Aging, Diet Modification, Healthy, Insulin Resistance
Conditions
Keywords
exogenous ketone, insulin resistance, glucose, diet, aging
Brief summary
In this study, we investigate the impact of insulin resistance on the acceleration of brain aging, and test whether increased neuron insulin resistance can be counteracted by utilization of alternate metabolic pathways (e.g., ketones rather than glucose). This study has three Arms, which together provide synergistic data. For all three Arms, subjects are tested in a within-subjects design that consists of 2-3 testing sessions, 1-14 days apart, and counter-balanced for order. During each session we measure the impact of fuel (glucose in one session, ketones in the other) on brain metabolism and associated functioning. For Arms 1-2, our primary experimental measure is functional magnetic resonance imaging (fMRI), which we will use to trace the self-organization of functional networks following changes in energy supply and demand. Arm 1 tests the impact of endogenous ketones produced by switching to a low carbohydrate diet, while Arm 2 tests the impact of exogenous ketones consumed as a nutritional supplement. For Arm 3, we use simultaneous magnetic resonance spectroscopy/positron-emission tomography (MR/PET) to quantify the impact of exogenous ketones on production of glutamate and GABA, key neurotransmitters. Subjects will be given the option to participate in more than one of the Arms, but doing so is not expected nor required. Prior to scans, subjects will receive a clinician-administered History and Physical (H&P), which includes vital signs, an oral glucose tolerance test (OGTT), and the comprehensive metabolic blood panel. These will be used to assess diabetes, kidney disease, and electrolytes. If subjects pass screening, they will be provided the option to participate in one or more Arms, which include neuroimaging. To provide a quantitative measure of time-varying metabolic activity throughout the scan, based upon quantitative models of glucose and ketone regulation, as well as to be able to implement safety stopping rules (see below), we will obtain pin-prick blood samples three times: prior to the scan, following consumption of the glucose or ketone drink, and following completion of the scan. To assess effects of increased metabolic demand, we measure brain response to cognitive load, transitioning from resting-state to spatial reasoning through a Tetris task. To assess effects of increased metabolic supply, we measure brain response to glucose or ketone bolus.
Interventions
DRUGKetones
Sports supplement that is administered mid-scan.
DRUGGlucose
Supplement is administered mid-scan.
Sponsors
Martinos Center for Biomedical Imaging
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 79 Years
Healthy volunteers
Yes
Exclusion criteria
* claustrophobia * history of neurological disease, heart attack, stroke, kidney disease, or myxedema * chronic usage of alcohol * current usage of psychotropic medication * Type 1 diabetes mellitus * Regular consumption of insulin, Metformin® or other medications (statins, NSAIDs, beta-blockers, glucocorticoids) that affect glucose and/or insulin utilization. * difficulty swallowing * pregnancy * breastfeeding * For PET: research imaging-related radiation exposure that exceeds current MGH Radiology Radiation Safety Commitee guidelines. Inclusion Criteria: * BMI \< 30 * 20/20 vision or correctable to 20/20 with contact lenses * MRI compatible * For PET with Optional 150 ml Blood Sampling Only: Must weigh at least 110 lbs to minimize risks per PHRC guidelines.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| fMRI stability measures: endogenous ketones vs exogenous glucose | Within two weeks of enrollment completion | BOLD signal measurements will be obtained at baseline and during either a glycolytic, fasting, or ketotic state. We hypothesize that ketones provide the brain with greater baseline access to energy, particularly as individuals age and become insulin resistant, and that subsequent ingestion of glucose disrupts this access. We also expect that these effects will become more pronounced when metabolic demands are higher (i.e., task vs resting-state). |
| fMRI stability measures: exogenous ketones vs exogenous glucose | Within two weeks of enrollment completion | BOLD signal measurements will be obtained at baseline and following either a glucose or ketone supplement. We hypothesize that ketones provide the brain with greater baseline access to energy, particularly as individuals age and become insulin resistant, and that subsequent ingestion of glucose disrupts this access. We also expect that these effects will become more pronounced when metabolic demands are higher (i.e., task vs resting-state). |
| PET: glucose uptake and neurotransmitter production with and without ketone supplement | Within two weeks of enrollment completion | During MR/PET scans, continuous FDG infusion will be used to measure glucose uptake both during rest and task. Magnetic resonance spectroscopy will be used to measure production of neurotransmitters. In individuals who are insulin resistant, we expect to find diminished neurotransmitter levels that will then be replenished through exogenous ketones. We also hypothesize that these effects will become more pronounced when metabolic demands are higher (i.e., task vs resting-state). |
Secondary
| Measure | Time frame |
|---|---|
| Cognitive performance will be assessed and correlated with brain stability values and insulin resistance levels | Within two weeks of enrollment completion |
Countries
United States
Contacts
Primary ContactLilianne Mujica-Parodi, PhD
Backup ContactAntoine Hone-Blanchet, PhD
Outcome results
None listed