Aging, Diet Modification, Healthy, Insulin Resistance
Conditions
Keywords
insulin resistance, exogenous ketone, glucose, diet, aging
Brief summary
The investigators are studying the impact of insulin resistance on the acceleration of brain aging and testing 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. Impact of fuel (glucose in one session, ketones in the other) on brain metabolism and associated functioning is measured during each session. For Arms 1-2, the primary experimental measure is functional magnetic resonance imaging (fMRI), which is used 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, simultaneous magnetic resonance spectroscopy/positron-emission tomography (MR/PET) is used 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), the investigators 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, the investigators measure brain response to cognitive load, transitioning from resting-state to spatial reasoning through a spatial navigation video task. To assess effects of increased metabolic supply, the investigators measure brain response to glucose or ketone bolus.
Interventions
DRUGKetones
Supplement administered mid-scan.
DRUGGlucose
Supplement administered mid-scan.
Sponsors
Martinos Center for Biomedical Imaging
Stony Brook University
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 * MRI compatible * For PET with Optional 150 ml Blood Sampling Only: Must weigh at least 110 lbs to minimize risks per PHRC guidelines. * 20/20 vision or correctable to 20/20 with contact lenses
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Diet related changes in brain network stability will be assessed by fMRI BOLD measurements. | Within two weeks of enrollment completion | Changes in BOLD signal measurements will be observed between baseline and during a glycolytic, fasting, or ketotic state. |
| Glucose uptake will be measured by PET, with and without ketone supplement | Within two weeks of enrollment completion | Continuous FDG PET infusion is used as a measure of glucose uptake during rest and task, with and without the ketone supplement. |
| Neurotransmitter production with and without ketone supplement will be measured by magnetic resonance spectroscopy | Within two weeks of enrollment completion | Changes in neurotransmitter concentration under metabolic demands (i.e., task vs resting-state) with and without ketone supplement will be assessed by magnetic resonance spectroscopy. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Insulin resistance will be assessed by blood insulin level. | Within two weeks of enrollment completion | All subjects will be tested for insulin resistance prior to MRI scanning using veinous blood collected and tested for insulin during a 2-hour Oral Glucose Tolerance Test (OGTT). |
| Cognitive performance will be assessed by Mini Mental State Exam (MMSE). | Within two weeks of enrollment completion | All subjects will undergo cognitive testing prior to MRI scanning using the MMSE exam. |
| Insulin resistance will be assessed by blood glucose level. | Within two weeks of enrollment completion | All subjects will be tested for insulin resistance prior to MRI scanning using veinous blood collected and tested for glucose during a 2-hour Oral Glucose Tolerance Test (OGTT). |
| Cognitive performance will be assessed by CNS Vital Signs. | Within two weeks of enrollment completion | All subjects will undergo cognitive testing prior to MRI scanning using the CNS Vital Signs exam. |
| Insulin resistance will be assessed by HbA1C. | Within two weeks of enrollment completion | All subjects will be tested for insulin resistance prior to MRI scanning using veinous blood collected and tested for HbA1C. |
Countries
United States
Contacts
Primary ContactLilianne Mujica-Parodi, PhD
Backup ContactLiam McMahon, BA
Outcome results
None listed