xml: <clinical_study>
    <!-- This xml conforms to an XML Schema at:
      https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
    <required_header>
      <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
      <link_text>Link to the current ClinicalTrials.gov record.</link_text>
      <url>https://clinicaltrials.gov/ct2/show/NCT06000605</url>
    </required_header>
    <id_info>
      <org_study_id>Brain_substrate_switch</org_study_id>
      <nct_id>NCT06000605</nct_id>
    </id_info>
    <brief_title>Brain Substrate Switch to Ketones and Lactate</brief_title>
    <acronym>BSS</acronym>
    <official_title>Does Cerebral Substrate Switching Underlie the Beneficial Brain Adaptations of Fasting and Exercise?</official_title>
    <sponsors>
      <lead_sponsor>
        <agency>University of British Columbia</agency>
        <agency_class>Other</agency_class>
      </lead_sponsor>
      <collaborator>
        <agency>University of Otago</agency>
        <agency_class>Other</agency_class>
      </collaborator>
    </sponsors>
    <source>University of British Columbia</source>
    <oversight_info>
      <has_dmc>No</has_dmc>
      <is_fda_regulated_drug>No</is_fda_regulated_drug>
      <is_fda_regulated_device>No</is_fda_regulated_device>
      <is_us_export>No</is_us_export>
    </oversight_info>
    <brief_summary>
      <textblock>
        The brain is constantly active and energetically expensive, making up a quarter of the body's&#xD;
        energy budget despite occupying only 2% of its mass. To fuel this incessant activity, the&#xD;
        brain relies on glucose, which accommodates 99% of its metabolic needs. In most cases,&#xD;
        glucose is the ideal fuel since it is in constant surplus owing to 24-hr access to sugar-rich&#xD;
        food. However, the brain is metabolically flexible and capable of metabolizing alternative&#xD;
        fuels when glucose is scarce, or, decreasing rapidly. For example, during fasting when&#xD;
        glucose stores are dwindling, ketone bodies can supplement the brain's metabolic needs.&#xD;
        During intense exercise, when glucose stores are being rapidly depleted, lactate - a&#xD;
        byproduct of this glucose turnover - similarly acts as an alternative fuel for the brain. In&#xD;
        healthy individuals, exploiting this 'brain metabolic flexibility' may be beneficial in&#xD;
        protecting the brain from aging.&#xD;
  &#xD;
        The main question is: Does the brain substrate switch that occurs during fasting and&#xD;
        high-intensity exercise underlie the beneficial effects on the brain?&#xD;
  &#xD;
        Young, healthy participants will fast for 3 days and complete high-intensity cycling&#xD;
        exercise, each of which will induce a brain substrate switch. Participants will also be&#xD;
        passively infused with ketones (to simulate fasting) and lactate (to simulate high-intensity&#xD;
        exercise) in the fed and rested state. In doing so, the investigators will isolate the brain&#xD;
        substrate switch from the broader, pluripotent stressors that encompass fasting and exercise.&#xD;
  &#xD;
        The main outcome variables are the brain biomarkers: brain-derived neurotrophic factor (BDNF)&#xD;
        and secreted amyloid beta precursor protein (sAPPA).&#xD;
      </textblock>
    </brief_summary>
    <detailed_description>
      <textblock>
        Objectives:&#xD;
  &#xD;
        Primary:&#xD;
  &#xD;
        • To determine if brain ketone and lactate metabolism cause the beneficial neurotrophic&#xD;
        responses associated with fasting and exercise, respectively.&#xD;
  &#xD;
        Secondary:&#xD;
  &#xD;
        • To determine if fasting and exercise improve the brain's uptake of glucose, ketones and&#xD;
        lactate.&#xD;
  &#xD;
        Endpoints:&#xD;
  &#xD;
        Primary:&#xD;
  &#xD;
          -  Brain-derived neurotrophic factor (BDNF)&#xD;
  &#xD;
          -  Secreted amyloid-beta precursor protein-alpha (sAPPA)&#xD;
  &#xD;
        Secondary:&#xD;
  &#xD;
          -  Brain glucose extraction&#xD;
  &#xD;
          -  Brain ketone extraction&#xD;
  &#xD;
          -  Brain lactate extraction&#xD;
  &#xD;
          -  Increased brain glucose extraction in response to intra-nasal insulin administration&#xD;
  &#xD;
        Hypothesis:&#xD;
  &#xD;
          1. Fasting and high-intensity exercise will increase the brain's release of BDNF and sAPPA,&#xD;
             and these responses will be the same when ketones and lactate are passively infused into&#xD;
             circulation in the fed and rested state.&#xD;
  &#xD;
          2. Fasting will increase brain ketone metabolism beyond that achieved when ketones are&#xD;
             passively infused into circulation in the fed state.&#xD;
  &#xD;
          3. High-intensity exercise will increase brain lactate metabolism beyond that achieved when&#xD;
             lactate is passively infused into circulation in the rested state.&#xD;
  &#xD;
