Ignite Creation Date:
2024-05-06 @ 7:24 PM
Last Modification Date:
2024-10-26 @ 3:06 PM
Study NCT ID:
NCT06000605
Status:
NOT_YET_RECRUITING
Last Update Posted:
2023-08-24
First Post:
2023-08-14
Brief Title:
Brain Substrate Switch to Ketones and Lactate
Sponsor:
University of British Columbia
Organization:
University of British Columbia
Study Overview
Official Title:
Does Cerebral Substrate Switching Underlie the Beneficial Brain Adaptations of Fasting and Exercise
Status:
NOT_YET_RECRUITING
Status Verified Date:
2023-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BSS
Brief Summary:
The brain is constantly active and energetically expensive making up a quarter of the bodys energy budget despite occupying only 2 of its mass To fuel this incessant activity the brain relies on glucose which accommodates 99 of its metabolic needs In most cases glucose is the ideal fuel since it is in constant surplus owing to 24-hr access to sugar-rich food However the brain is metabolically flexible and capable of metabolizing alternative fuels when glucose is scarce or decreasing rapidly For example during fasting when glucose stores are dwindling ketone bodies can supplement the brains metabolic needs During intense exercise when glucose stores are being rapidly depleted lactate - a byproduct of this glucose turnover - similarly acts as an alternative fuel for the brain In healthy individuals exploiting this brain metabolic flexibility may be beneficial in protecting the brain from aging
The main question is Does the brain substrate switch that occurs during fasting and high-intensity exercise underlie the beneficial effects on the brain
Young healthy participants will fast for 3 days and complete high-intensity cycling exercise each of which will induce a brain substrate switch Participants will also be passively infused with ketones to simulate fasting and lactate to simulate high-intensity exercise in the fed and rested state In doing so the investigators will isolate the brain substrate switch from the broader pluripotent stressors that encompass fasting and exercise
The main outcome variables are the brain biomarkers brain-derived neurotrophic factor BDNF and secreted amyloid beta precursor protein sAPPA
The main question is Does the brain substrate switch that occurs during fasting and high-intensity exercise underlie the beneficial effects on the brain
Young healthy participants will fast for 3 days and complete high-intensity cycling exercise each of which will induce a brain substrate switch Participants will also be passively infused with ketones to simulate fasting and lactate to simulate high-intensity exercise in the fed and rested state In doing so the investigators will isolate the brain substrate switch from the broader pluripotent stressors that encompass fasting and exercise
The main outcome variables are the brain biomarkers brain-derived neurotrophic factor BDNF and secreted amyloid beta precursor protein sAPPA
Detailed Description:
Objectives
Primary
To determine if brain ketone and lactate metabolism cause the beneficial neurotrophic responses associated with fasting and exercise respectively
Secondary
To determine if fasting and exercise improve the brains uptake of glucose ketones and lactate
Endpoints
Primary
Brain-derived neurotrophic factor BDNF
Secreted amyloid-beta precursor protein-alpha sAPPA
Secondary
Brain glucose extraction
Brain ketone extraction
Brain lactate extraction
Increased brain glucose extraction in response to intra-nasal insulin administration
Hypothesis
1 Fasting and high-intensity exercise will increase the brains release of BDNF and sAPPA and these responses will be the same when ketones and lactate are passively infused into circulation in the fed and rested state
2 Fasting will increase brain ketone metabolism beyond that achieved when ketones are passively infused into circulation in the fed state
3 High-intensity exercise will increase brain lactate metabolism beyond that achieved when lactate is passively infused into circulation in the rested state
4 High-intensity exercise will improve the brains insulin sensitivity to glucose as shown by increase brain glucose uptake in response to intra-nasal insulin
Design
This will be a repeated-measures cross-over design with participants completing two conditions separated by 4-6 weeks
1 Fed exercise and passive infusions of lactate and ketones
2 72-hr fasted exercise and passive infusions of lactate and ketones
On both visits participants will be instrumented with arterial radial and venous internal jugular catheters to quantify cerebral oxidative and substrate glucose ketones lactate metabolism in response to 1 fasting 2 6 minutes of high-intensity exercise 3 a passive graded infusion of ketones to mimic fasting and 4 a passive graded infusion of lactate to mimic exercise Brain insulin sensitivity to glucose will be quantified in the fed and fasted states before and after exercise by a one-time dose of intranasal insulin In the fed and fasted states at rest a cerebrospinal fluid sample will be collected from the lumbar spine to quantify metabolomics and the production and release of neurotrophic factors BDNF and sAPPa from the brain
Trial Sites All testing will take place in the ARTs Building Room 184 in the Centre for Heart Lung and Vascular Health research laboratory in Kelowna British Columbia Canada
Participants Sample size The investigators will collect data in 12 subjects with both sexes included A sample size calculation power 08 significance 005 based on our preliminary data indicates 8 participants are required the investigators will aim to recruit 12 volunteers of both sexes to better represent the population not to investigate sex differences Written informed consent will be obtained from participants The investigators anticipate a dropout rate of 5
Inclusion criteria
Aged 19 - 40 years old
Regularly physically active as determined via questionnaires
Exclusion criteria
Current smokers
Acute bronchial asthma chronic obstructive airway or status asthmaticus
Obese body mass index greater than 30 kg m-2
Requiring daily prescription medications that may affect responses to exercise eg anti-hypertensives anti-arrhythmogenics inhalers
History of diseasedysfunction that could cause complication with exercise eg cardiovascular respiratory neurological or musculoskeletal diseases
Irregular or absent menstrual cycle females
Pregnant or may suspect pregnancy or post-menopausal females
Any unexpected adverse responses to pre-experimental exercise tests
Any contraindication to a lumbar subarachnoid access
ScreeningBaseline Evaluation
The above inclusion and exclusion criteria will be examined via a health screening questionnaire and a clinical screening performed by a physician This screening will include
Resting blood pressure
12-lead electrocardiogram
Cardiopulmonary exercise testing
Fasting blood glucose
Discontinuation criteria
Any adverse response to invasive procedures ie catheterization and cerebrospinal fluid sampling please see Risks below
In addition to the above and as per UBC Clinical Research Ethics Board guidelines all research participants are able to withdraw from the study at any time and without reason
Experimental procedures
Participants will visit the lab on two occasions Details of the experimental visits are outlined below
1 Fed exercise and passive infusions of lactate and ketones
Participants will arrive to the lab 1 hr after eating a light meal of their choice Participants will lie on a bed and will be instrumented with indwelling radial artery and internal jugular vein catheters One hour after catheterizations cerebral blood flow will be measured non-invasively by Duplex ultrasound of the internal carotid and vertebral arteries Blood samples will be collected from the arterial and venous circulations for resting measures of brain oxidative and substrate glucose ketones and lactate metabolism A single cerebrospinal fluid sample will be collected from the lumbar spine between L4 and L5 This procedure will be performed by a highly trained physician who uses these techniques routinely for patient care on a near daily basis Thereafter the primary ketone beta-hydroxybutyrate Bhb will be infused via an antecubital arm vein in a stepwise manner to induce circulating concentrations of 1 3 and 5 mmolL Following a complete recovery ie Bhb concentration return to resting values intravenous lactate will be infused in a stepwise manner to induce circulating concentrations of 5 10 and 15 mmolL Following a complete recovery of blood lactate levels an intravenous combined infusion Bhb and lactate will be administered to induce circulating concentrations of 3 and 10 mmolL respectively Participants will then be given a light standardized meal and 1 hour to rest and digest Lastly participants will self-administer a single-dose of intranasal insulin before and after completing 6-minutes of high-intensity cycling intervals After the final dose of intranasal insulin participants will be de-instrumented marking the end of the visit The total time for this visit is estimated to be 3-4 hours
2 72-hr fasted exercise and passive infusions of lactate and ketones
This visit is identical to condition 1 except that participants will arrive at the lab 72 hr fasted and will not be provided with a light meal until completion of all experimental procedures Prior to initiating the fast participants will be equipped with a continuous glucose monitor so that the researchers can track their blood glucose during the fast As such the total time for this visit is also estimated to be 3-4 hours
High-intensity exercise protocol Participants will complete six 40-s bouts of cycling at a work rate that elicits 100 maximal aerobic power VO2max followed by 20 s of active recovery at 25 VO2max The investigators have shown this exercise bout to increase lactate 5-fold in both the fed and fasted state
Randomization of conditions The order of conditions ie fed or fasted will be randomized It is impossible to blind the participants to the fed and fasted conditions since fasting requires abstaining for eating prior to visiting the lab Researchers will not be blinded because they will be monitoring the subjects while they are fasting prior to visiting the lab
Primary
To determine if brain ketone and lactate metabolism cause the beneficial neurotrophic responses associated with fasting and exercise respectively
Secondary
To determine if fasting and exercise improve the brains uptake of glucose ketones and lactate
Endpoints
Primary
Brain-derived neurotrophic factor BDNF
Secreted amyloid-beta precursor protein-alpha sAPPA
Secondary
Brain glucose extraction
Brain ketone extraction
Brain lactate extraction
Increased brain glucose extraction in response to intra-nasal insulin administration
Hypothesis
1 Fasting and high-intensity exercise will increase the brains release of BDNF and sAPPA and these responses will be the same when ketones and lactate are passively infused into circulation in the fed and rested state
2 Fasting will increase brain ketone metabolism beyond that achieved when ketones are passively infused into circulation in the fed state
3 High-intensity exercise will increase brain lactate metabolism beyond that achieved when lactate is passively infused into circulation in the rested state
4 High-intensity exercise will improve the brains insulin sensitivity to glucose as shown by increase brain glucose uptake in response to intra-nasal insulin
Design
This will be a repeated-measures cross-over design with participants completing two conditions separated by 4-6 weeks
1 Fed exercise and passive infusions of lactate and ketones
2 72-hr fasted exercise and passive infusions of lactate and ketones
