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

Dietary Ketosis a Metabolic Sister to Calorie Restriction (CR): Fatty Acids Activate AMPK Energy Circuits Modulating Global Methylation Via the SAM/SAH Axis

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.

Study Overview

• Status: Completed
• Conditions: Metabolic Syndrome; Mild Cognitive Impairment
• Intervention / Treatment: Behavioral: Dietary intervention

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?

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Maple Grove, Minnesota, United States, 55311
      • Bristlecone Health, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / 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).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
MoCA (Montreal Cognitive Assessment)	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.	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
NMR Lipoprofile Particle Size - Small LDL-P	Assessment of changes in Small LDL-P (total small Pattern B)	12 weeks
NMR Lipoprofile Particle Size - LP-IR Score (Lipoprotein Insulin Resistance) Ideal Range: <45	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).	12 weeks
Fasting Triglycerides	Assessment of changes in fasting triglycerides over time. Ranges: < 150 mg/dL	12 weeks
Triglyceride/HDL Ratio	Assessment of changes in Triglyceride/HDL ratio over time.	12 weeks
Fasting Insulin	Assessment of changes in fasting insulin over time. Ranges: < 2.6-11.1 mU/L	12-weeks
Fasting Glucose	Assessment of changes in fasting glucose over time. Ranges: < 74-100 mg/dL	12-weeks
HOMA-IR	Assessment of changes in HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) over time. Ranges: < 1.0	12-weeks
HgA1c	Assessment of changes in HgA1c (Hemoglobin A1c) over time.	12-weeks
Weight	Assessment of changes in weight over time as measured in pounds.	12-weeks
Body Fat Mass (BFM)	Assessment of changes in body fat mass over time as measured in pounds.	12-weeks
VLDL	Assessment of changes in VLDL (very low density lipoprotein carrier) over time. Ranges: < 5-40 mg/dL	12-weeks
SAM/SAH Ratio (S-adenosylmethionine/S-adenosylhomocysteine)	Assessment of changes in SAM/SAH (S-adenosylmethionine/S-adenosylhomocysteine) ratio Range: >4.0	12-weeks
SAM (S-adenosylmethionine)	Assessment of changes in SAM (S-adenosylmethionine)	12-weeks
SAH (S-adenosylhomocysteine)	Assessment of changes in SAH (S-adenosylhomocysteine) Range: 10-22 nmol/L	12-weeks
Adenosine	Assessment of changes in Adenosine Range: 20-80 nmol/L	12-weeks

Collaborators and Investigators

• Sponsor: Bristlecone Health, Inc.
• Collaborators: University of Minnesota
• Investigators: Principal Investigator: Kelly J Gibas, Doctorate, Bristlecone Health, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): October 15, 2017
• Primary Completion (Actual): September 30, 2018
• Study Completion (Actual): September 30, 2018

Study Registration Dates

• First Submitted: October 14, 2017
• First Submitted That Met QC Criteria: October 19, 2017
• First Posted (Actual): October 24, 2017

Study Record Updates

• Last Update Posted (Actual): November 12, 2019
• Last Update Submitted That Met QC Criteria: November 7, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Metabolic Syndrome; Mild Cognitive Impairment; HOMA-IR; Ketogenic diet; Montreal Cognitive Assessment (MoCA); AMPK activation; DNA global hypo-methylation; 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; Brief Visual Memory Test-Revised (BVMT-R); Rey Auditory Verbal Learning Task (RAVLT)
• Additional Relevant MeSH Terms: Mental Disorders; Glucose Metabolism Disorders; Metabolic Diseases; Neurocognitive Disorders; Insulin Resistance; Hyperinsulinism; Cognition Disorders; Metabolic Syndrome; Cognitive Dysfunction
• Other Study ID Numbers: Bristlecone-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No