<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/NCT02971098</url>
  </required_header>
  <id_info>
    <org_study_id>84354</org_study_id>
    <nct_id>NCT02971098</nct_id>
  </id_info>
  <brief_title>Mechanisms of Skeletal Muscle Insulin Resistance in Older Adults</brief_title>
  <official_title>Novel Molecular Mechanisms of Skeletal Muscle Insulin, Resistance if Physically Inactive Older Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Utah</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Utah</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The over-65 population is not only increasing at an alarming rate, but because six out of 10&#xD;
      will be managing more than one chronic condition by 2030, they will make up a much greater&#xD;
      proportion of hospitalizations than ever before. Hospitalizations for disease, injury, and/or&#xD;
      surgery in this group are likely to impair physical mobility and, therefore, the older adults&#xD;
      capacity to be physically active both during hospitalization and beyond. The resulting&#xD;
      sedentary lifestyle is likely to be accepted as the &quot;new normal&quot;, ultimately increasing the&#xD;
      risk of skeletal muscle and metabolic dysfunction (e.g. impaired glucose disposal, insulin&#xD;
      resistance). These devastating outcomes are neither inevitable nor necessary if prevented&#xD;
      with an appropriate mechanism-based intervention.&#xD;
&#xD;
      A novel mechanism that may contribute to physical inactivity-induced insulin resistance is&#xD;
      accumulation of inflammation and ceramide within skeletal muscle. Of interest, increased&#xD;
      skeletal muscle inflammation and ceramide has been tied to various metabolic disturbances&#xD;
      such as diabetes and insulin resistance. However, it is currently unknown if skeletal muscle&#xD;
      inflammation and ceramide are a key mechanism associated with insulin resistance due to&#xD;
      physical inactivity in older adults.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The investigator team will recruit younger and older (N=8; 18-35y and 60-85 yrs) male and&#xD;
      female adults recruited in the Salt Lake City area.&#xD;
&#xD;
      The investigator team will then schedule separate visits for Strength, Power and Physical&#xD;
      Function and the separate visits for Lean Mass and OGTT measurements (see description below).&#xD;
&#xD;
        1. Lean Mass, oral glucose tolerance test , Strength, Power, Exercise Testing and Physical&#xD;
           Function Measurements. Lean mass assessment via dual-energy X-ray absorptiometry (DXA),&#xD;
           ultra sound and peripheral quantitative computed tomography (pQCT) will be assessed in&#xD;
           the center for clinical and translational sciences (CCTS) while knee extensor isometric&#xD;
           strength, power and physical function testing will be conducted in the Skeletal muscle&#xD;
           exercise research facility (SMERF) laboratory (520 Wakara Way). These endpoints will be&#xD;
           considered secondary objectives to determine relationships with insulin sensitivity and&#xD;
           muscle cell signaling events. These tests will occur within one week before the reduced&#xD;
           activity experiment and will be repeated after completing the reduced activity period&#xD;
           and after exercise training. For lean mass assessment, subjects will be tested in the&#xD;
           morning after an overnight fast prior to the DXA scan. Isometric strength will be&#xD;
           assessed in both legs with a maximal voluntary isometric contraction effort (at a 600&#xD;
           knee angle) developed by the knee extensors (quadriceps) and plantar/dorsi flexor&#xD;
           muscles on a dynamometer. For lower extremity extension power testing a Nottingham power&#xD;
           rig will be used. The following battery of functional performance tests will be used:&#xD;
           Stair ascent/descent time, six-minute walk distance, 50 foot walk time, and the timed up&#xD;
           and go test. All tests are tests that we frequently and safely perform in older&#xD;
           individuals.&#xD;
&#xD;
           Maximal oxygen consumption (exercise testing) will be measured by a metabolic cart&#xD;
           during a graded maximal exercise test on a stationary cycle ergometer. This test will be&#xD;
           performed in the CCTS under direct supervision of an exercise physiologist.&#xD;
&#xD;
        2. Physical Activity Monitoring, Dietary Record. Subjects will be fitted with an ankle Step&#xD;
           Activity Monitor in order to determine their daily level of physical activity over 7&#xD;
           days period preceding the reduced physical activity study. Additionally, a 3-day daily&#xD;
           dietary record will be self-reported before this period. The participant will be&#xD;
           properly instructed by a research team member on how to conduct this reporting and how&#xD;
           to wear the ankle activity monitor.&#xD;
&#xD;
        3. Insulin Clamp Study, Metabolic Rate and Muscle Biopsies. On a separate day, participants&#xD;
           will arrive at the CCTS fasted in the morning on Day 1 and a euglycemic-hyperinsulinemic&#xD;
           clamp study will be performed as we have done previously. The research team physician&#xD;
           will oversee the clamp procedure as he is very experienced using this method.&#xD;
&#xD;
           Metabolic rate will be determined 30 minutes before the initiation of the insulin&#xD;
           infusion and 30 minutes at the end of the insulin infusion period. Metabolic rate will&#xD;
           be determined using a indirect calorimeter housed at the CCTS. To do so, the participant&#xD;
           will be fitted with a canopy hood. The participant with breathe normally for 30 minutes&#xD;
           during the procedure. The canopy will be removed then the first muscle biopsy will&#xD;
           occur.&#xD;
&#xD;
           A vastus lateralis muscle biopsy will be sampled before and 3h after the clamp combined&#xD;
           with periodic blood sampling for measure of fasting and insulin-stimulated insulin,&#xD;
           glucose, muscle cell signaling endpoints, and specific ceramide species. Biopsies will&#xD;
           occur on opposite legs. Muscle biopsies were be performed by trained CCTS nurses as we&#xD;
           have done routinely in our bed rest studies in older adults. Muscle samples will then be&#xD;
           flash-frozen in liquid nitrogen and stored for later analysis. After the clamp&#xD;
           experiment, subjects will begin the reduced physical inactivity study which will take&#xD;
           place at the participant home.&#xD;
&#xD;
           On Day 14, the participant again will return to the CCTS following an overnight fast and&#xD;
           the insulin clamp study will be repeated in order to make comparisons to the pre insulin&#xD;
           clamp study (Day 1).&#xD;
&#xD;
        4. Reduced Physical inactivity experiment. After completion of the first insulin clamp&#xD;
           experiment (Day 1), subjects will adhere to 14-days of reduced physical activity at&#xD;
           their home as has been conduced before. The goal will be for the participant to maintain&#xD;
           no more than ~2000 steps/day as determined by a monitor that the subject will be able to&#xD;
           see and record. The investigators will inform the participant that their normal diet&#xD;
           should remain the same. As mentioned above, on day 7, the participant will return for a&#xD;
           DXA scan, OGTT's and thigh muscle biopsies. Also mentioned above, on Day 14, after an&#xD;
           overnight fast, a second insulin clamp study coupled with muscle biopsies will be&#xD;
           conducted as detailed above in the CCTS. Lean mass, strength, power, and physical&#xD;
           function measurements will be re-assessed on a later day following the reduced activity&#xD;
           study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2016</start_date>
  <completion_date type="Actual">December 17, 2019</completion_date>
  <primary_completion_date type="Actual">December 17, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>2 weeks of physical inactivity</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Steady state glucose infusion rate</measure>
    <time_frame>percent change from baseline at 14 days</time_frame>
    <description>Glucose infusion rate will be determined by a hyperinsulinemic-euglycemic clamp</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>lean mass</measure>
    <time_frame>percent change from baseline at 14 days</time_frame>
    <description>lean mass will be determined by DXA scan</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Reduced Physical Activity</condition>
  <arm_group>
    <arm_group_label>Reduced activity</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>participants will undergo a reduced physical activity period (75% step reduction) for two weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Reduced activity</intervention_name>
    <description>Participants will reduced their physical activity level to approximately 2000 steps or 75% of their normal activity levels.</description>
    <arm_group_label>Reduced activity</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age between 60-85 yrs&#xD;
&#xD;
          -  Ability to sign informed consent&#xD;
&#xD;
          -  Free-living, prior to admission&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The participant must not have participated in any previous research studies utilizing&#xD;
             ionizing radiation (either radioisotopes or diagnostic x-rays) during the past 12&#xD;
             months in order to participate in this study. Cardiac abnormalities considered&#xD;
             exclusionary by the study physician&#xD;
&#xD;
          -  Uncontrolled endocrine or metabolic disease (e.g., hypo/hyperthyroidism, diabetes)&#xD;
&#xD;
          -  History of kidney disease or failure&#xD;
&#xD;
          -  Vascular disease or risk factors of peripheral atherosclerosis. (e.g., uncontrolled&#xD;
             hypertension, obesity, diabetes, hypercholesterolemia &gt; 250 mg/dl, claudication or&#xD;
             evidence of venous or arterial insufficiency upon palpitation of femoral, popliteal&#xD;
             and pedal arteries)&#xD;
&#xD;
          -  Risk of deep vein thrombosis (DVT) including family history of thrombophilia, DVT,&#xD;
             pulmonary emboli, myeloproliferative diseases including polycythemia (Hb&gt;18 g/dL) or&#xD;
             thrombocytosis (platelets&gt;400x103/mL), and connective tissue diseases (positive lupus&#xD;
             anticoagulant), hyperhomocysteinemia, deficiencies of factor V Leiden, proteins S and&#xD;
             C, and antithrombin III&#xD;
&#xD;
          -  Use of anticoagulant therapy (e.g., Coumadin, heparin)&#xD;
&#xD;
          -  Elevated systolic pressure &gt;150 or a diastolic blood pressure &gt; 100&#xD;
&#xD;
          -  Implanted electronic devices (e.g., pacemakers, electronic infusion pumps,&#xD;
             stimulators)&#xD;
&#xD;
          -  Cancer or history of successfully treated cancer (less than 1 year) other than basal&#xD;
             cell carcinoma&#xD;
&#xD;
          -  Currently on a weight-loss diet or body mass index &gt; 30 kg/m2&#xD;
&#xD;
          -  Recent anabolic or corticosteroids use (within 3 months)&#xD;
&#xD;
          -  History of stroke with motor disability&#xD;
&#xD;
          -  A recent history (&lt;12 months) of GI bleed&#xD;
&#xD;
          -  Exercise training (&gt;2 session of moderate to high intensity aerobic or resistance&#xD;
             exercise/week)&#xD;
&#xD;
          -  History of liver disease&#xD;
&#xD;
          -  History of respiratory disease (acute upper respiratory infection, history of chronic&#xD;
             lung disease)&#xD;
&#xD;
          -  Prior history of Heparin-Induced Thrombocytopenia (HIT)&#xD;
&#xD;
          -  Any other condition or event considered exclusionary by the PI and faculty physician&#xD;
&#xD;
          -  An HbA1c value at or greater than 6.5%&#xD;
&#xD;
          -  Subjects may not participate if they have utilized ionizing radiation (either&#xD;
             radioisotopes or diagnostic x-rays) during the past 12 months&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>85 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Micah J Drummond, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Utah</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Utah</name>
      <address>
        <city>Salt Lake City</city>
        <state>Utah</state>
        <zip>84108</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>November 15, 2016</study_first_submitted>
  <study_first_submitted_qc>November 17, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <last_update_submitted>June 17, 2022</last_update_submitted>
  <last_update_submitted_qc>June 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Utah</investigator_affiliation>
    <investigator_full_name>Micah Drummond</investigator_full_name>
    <investigator_title>Ph.D.</investigator_title>
  </responsible_party>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