          4. High-intensity exercise will improve the brain's insulin sensitivity to glucose, as&#xD;
             shown by increase brain glucose uptake in response to intra-nasal insulin.&#xD;
  &#xD;
        Design&#xD;
  &#xD;
        This will be a repeated-measures cross-over design with participants completing two&#xD;
        conditions separated by 4-6 weeks:&#xD;
  &#xD;
          1. Fed exercise and passive infusions of lactate and ketones&#xD;
  &#xD;
          2. 72-hr fasted exercise and passive infusions of lactate and ketones&#xD;
  &#xD;
        On both visits, participants will be instrumented with arterial (radial) and venous (internal&#xD;
        jugular) catheters to quantify cerebral oxidative and substrate (glucose, ketones, lactate)&#xD;
        metabolism in response to: 1) fasting, 2) 6 minutes of high-intensity exercise, 3) a passive&#xD;
        graded infusion of ketones (to mimic fasting); and 4) a passive graded infusion of lactate&#xD;
        (to mimic exercise). Brain insulin sensitivity to glucose will be quantified in the fed and&#xD;
        fasted states before and after exercise by a one-time dose of intranasal insulin. In the fed&#xD;
        and fasted states at rest, a cerebrospinal fluid sample will be collected from the lumbar&#xD;
        spine to quantify metabolomics and the production and release of neurotrophic factors (BDNF&#xD;
        and sAPPa) from the brain.&#xD;
  &#xD;
        Trial Sites All testing will take place in the ARTs Building (Room 184) in the Centre for&#xD;
        Heart, Lung and Vascular Health research laboratory in Kelowna, British Columbia, Canada.&#xD;
  &#xD;
        Participants Sample size The investigators will collect data in 12 subjects with both sexes&#xD;
        included. A sample size calculation (power &gt;0.8, significance &lt; 0.05) based on our&#xD;
        preliminary data indicates 8 participants are required; the investigators will aim to recruit&#xD;
        12 volunteers of both sexes to better represent the population, not to investigate sex&#xD;
        differences. Written, informed consent will be obtained from participants. The investigators&#xD;
        anticipate a dropout rate of &lt;5%.&#xD;
  &#xD;
        Inclusion criteria&#xD;
  &#xD;
          -  Aged 19 - 40 years old&#xD;
  &#xD;
          -  Regularly physically active, as determined via questionnaires&#xD;
  &#xD;
        Exclusion criteria&#xD;
  &#xD;
          -  Current smokers&#xD;
  &#xD;
          -  Acute bronchial asthma, chronic obstructive airway or status asthmaticus&#xD;
  &#xD;
          -  Obese (body mass index greater than 30 kg m-2)&#xD;
  &#xD;
          -  Requiring daily prescription medications that may affect responses to exercise, e.g.,&#xD;
             anti-hypertensives, anti-arrhythmogenics, inhalers&#xD;
  &#xD;
          -  History of disease/dysfunction that could cause complication with exercise, e.g.&#xD;
             cardiovascular, respiratory, neurological or musculoskeletal diseases&#xD;
  &#xD;
          -  Irregular or absent menstrual cycle (females)&#xD;
  &#xD;
          -  Pregnant or may suspect pregnancy, or post-menopausal (females)&#xD;
  &#xD;
          -  Any unexpected adverse responses to pre-experimental exercise tests&#xD;
  &#xD;
          -  Any contraindication to a lumbar subarachnoid access&#xD;
  &#xD;
        Screening/Baseline Evaluation&#xD;
  &#xD;
        The above inclusion and exclusion criteria will be examined via a health screening&#xD;
        questionnaire and a clinical screening performed by a physician. This screening will include:&#xD;
  &#xD;
          -  Resting blood pressure,&#xD;
  &#xD;
          -  12-lead electrocardiogram,&#xD;
  &#xD;
          -  Cardiopulmonary exercise testing,&#xD;
  &#xD;
          -  Fasting blood glucose.&#xD;
  &#xD;
        Discontinuation criteria&#xD;
  &#xD;
        • Any adverse response to invasive procedures, i.e., catheterization and cerebrospinal fluid&#xD;
        sampling (please see Risks below)&#xD;
  &#xD;
        In addition to the above and as per UBC Clinical Research Ethics Board guidelines, all&#xD;
        research participants are able to withdraw from the study at any time and without reason.&#xD;
  &#xD;
        Experimental procedures&#xD;
  &#xD;
        Participants will visit the lab on two occasions. Details of the experimental visits are&#xD;
        outlined below:&#xD;
  &#xD;
          1. Fed exercise and passive infusions of lactate and ketones&#xD;
  &#xD;
             Participants will arrive to the lab 1 hr after eating a light meal of their choice.&#xD;
             Participants will lie on a bed and will be instrumented with indwelling radial artery&#xD;
             and internal jugular vein catheters. One hour after catheterizations, cerebral blood&#xD;
             flow will be measured non-invasively by Duplex ultrasound of the internal carotid and&#xD;
             vertebral arteries. Blood samples will be collected from the arterial and venous&#xD;