On both visits participants will be instrumented with arterial radial and venous internal jugular catheters to quantify cerebral oxidative and substrate glucose ketones lactate metabolism in response to 1 fasting 2 6 minutes of high-intensity exercise 3 a passive graded infusion of ketones to mimic fasting and 4 a passive graded infusion of lactate to mimic exercise Brain insulin sensitivity to glucose will be quantified in the fed and fasted states before and after exercise by a one-time dose of intranasal insulin In the fed and fasted states at rest a cerebrospinal fluid sample will be collected from the lumbar spine to quantify metabolomics and the production and release of neurotrophic factors BDNF and sAPPa from the brain
Trial Sites All testing will take place in the ARTs Building Room 184 in the Centre for Heart Lung and Vascular Health research laboratory in Kelowna British Columbia Canada
Participants Sample size The investigators will collect data in 12 subjects with both sexes included A sample size calculation power 08 significance 005 based on our preliminary data indicates 8 participants are required the investigators will aim to recruit 12 volunteers of both sexes to better represent the population not to investigate sex differences Written informed consent will be obtained from participants The investigators anticipate a dropout rate of 5
Inclusion criteria
Aged 19 - 40 years old
Regularly physically active as determined via questionnaires
Exclusion criteria
Current smokers
Acute bronchial asthma chronic obstructive airway or status asthmaticus
Obese body mass index greater than 30 kg m-2
Requiring daily prescription medications that may affect responses to exercise eg anti-hypertensives anti-arrhythmogenics inhalers
History of diseasedysfunction that could cause complication with exercise eg cardiovascular respiratory neurological or musculoskeletal diseases
Irregular or absent menstrual cycle females
Pregnant or may suspect pregnancy or post-menopausal females
Any unexpected adverse responses to pre-experimental exercise tests
Any contraindication to a lumbar subarachnoid access
ScreeningBaseline Evaluation
The above inclusion and exclusion criteria will be examined via a health screening questionnaire and a clinical screening performed by a physician This screening will include
Resting blood pressure
12-lead electrocardiogram
Cardiopulmonary exercise testing
Fasting blood glucose
Discontinuation criteria
Any adverse response to invasive procedures ie catheterization and cerebrospinal fluid sampling please see Risks below
In addition to the above and as per UBC Clinical Research Ethics Board guidelines all research participants are able to withdraw from the study at any time and without reason
Experimental procedures
Participants will visit the lab on two occasions Details of the experimental visits are outlined below
1 Fed exercise and passive infusions of lactate and ketones
Participants will arrive to the lab 1 hr after eating a light meal of their choice Participants will lie on a bed and will be instrumented with indwelling radial artery and internal jugular vein catheters One hour after catheterizations cerebral blood flow will be measured non-invasively by Duplex ultrasound of the internal carotid and vertebral arteries Blood samples will be collected from the arterial and venous circulations for resting measures of brain oxidative and substrate glucose ketones and lactate metabolism A single cerebrospinal fluid sample will be collected from the lumbar spine between L4 and L5 This procedure will be performed by a highly trained physician who uses these techniques routinely for patient care on a near daily basis Thereafter the primary ketone beta-hydroxybutyrate Bhb will be infused via an antecubital arm vein in a stepwise manner to induce circulating concentrations of 1 3 and 5 mmolL Following a complete recovery ie Bhb concentration return to resting values intravenous lactate will be infused in a stepwise manner to induce circulating concentrations of 5 10 and 15 mmolL Following a complete recovery of blood lactate levels an intravenous combined infusion Bhb and lactate will be administered to induce circulating concentrations of 3 and 10 mmolL respectively Participants will then be given a light standardized meal and 1 hour to rest and digest Lastly participants will self-administer a single-dose of intranasal insulin before and after completing 6-minutes of high-intensity cycling intervals After the final dose of intranasal insulin participants will be de-instrumented marking the end of the visit The total time for this visit is estimated to be 3-4 hours
2 72-hr fasted exercise and passive infusions of lactate and ketones
This visit is identical to condition 1 except that participants will arrive at the lab 72 hr fasted and will not be provided with a light meal until completion of all experimental procedures Prior to initiating the fast participants will be equipped with a continuous glucose monitor so that the researchers can track their blood glucose during the fast As such the total time for this visit is also estimated to be 3-4 hours
High-intensity exercise protocol Participants will complete six 40-s bouts of cycling at a work rate that elicits 100 maximal aerobic power VO2max followed by 20 s of active recovery at 25 VO2max The investigators have shown this exercise bout to increase lactate 5-fold in both the fed and fasted state
Randomization of conditions The order of conditions ie fed or fasted will be randomized It is impossible to blind the participants to the fed and fasted conditions since fasting requires abstaining for eating prior to visiting the lab Researchers will not be blinded because they will be monitoring the subjects while they are fasting prior to visiting the lab
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
False
Is an FDA AA801 Violation?:
None