Clinical trial NCT03319173: Dietary Ketosis: Fatty Acids Activate AMPK Energy Circuits Modulating Global Methylation
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Mild Cognitive Impairment
Metabolic Syndrome
Keywords: 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
Lead sponsor: Bristlecone Health, Inc.
Sponsor class: INDUSTRY
Collaborators: name: University of Minnesota
First posted: 2017-10-24
Enrollment: 98
Sex: ALL
Minimum age (years): 35
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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?

Eligibility 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

Primary outcomes:
measure: MoCA (Montreal Cognitive Assessment)
timeFrame: 12 weeks
Secondary outcomes:
measure: NMR Lipoprofile Particle Size - Small LDL-P
timeFrame: 12 weeks
measure: NMR Lipoprofile Particle Size - LP-IR Score (Lipoprotein Insulin Resistance) Ideal Range: <45
timeFrame: 12 weeks
measure: Fasting Triglycerides
timeFrame: 12 weeks
measure: Triglyceride/HDL Ratio
timeFrame: 12 weeks
measure: Fasting Insulin
timeFrame: 12-weeks
measure: Fasting Glucose
timeFrame: 12-weeks
measure: HOMA-IR
timeFrame: 12-weeks
measure: HgA1c
timeFrame: 12-weeks
measure: Weight
timeFrame: 12-weeks
measure: Body Fat Mass (BFM)
timeFrame: 12-weeks
measure: VLDL
timeFrame: 12-weeks
measure: SAM/SAH Ratio (S-adenosylmethionine/S-adenosylhomocysteine)
timeFrame: 12-weeks
measure: SAM (S-adenosylmethionine)
timeFrame: 12-weeks
measure: SAH (S-adenosylhomocysteine)
timeFrame: 12-weeks
measure: Adenosine
timeFrame: 12-weeks
Other outcomes:
Locations:
city: Maple Grove
country: United States
facility: Bristlecone Health, Inc.
state: Minnesota
Study officials:
affiliation: Bristlecone Health, Inc.
name: Kelly J Gibas, Doctorate
role: PRINCIPAL_INVESTIGATOR
References: