<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/NCT03259984</url>
  </required_header>
  <id_info>
    <org_study_id>1612045470</org_study_id>
    <nct_id>NCT03259984</nct_id>
  </id_info>
  <brief_title>Epigenetics of Muscle Insulin Resistance</brief_title>
  <official_title>Epigenetics and the Origin of Muscle Insulin Resistance in Humans Aims 1-3</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Arizona</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Arizona</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators are trying to understand the role of DNA (deoxyribonucleic acid)&#xD;
      methylation in insulin resistance in skeletal muscle and blood tissues. DNA methylation is a&#xD;
      normal chemical process in the body that modifies DNA. By studying this, the investigators&#xD;
      hope to better understand the causes of insulin resistance.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Insulin resistance is defined as the decreased ability of insulin to perform its biological&#xD;
      function in the muscle, liver and fat. Genetic and environmental factors are known to&#xD;
      influence insulin sensitivity. It is not known how this is mediated. This study looks at the&#xD;
      role of epigenetics (modifications of proteins associated with DNA and methylation of DNA) in&#xD;
      alterations in insulin resistance. The investigators will study lean healthy people, obese&#xD;
      non-diabetic people and people with type 2 diabetes to characterize the DNA methylation&#xD;
      patterns in muscle in each group. The second aim of the study is to see how a single bout of&#xD;
      exercise affects the DNA methylation in the muscle. The third aim looks at the effect of 8&#xD;
      weeks of supervised exercise on the DNA methylation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 2016</start_date>
  <completion_date type="Actual">November 2, 2018</completion_date>
  <primary_completion_date type="Actual">November 2, 2018</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>DNA methylation of genes in insulin resistance</measure>
    <time_frame>9 months</time_frame>
    <description>DNA methylation of genes involved in mitochondrial biogenesis, oxidative phosphorylation, extracellular matrix and cytoskeleton proteins in insulin resistance, with an acute episode of exercise, and with eight weeks of training exercise.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>mRNA expression of genes</measure>
    <time_frame>9 months</time_frame>
    <description>mRNA expression of genes involved in mitochondrial biogenesis, oxidative phosphorylation, extracellular matrix and cytoskeletal signaling are altered in insulin resistance, with an acute episode of exercise and with 8 weeks of exercise training.</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Actual">72</enrollment>
  <condition>Diabetes Mellitus, Type 2</condition>
  <condition>Obesity</condition>
  <arm_group>
    <arm_group_label>Aim 1</arm_group_label>
    <description>This experiment will use the next generation sequencing reduced representation bisulfite sequencing to define patterns of DNA methylation in skeletal muscle and whole blood tissue of metabolically well-characterized lean healthy, obese nondiabetic, and type 2 diabetic volunteers. The investigators will test the hypotheses that: (a) There is an increased methylation of genes involved in mitochondrial biogenesis and oxidative phosphorylation and altered methylation of promoters of genes coding for extracellular matrix and cytoskeletal proteins in insulin resistance, (b) The altered methylation patterns observed correspond to protein and mRNA expression changes, and (c) There are coordinated patterns of DNA methylation between the skeletal muscle and whole blood tissues in insulin resistance.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Aim 2</arm_group_label>
    <description>This experiment will test the hypotheses in lean healthy, obese non-diabetic and type 2 diabetic volunteers that: (a) Increased methylation of the PGC-1α promoter predicts a decreased response of this gene to a single bout of exercise, and (b) Altered methylation of promoters of nuclear encoded mitochondrial genes predicts a decreased response of this gene to a single bout of exercise.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Aim 3</arm_group_label>
    <description>This experiment will test the hypothesis in lean healthy, obese non-diabetic and type 2 diabetic volunteers that: (a) There is decreased methylation of genes involved in mitochondrial biogenesis and oxidative phosphorylation, and the altered methylation corresponds to protein and mRNA (messenger ribonucleic acid) expression changes, (b) There is altered methylation of genes involved in inflammation and cytoskeletal structure.</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      DNA will be extracted from vastus lateralis skeletal muscle biopsies and blood samples&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Three groups of volunteers will be studied: 1) lean, healthy volunteers, 2) obese&#xD;
        volunteers without type 2 diabetes, and 3) volunteers with type 2 diabetes&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria&#xD;
&#xD;
          1. Age 21-55&#xD;
&#xD;
          2. BMI: Lean, BMI less than or equal to 25; Obese, BMI between 30- 50; type 2 diabetic,&#xD;
             BMI between 30- 50.&#xD;
&#xD;
          3. Subjects must be able to communicate meaningfully with the investigator and must be&#xD;
             legally competent to provide written informed consent.&#xD;
&#xD;
          4. Subjects may be of either sex with age as described in each protocol. Female subjects&#xD;
             must be non-lactating and will be eligible only if they have a negative pregnancy test&#xD;
             throughout the study period.&#xD;
&#xD;
          5. Subjects must range in age as described in each specific protocol.&#xD;
&#xD;
          6. Subjects must have the following laboratory values:&#xD;
&#xD;
               1. Hematocrit ≥ 35 vol%&#xD;
&#xD;
               2. Serum creatinine ≤ 1.6 mg/dl&#xD;
&#xD;
               3. AST (SGOT) &lt; 2 times upper limit of normal&#xD;
&#xD;
               4. ALT (SGPT) &lt; 2 times upper limit of normal&#xD;
&#xD;
               5. Alkaline phosphatase &lt; 2 times upper limit of normal&#xD;
&#xD;
               6. Triglycerides &lt; 150 mg/dl for nondiabetics&#xD;
&#xD;
               7. Triglycerides &lt;300 for diabetics&#xD;
&#xD;
               8. INR ≤ 1.3&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Subjects must not be receiving any of the following medications: thiazide or&#xD;
             furosemide diuretics, beta-blockers, or other chronic medications with known adverse&#xD;
             effects on glucose tolerance levels unless the patient has been on a stable dose of&#xD;
             such agents for the past three months before entry into the study. Subjects may be&#xD;
             taking a stable dose of estrogens or other hormonal replacement therapy, if the&#xD;
             subject has been on these agents for the prior three months. Subjects taking systemic&#xD;
             glucocorticoids are excluded. Patients with type 2 diabetes will be excluded if they&#xD;
             are taking thiazolidinediones, but may be taking sulfonylureas or other medications&#xD;
             known to work through effects on insulin secretion.&#xD;
&#xD;
          2. Subjects receiving Gemfibrozil must not also be receiving a statin.&#xD;
&#xD;
          3. Subjects with a history of clinically significant heart disease (New York Heart&#xD;
             Classification greater than grade II; more than non-specific ST-T wave changes on the&#xD;
             EKG), peripheral vascular disease (history of claudication), or pulmonary disease&#xD;
             (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation)&#xD;
             will not be studied.&#xD;
&#xD;
          4. Recent systemic or pulmonary embolus, untreated high-risk proliferative retinopathy,&#xD;
             recent retinal hemorrhage, uncontrolled hypertension, systolic BP&gt;180, diastolic&#xD;
             BP&gt;105, autonomic neuropathy, resting heart rate &gt;100, electrolyte abnormalities.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>55 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dawn K Coletta, Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Arizona</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Arizona</name>
      <address>
        <city>Tucson</city>
        <state>Arizona</state>
        <zip>85724</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>August 21, 2017</study_first_submitted>
  <study_first_submitted_qc>August 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 24, 2017</study_first_posted>
  <last_update_submitted>October 11, 2019</last_update_submitted>
  <last_update_submitted_qc>October 11, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 14, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Arizona</investigator_affiliation>
    <investigator_full_name>Dawn K Coletta</investigator_full_name>
    <investigator_title>Associate Professor of Medicine</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
  </condition_browse>
  <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/NCT03259984
org study id: 1612045470
nct id: NCT03259984
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The investigators are trying to understand the role of DNA (deoxyribonucleic acid)
      methylation in insulin resistance in skeletal muscle and blood tissues. DNA methylation is a
      normal chemical process in the body that modifies DNA. By studying this, the investigators
      hope to better understand the causes of insulin resistance.
Insulin resistance is defined as the decreased ability of insulin to perform its biological
      function in the muscle, liver and fat. Genetic and environmental factors are known to
      influence insulin sensitivity. It is not known how this is mediated. This study looks at the
      role of epigenetics (modifications of proteins associated with DNA and methylation of DNA) in
      alterations in insulin resistance. The investigators will study lean healthy people, obese
      non-diabetic people and people with type 2 diabetes to characterize the DNA methylation
      patterns in muscle in each group. The second aim of the study is to see how a single bout of
      exercise affects the DNA methylation in the muscle. The third aim looks at the effect of 8
      weeks of supervised exercise on the DNA methylation.
observational model: Cohort
time perspective: Prospective
measure: DNA methylation of genes in insulin resistance
time frame: 9 months
description: DNA methylation of genes involved in mitochondrial biogenesis, oxidative phosphorylation, extracellular matrix and cytoskeleton proteins in insulin resistance, with an acute episode of exercise, and with eight weeks of training exercise.
measure: mRNA expression of genes
time frame: 9 months
description: mRNA expression of genes involved in mitochondrial biogenesis, oxidative phosphorylation, extracellular matrix and cytoskeletal signaling are altered in insulin resistance, with an acute episode of exercise and with 8 weeks of exercise training.
arm group label: Aim 1
description: This experiment will use the next generation sequencing reduced representation bisulfite sequencing to define patterns of DNA methylation in skeletal muscle and whole blood tissue of metabolically well-characterized lean healthy, obese nondiabetic, and type 2 diabetic volunteers. The investigators will test the hypotheses that: (a) There is an increased methylation of genes involved in mitochondrial biogenesis and oxidative phosphorylation and altered methylation of promoters of genes coding for extracellular matrix and cytoskeletal proteins in insulin resistance, (b) The altered methylation patterns observed correspond to protein and mRNA expression changes, and (c) There are coordinated patterns of DNA methylation between the skeletal muscle and whole blood tissues in insulin resistance.
arm group label: Aim 2
description: This experiment will test the hypotheses in lean healthy, obese non-diabetic and type 2 diabetic volunteers that: (a) Increased methylation of the PGC-1α promoter predicts a decreased response of this gene to a single bout of exercise, and (b) Altered methylation of promoters of nuclear encoded mitochondrial genes predicts a decreased response of this gene to a single bout of exercise.
arm group label: Aim 3
description: This experiment will test the hypothesis in lean healthy, obese non-diabetic and type 2 diabetic volunteers that: (a) There is decreased methylation of genes involved in mitochondrial biogenesis and oxidative phosphorylation, and the altered methylation corresponds to protein and mRNA (messenger ribonucleic acid) expression changes, (b) There is altered methylation of genes involved in inflammation and cytoskeletal structure.
DNA will be extracted from vastus lateralis skeletal muscle biopsies and blood samples
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 21 Years
maximum age: 55 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Dawn K Coletta, Ph.D.
role: Principal Investigator
affiliation: University of Arizona
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Arizona
investigator full name: Dawn K Coletta
investigator title: Associate Professor of Medicine
mesh term: Diabetes Mellitus, Type 2
mesh term: Insulin Resistance
sharing ipd: No