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/NCT02971098
org study id: 84354
nct id: NCT02971098
lead sponsor: 
has dmc: Yes
The over-65 population is not only increasing at an alarming rate, but because six out of 10
      will be managing more than one chronic condition by 2030, they will make up a much greater
      proportion of hospitalizations than ever before. Hospitalizations for disease, injury, and/or
      surgery in this group are likely to impair physical mobility and, therefore, the older adults
      capacity to be physically active both during hospitalization and beyond. The resulting
      sedentary lifestyle is likely to be accepted as the "new normal", ultimately increasing the
      risk of skeletal muscle and metabolic dysfunction (e.g. impaired glucose disposal, insulin
      resistance). These devastating outcomes are neither inevitable nor necessary if prevented
      with an appropriate mechanism-based intervention.

      A novel mechanism that may contribute to physical inactivity-induced insulin resistance is
      accumulation of inflammation and ceramide within skeletal muscle. Of interest, increased
      skeletal muscle inflammation and ceramide has been tied to various metabolic disturbances
      such as diabetes and insulin resistance. However, it is currently unknown if skeletal muscle
      inflammation and ceramide are a key mechanism associated with insulin resistance due to
      physical inactivity in older adults.
The investigator team will recruit younger and older (N=8; 18-35y and 60-85 yrs) male and
      female adults recruited in the Salt Lake City area.

      The investigator team will then schedule separate visits for Strength, Power and Physical
      Function and the separate visits for Lean Mass and OGTT measurements (see description below).

        1. Lean Mass, oral glucose tolerance test , Strength, Power, Exercise Testing and Physical
           Function Measurements. Lean mass assessment via dual-energy X-ray absorptiometry (DXA),
           ultra sound and peripheral quantitative computed tomography (pQCT) will be assessed in
           the center for clinical and translational sciences (CCTS) while knee extensor isometric
           strength, power and physical function testing will be conducted in the Skeletal muscle
           exercise research facility (SMERF) laboratory (520 Wakara Way). These endpoints will be
           considered secondary objectives to determine relationships with insulin sensitivity and
           muscle cell signaling events. These tests will occur within one week before the reduced
           activity experiment and will be repeated after completing the reduced activity period
           and after exercise training. For lean mass assessment, subjects will be tested in the
           morning after an overnight fast prior to the DXA scan. Isometric strength will be
           assessed in both legs with a maximal voluntary isometric contraction effort (at a 600
           knee angle) developed by the knee extensors (quadriceps) and plantar/dorsi flexor
           muscles on a dynamometer. For lower extremity extension power testing a Nottingham power
           rig will be used. The following battery of functional performance tests will be used:
           Stair ascent/descent time, six-minute walk distance, 50 foot walk time, and the timed up
           and go test. All tests are tests that we frequently and safely perform in older
           individuals.

           Maximal oxygen consumption (exercise testing) will be measured by a metabolic cart
           during a graded maximal exercise test on a stationary cycle ergometer. This test will be
           performed in the CCTS under direct supervision of an exercise physiologist.

        2. Physical Activity Monitoring, Dietary Record. Subjects will be fitted with an ankle Step
           Activity Monitor in order to determine their daily level of physical activity over 7
           days period preceding the reduced physical activity study. Additionally, a 3-day daily
           dietary record will be self-reported before this period. The participant will be
           properly instructed by a research team member on how to conduct this reporting and how
           to wear the ankle activity monitor.

        3. Insulin Clamp Study, Metabolic Rate and Muscle Biopsies. On a separate day, participants
           will arrive at the CCTS fasted in the morning on Day 1 and a euglycemic-hyperinsulinemic
           clamp study will be performed as we have done previously. The research team physician
           will oversee the clamp procedure as he is very experienced using this method.

           Metabolic rate will be determined 30 minutes before the initiation of the insulin
           infusion and 30 minutes at the end of the insulin infusion period. Metabolic rate will
           be determined using a indirect calorimeter housed at the CCTS. To do so, the participant
           will be fitted with a canopy hood. The participant with breathe normally for 30 minutes
           during the procedure. The canopy will be removed then the first muscle biopsy will
           occur.

           A vastus lateralis muscle biopsy will be sampled before and 3h after the clamp combined
           with periodic blood sampling for measure of fasting and insulin-stimulated insulin,
           glucose, muscle cell signaling endpoints, and specific ceramide species. Biopsies will
           occur on opposite legs. Muscle biopsies were be performed by trained CCTS nurses as we
           have done routinely in our bed rest studies in older adults. Muscle samples will then be
           flash-frozen in liquid nitrogen and stored for later analysis. After the clamp
           experiment, subjects will begin the reduced physical inactivity study which will take
           place at the participant home.

           On Day 14, the participant again will return to the CCTS following an overnight fast and
           the insulin clamp study will be repeated in order to make comparisons to the pre insulin
           clamp study (Day 1).

        4. Reduced Physical inactivity experiment. After completion of the first insulin clamp
           experiment (Day 1), subjects will adhere to 14-days of reduced physical activity at
           their home as has been conduced before. The goal will be for the participant to maintain
           no more than ~2000 steps/day as determined by a monitor that the subject will be able to
           see and record. The investigators will inform the participant that their normal diet
           should remain the same. As mentioned above, on day 7, the participant will return for a
           DXA scan, OGTT's and thigh muscle biopsies. Also mentioned above, on Day 14, after an
           overnight fast, a second insulin clamp study coupled with muscle biopsies will be
           conducted as detailed above in the CCTS. Lean mass, strength, power, and physical
           function measurements will be re-assessed on a later day following the reduced activity
           study.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: 2 weeks of physical inactivity
primary purpose: Treatment
masking: None (Open Label)
measure: Steady state glucose infusion rate
time frame: percent change from baseline at 14 days
description: Glucose infusion rate will be determined by a hyperinsulinemic-euglycemic clamp
measure: lean mass
time frame: percent change from baseline at 14 days
description: lean mass will be determined by DXA scan
arm group label: Reduced activity
arm group type: Experimental
description: participants will undergo a reduced physical activity period (75% step reduction) for two weeks.
intervention type: Procedure
intervention name: Reduced activity
description: Participants will reduced their physical activity level to approximately 2000 steps or 75% of their normal activity levels.
arm group label: Reduced activity
criteria: 
gender: All
minimum age: 60 Years
maximum age: 85 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Micah J Drummond, PhD
role: Principal Investigator
affiliation: University of Utah
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Utah
investigator full name: Micah Drummond
investigator title: Ph.D.
sharing ipd: No