             circulations for resting measures of brain oxidative and substrate (glucose, ketones and&#xD;
             lactate) metabolism. A single cerebrospinal fluid sample will be collected from the&#xD;
             lumbar spine between L4 and L5. This procedure will be performed by a highly trained&#xD;
             physician who uses these techniques routinely for patient care on a near daily basis.&#xD;
             Thereafter, the primary ketone, beta-hydroxybutyrate (Bhb), will be infused via an&#xD;
             antecubital (arm) vein in a stepwise manner to induce circulating concentrations of 1, 3&#xD;
             and 5 mmol/L. Following a complete recovery, i.e., Bhb concentration return to resting&#xD;
             values, intravenous lactate will be infused in a stepwise manner to induce circulating&#xD;
             concentrations of 5, 10 and 15 mmol/L. Following a complete recovery of blood lactate&#xD;
             levels, an intravenous combined infusion (Bhb and lactate) will be administered to&#xD;
             induce circulating concentrations of 3 and 10 mmol/L, respectively. Participants will&#xD;
             then be given a light standardized meal and 1 hour to rest and digest. Lastly,&#xD;
             participants will self-administer a single-dose of intranasal insulin before and after&#xD;
             completing 6-minutes of high-intensity cycling intervals. After the final dose of&#xD;
             intranasal insulin, participants will be de-instrumented marking the end of the visit.&#xD;
             The total time for this visit is estimated to be 3-4 hours.&#xD;
  &#xD;
          2. 72-hr fasted exercise and passive infusions of lactate and ketones&#xD;
  &#xD;
        This visit is identical to condition 1, except that participants will arrive at the lab 72 hr&#xD;
        fasted and will not be provided with a light meal until completion of all experimental&#xD;
        procedures. Prior to initiating the fast, participants will be equipped with a continuous&#xD;
        glucose monitor so that the researchers can track their blood glucose during the fast. As&#xD;
        such, the total time for this visit is also estimated to be 3-4 hours.&#xD;
  &#xD;
        High-intensity exercise protocol. Participants will complete six 40-s bouts of cycling at a&#xD;
        work rate that elicits 100% maximal aerobic power (V̇O2max) followed by 20 s of active&#xD;
        recovery at 25% VO2max. The investigators have shown this exercise bout to increase lactate&#xD;
        &gt;5-fold in both the fed and fasted state.&#xD;
  &#xD;
        Randomization of conditions. The order of conditions, i.e., fed or fasted, will be&#xD;
        randomized. It is impossible to blind the participants to the fed and fasted conditions since&#xD;
        fasting requires abstaining for eating prior to visiting the lab. Researchers will not be&#xD;
        blinded because they will be monitoring the subjects while they are fasting prior to visiting&#xD;
        the lab.&#xD;
      </textblock>
    </detailed_description>
    <overall_status>Not yet recruiting</overall_status>
    <start_date type="Anticipated">October 1, 2023</start_date>
    <completion_date type="Anticipated">January 1, 2024</completion_date>
    <primary_completion_date type="Anticipated">January 1, 2024</primary_completion_date>
    <phase>N/A</phase>
    <study_type>Interventional</study_type>
    <has_expanded_access>No</has_expanded_access>
    <study_design_info>
      <allocation>Randomized</allocation>
      <intervention_model>Crossover Assignment</intervention_model>
      <intervention_model_description>Participants will complete both arms: 1) fasted and 2) fed.</intervention_model_description>
      <primary_purpose>Basic Science</primary_purpose>
      <masking>Single (Investigator)</masking>
      <masking_description>The participant will not be blinded because they must consciously adhere to study requirements, i.e., fasting for 3 days. The investigators will be blinded to the fasting and fed conditions.</masking_description>
    </study_design_info>
    <primary_outcome>
      <measure>Brain-derived neurotrophic factor, secreted amyloid beta precursor protein</measure>
      <time_frame>Data collected at rest, during graded infusions of lactate and ketones, pre- and post- 6 minutes of high-intensity cycling exercise</time_frame>
      <description>Biomarker to index neuroplasticity and resilience</description>
    </primary_outcome>
    <secondary_outcome>
      <measure>Brain substrate metabolism</measure>
      <time_frame>Data collected at rest, during graded infusions of lactate and ketones, pre- and post- 6 minutes of high-intensity cycling exercise</time_frame>
      <description>The brain's turnover of glucose, beta-hydroxybutyrate (ketone body) and lactate</description>
    </secondary_outcome>
    <number_of_arms>2</number_of_arms>
    <enrollment type="Anticipated">12</enrollment>
    <condition>Metabolic Diseases</condition>
