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| Name | Class |
|---|---|
| University of Minnesota | OTHER |
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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.
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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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Experimental group | Experimental | 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. |
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| Control group | Active Comparator | 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. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Dietary intervention | Behavioral | 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). |
| 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 |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Kelly J Gibas, Doctorate | Bristlecone Health, Inc. | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Bristlecone Health, Inc. | Maple Grove | Minnesota | 55311 | United States |
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| ID | Title | Description |
|---|---|---|
| FG000 | 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 mobile devices for 75 minutes per week. 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). |
| FG001 | 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. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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. 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. |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | Posted | Least Squares Mean | Standard Error | score on a scale | 12 weeks |
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12-weeks
Study protocol/procedures non-invasive
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | 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. 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. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Kelly J. Gibas | Bristlecone Health, Inc. | 763-913-4600 | kelly-gibas@bethel.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Sep 15, 2017 | Aug 26, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Jan 15, 2019 | Aug 26, 2019 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D060825 | Cognitive Dysfunction |
| D024821 | Metabolic Syndrome |
| ID | Term |
|---|---|
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D007333 | Insulin Resistance |
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| ID | Term |
|---|---|
| D004035 | Diet Therapy |
| ID | Term |
|---|---|
| D044623 | Nutrition Therapy |
| D013812 | Therapeutics |
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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.
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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 |
| BG001 | 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. Dietary intervention: Subjects in the control group will follow the their current dietary protocol (Standard American Diet-SAD). |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race and Ethnicity Not Collected | Race and Ethnicity were not collected from any participant. | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| MoCA (Montreal Cognitive Assessment) | MoCA score ranges: Normal: >= 26; MCI (mild cognitive impairment): 17-25 | Least Squares Mean | Inter-Quartile Range | units on a scale |
|
| Units | Counts |
|---|
| Participants |
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| Secondary | NMR Lipoprofile Particle Size - Small LDL-P | Assessment of changes in Small LDL-P (total small Pattern B) | Posted | Geometric Least Squares Mean | Standard Error | nmol/L | 12 weeks |
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| 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). | Posted | Geometric Least Squares Mean | 95% Confidence Interval | score on a scale | 12 weeks |
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| Secondary | Fasting Triglycerides | Assessment of changes in fasting triglycerides over time. Ranges: < 150 mg/dL | Posted | Geometric Least Squares Mean | 95% Confidence Interval | mg/dL | 12 weeks |
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| Secondary | Triglyceride/HDL Ratio | Assessment of changes in Triglyceride/HDL ratio over time. | Posted | Geometric Least Squares Mean | 95% Confidence Interval | ratio | 12 weeks |
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| Secondary | Fasting Insulin | Assessment of changes in fasting insulin over time. Ranges: < 2.6-11.1 mU/L | Posted | Geometric Least Squares Mean | 95% Confidence Interval | mU/L | 12-weeks |
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| Secondary | Fasting Glucose | Assessment of changes in fasting glucose over time. Ranges: < 74-100 mg/dL | Posted | Geometric Least Squares Mean | 95% Confidence Interval | mg/dL | 12-weeks |
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| Secondary | HOMA-IR | Assessment of changes in HOMA-IR (Homeostatic Model Assessment of Insulin Resistance) over time. Ranges: < 1.0 | Posted | Geometric Least Squares Mean | 95% Confidence Interval | units on a scale | 12-weeks |
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| Secondary | HgA1c | Assessment of changes in HgA1c (Hemoglobin A1c) over time. | Posted | Geometric Least Squares Mean | 95% Confidence Interval | percentage of glycated hemoglobin | 12-weeks |
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| Secondary | Weight | Assessment of changes in weight over time as measured in pounds. | Posted | Geometric Least Squares Mean | 95% Confidence Interval | pounds | 12-weeks |
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| Secondary | Body Fat Mass (BFM) | Assessment of changes in body fat mass over time as measured in pounds. | Posted | Geometric Least Squares Mean | 95% Confidence Interval | pounds | 12-weeks |
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| Secondary | VLDL | Assessment of changes in VLDL (very low density lipoprotein carrier) over time. Ranges: < 5-40 mg/dL | Posted | Geometric Least Squares Mean | 95% Confidence Interval | mg/dL | 12-weeks |
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| Secondary | SAM/SAH Ratio (S-adenosylmethionine/S-adenosylhomocysteine) | Assessment of changes in SAM/SAH (S-adenosylmethionine/S-adenosylhomocysteine) ratio Range: >4.0 | Posted | Geometric Least Squares Mean | 95% Confidence Interval | ratio | 12-weeks |
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| Secondary | SAM (S-adenosylmethionine) | Assessment of changes in SAM (S-adenosylmethionine) | Posted | Geometric Least Squares Mean | 95% Confidence Interval | nmol/L | 12-weeks |
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| Secondary | SAH (S-adenosylhomocysteine) | Assessment of changes in SAH (S-adenosylhomocysteine) Range: 10-22 nmol/L | Posted | Geometric Least Squares Mean | 95% Confidence Interval | nmol/L | 12-weeks |
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| Secondary | Adenosine | Assessment of changes in Adenosine Range: 20-80 nmol/L | Posted | Geometric Least Squares Mean | 95% Confidence Interval | nmol/L | 12-weeks |
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| 0 |
| 48 |
| 0 |
| 48 |
| 0 |
| 48 |
| EG001 | 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. Subjects in the control group will follow the their current dietary protocol (Standard American Diet-SAD). | 0 | 50 | 0 | 50 | 0 | 50 |
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| D006946 |
| Hyperinsulinism |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |