosylhomocysteine) [ Time Frame: 12-weeks ]
    Assessment of changes in SAH (S-adenosylhomocysteine) Range: 10-22 nmol/L

  15. Adenosine [ Time Frame: 12-weeks ]
    Assessment of changes in Adenosine Range: 20-80 nmol/L



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 two of the following physiological measures: type 2 diabetes, BMI > 30, HgA1c > 5.7%, waist/height ratio > .6, fasting glucose > 125 mg/dL
  • 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


Locations
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United States, Minnesota
Bristlecone Health, Inc.
Maple Grove, Minnesota, United States, 55311
Sponsors and Collaborators
Bristlecone Health, Inc.
University of Minnesota
Investigators
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Principal Investigator: Kelly J Gibas, Doctorate Bristlecone Health, Inc.
  Study Documents (Full-Text)

Documents provided by Bristlecone Health, Inc.:
Study Protocol  [PDF] September 15, 2017
Statistical Analysis Plan  [PDF] January 15, 2019

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Responsible Party: Bristlecone Health, Inc.
ClinicalTrials.gov Identifier: NCT03319173    
Other Study ID Numbers: Bristlecone-001
First Posted: October 24, 2017    Key Record Dates
Results First Posted: November 12, 2019
Last Update Posted: November 12, 2019
Last Verified: November 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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
SAM/SAH Index
S-adenosylmethionine (SAM)
S-adenosylhomocysteine (SAH)
Region-Specific hyper-methylation
mTOR kinase pathway
AMP/ATP ratio
Low Reduction Potential
High Reduction Potential
Delta G
Exergonic
Endergonic
Epigenetic Histone Modification
Montreal Cognitive Assessment (MoCA)
Brief Visual Memory Test-Revised (BVMT-R)
Rey Auditory Verbal Learning Task (RAVLT)
HOMA-IR
Additional relevant MeSH terms:
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Metabolic Syndrome
Cognitive Dysfunction
Insulin Resistance
Hyperinsulinism
Glucose Metabolism Disorders
Metabolic Diseases
Cognition Disorders
Neurocognitive Disorders
Mental Disorders