    <condition>Aging Problems</condition>
    <arm_group>
      <arm_group_label>Fed</arm_group_label>
      <arm_group_type>Active Comparator</arm_group_type>
      <description>Exercise and passive infusions of ketones and lactate in the fed state. Participants will be fed a small meal in the middle of the protocol, also.</description>
    </arm_group>
    <arm_group>
      <arm_group_label>Fasted</arm_group_label>
      <arm_group_type>Experimental</arm_group_type>
      <description>Exercise and passive infusions of ketones and lactate in the fasted state. Participants will be required to fast for 72 hours prior to arriving to the lab for this testing arm.</description>
    </arm_group>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Fed</intervention_name>
      <description>Participants will eat a light meal prior to testing and be fed a light meal during testing.</description>
      <arm_group_label>Fed</arm_group_label>
    </intervention>
    <intervention>
      <intervention_type>Other</intervention_type>
      <intervention_name>Fasted</intervention_name>
      <description>Participants will completely abstain from calories for 72 hours prior to testing and not receive any calories during testing.</description>
      <arm_group_label>Fasted</arm_group_label>
    </intervention>
    <eligibility>
      <criteria>
        <textblock>
          Inclusion Criteria:&#xD;
  &#xD;
            -  Regularly physically active, as determined via questionnaires&#xD;
  &#xD;
          Exclusion Criteria:&#xD;
  &#xD;
            -  Current smokers&#xD;
  &#xD;
            -  Acute bronchial asthma, chronic obstructive airway or status asthmaticus&#xD;
  &#xD;
            -  Obese (body mass index greater than 30 kg m-2)&#xD;
  &#xD;
            -  Requiring daily prescription medications that may affect responses to exercise, e.g.,&#xD;
               anti-hypertensives, anti-arrhythmogenics, inhalers&#xD;
  &#xD;
            -  History of disease/dysfunction that could cause complication with exercise, e.g.&#xD;
               cardiovascular, respiratory, neurological or musculoskeletal diseases&#xD;
  &#xD;
            -  Irregular or absent menstrual cycle (females)&#xD;
  &#xD;
            -  Pregnant or may suspect pregnancy, or post-menopausal (females)&#xD;
  &#xD;
            -  Any unexpected adverse responses to pre-experimental exercise tests&#xD;
  &#xD;
            -  Any contraindication to a lumbar subarachnoid access&#xD;
        </textblock>
      </criteria>
      <gender>All</gender>
      <minimum_age>19 Years</minimum_age>
      <maximum_age>40 Years</maximum_age>
      <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
    </eligibility>
    <overall_contact>
      <last_name>Travis D Gibbons, PhD</last_name>
      <phone>7785836976</phone>
      <email>travis.gibbons@ubc.ca</email>
    </overall_contact>
    <overall_contact_backup>
      <last_name>Philip N Ainslie, PhD</last_name>
      <phone>2508078089</phone>
      <email>phil.ainslie@ubc.ca</email>
    </overall_contact_backup>
    <location>
      <facility>
        <name>University of British Columbia - Okanagan Campus</name>
        <address>
          <city>Kelowna</city>
          <state>British Columbia</state>
          <zip>V1V1V7</zip>
          <country>Canada</country>
        </address>
      </facility>
    </location>
    <location_countries>
      <country>Canada</country>
    </location_countries>
    <verification_date>August 2023</verification_date>
    <study_first_submitted>August 14, 2023</study_first_submitted>
    <study_first_submitted_qc>August 14, 2023</study_first_submitted_qc>
    <study_first_posted type="Actual">August 21, 2023</study_first_posted>
    <last_update_submitted>August 22, 2023</last_update_submitted>
    <last_update_submitted_qc>August 22, 2023</last_update_submitted_qc>
    <last_update_posted type="Actual">August 24, 2023</last_update_posted>
    <responsible_party>
      <responsible_party_type>Principal Investigator</responsible_party_type>
      <investigator_affiliation>University of British Columbia</investigator_affiliation>
      <investigator_full_name>Phil Ainslie</investigator_full_name>
      <investigator_title>Professor</investigator_title>
    </responsible_party>
    <keyword>brain</keyword>
    <keyword>BDNF</keyword>
    <keyword>metabolism</keyword>
    <keyword>ketones</keyword>
    <keyword>lactate</keyword>
    <condition_browse>
      <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
      <mesh_term>Metabolic Diseases</mesh_term>
    </condition_browse>
    <patient_data>
      <sharing_ipd>No</sharing_ipd>
      <ipd_description>No personal data will be made available publicly or to other researchers.</ipd_description>
    </patient_data>
    <!-- Results have not yet been posted for this study                                          -->
  </clinical_study>
  
  
text: download date: ClinicalTrials.gov processed this data on September 20, 2023
  link text: Link to the current ClinicalTrials.gov record.
