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

Metabolic Syndrome Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03319173
• Other study ID #: Bristlecone-001
• Status: Completed
• Phase: N/A
• Start date: October 15, 2017
• Est. completion date: September 30, 2018

Study information

• Verified date: November 2019
• Source: Bristlecone Health, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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), 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?

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: September 30, 2018
• Est. primary completion date: September 30, 2018
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 35 Years to 80 Years

Eligibility

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

Related Conditions & MeSH terms

• Cognitive Dysfunction
• Metabolic Syndrome
• Mild Cognitive Impairment

Intervention

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).

Locations

Country	Name	City	State
United States	Bristlecone Health, Inc.	Maple Grove	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Bristlecone Health, Inc.	University of Minnesota

Country where clinical trial is conducted

United States, 

Outcome

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