  url: https://clinicaltrials.gov/ct2/show/NCT06000605
  org study id: Brain_substrate_switch
  nct id: NCT06000605
  lead sponsor: 
  collaborator: 
  has dmc: No
  is fda regulated drug: No
  is fda regulated device: No
  is us export: No
  The brain is constantly active and energetically expensive, making up a quarter of the body's
        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 brain's 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).
  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 brain's 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 brain's 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 brain's 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 >0.8, significance < 0.05) 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, e.g.,
             anti-hypertensives, anti-arrhythmogenics, inhalers
  
          -  History of disease/dysfunction that could cause complication with exercise, e.g.
             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
  
        Screening/Baseline 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, i.e., 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 mmol/L. Following a complete recovery, i.e., Bhb concentration return to resting
             values, intravenous lactate will be infused in a stepwise manner to induce circulating
             concentrations of 5, 10 and 15 mmol/L. 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 mmol/L, 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 (V̇O2max) 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, i.e., 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.
  allocation: Randomized
  intervention model: Crossover Assignment
  intervention model description: Participants will complete both arms: 1) fasted and 2) fed.
  primary purpose: Basic Science
  masking: Single (Investigator)
  masking description: The participant will not be blinded because they must consciously adhere to study requirements, i.e., fasting for 3 days. The investigators will be blinded to the fasting and fed conditions.
  measure: Brain-derived neurotrophic factor, secreted amyloid beta precursor protein
  time frame: Data collected at rest, during graded infusions of lactate and ketones, pre- and post- 6 minutes of high-intensity cycling exercise
  description: Biomarker to index neuroplasticity and resilience
  measure: Brain substrate metabolism
  time frame: Data collected at rest, during graded infusions of lactate and ketones, pre- and post- 6 minutes of high-intensity cycling exercise
  description: The brain's turnover of glucose, beta-hydroxybutyrate (ketone body) and lactate
  arm group label: Fed
  arm group type: Active Comparator
  description: Exercise and passive infusions of ketones and lactate in the fed state. Participants will be fed a small meal in the middle of the protocol, also.
  arm group label: Fasted
  arm group type: Experimental
  description: Exercise and passive infusions of ketones and lactate in the fasted state. Participants will be required to fast for 72 hours prior to arriving to the lab for this testing arm.
  intervention type: Other
  intervention name: Fed
  description: Participants will eat a light meal prior to testing and be fed a light meal during testing.
  arm group label: Fed
  intervention type: Other
  intervention name: Fasted
  description: Participants will completely abstain from calories for 72 hours prior to testing and not receive any calories during testing.
  arm group label: Fasted
  criteria: 
  gender: All
  minimum age: 19 Years
  maximum age: 40 Years
  healthy volunteers: Accepts Healthy Volunteers
  last name: Travis D Gibbons, PhD
  phone: 7785836976
  email: travis.gibbons@ubc.ca
  last name: Philip N Ainslie, PhD
  phone: 2508078089
  email: phil.ainslie@ubc.ca
  facility: 
  country: Canada
  responsible party type: Principal Investigator
  investigator affiliation: University of British Columbia
  investigator full name: Phil Ainslie
  investigator title: Professor
  mesh term: Metabolic Diseases
  sharing ipd: No
  ipd description: No personal data will be made available publicly or to other researchers.