<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/NCT02193295</url>
  </required_header>
  <id_info>
    <org_study_id>02029020997_a</org_study_id>
    <secondary_id>R01DK113984</secondary_id>
    <secondary_id>R01DK124272</secondary_id>
    <nct_id>NCT02193295</nct_id>
  </id_info>
  <brief_title>Reversal of Lipid-Induced Insulin Resistance</brief_title>
  <official_title>Reversal of Lipid-Induced Insulin Resistance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Yale University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Yale University</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to examine whether weight reduction decreases intramyocellular&#xD;
      (IMCL) and hepatic lipid content, and improves insulin sensitivity of muscle and fat tissue&#xD;
      in people who are insulin resistant and have a family history of type 2 diabetes.&#xD;
&#xD;
      Hepatic mitochondrial oxidation will be assesses using a 3 hour triple tracer study (D7&#xD;
      glucose, 3-13C lactate and 13C4 beta-hydroxybutyrate).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In this study, we will examine whether a small weight loss in lean, insulin-resistant&#xD;
      offspring of type 2 diabetic patients will improve insulin resistance. The control group will&#xD;
      consist of subjects matched for gender, age and body weight with no family history of&#xD;
      diabetes. Before and after weight loss, rates of basal and insulin stimulated whole body&#xD;
      glucose metabolism will be measured using [6,6-2H] glucose during a 3 hour basal period and a&#xD;
      4 hour euglycemic hyperinsulinemic (20 mU/m2-min) clamp. Rates of whole body lipolysis will&#xD;
      be determined using [2H5] glycerol, localized rates of lipolysis will be measured using the&#xD;
      microdialysis technique and muscle PI 3-kinase activity will be assessed in muscle biopsies.&#xD;
      FFA metabolites (fatty acyl CoA, ceramides, diacylglycerol) will be measured in fat tissue&#xD;
      collected from the abdominal subcutaneous fat cell depot. Body composition will be determined&#xD;
      with bioelectrical impedance and whole body MRI; IMCL will be measured with MRS. Before and&#xD;
      after weight loss, insulin secretion will be measured with the hyperglycemic clamp (as&#xD;
      described under Day 2 Hyperglycemic Clamp).&#xD;
&#xD;
      Hepatic mitochondrial fat oxidation will be assessed in a separate study at baseline.&#xD;
      Participants will be admitted to the Yale HRU at 7 AM after an overnight fast. An IV line&#xD;
      will be placed in antecubital vein for tracer infusions and a retrograde IV line will be&#xD;
      placed in a hand vein for blood collections. The hand will be warmed in a 'hot box' 37°C to&#xD;
      approximate collection of 'arterial' blood samples. After collection of a baseline blood&#xD;
      samples, infusions of 13C lactate (0.9 mM, 99% 13C, infusion rate: 8.7 micromol/(Kg-min)),&#xD;
      D7glucose (25 mg/mL, 99% 13C, infusion rate: 0.84 mg/(m2-min)) and 13C-BHOB (2 mg/mL,&#xD;
      99%rate: 0.01 mg/(Kg-min)) will be started and continued for 180 minutes. During the final 20&#xD;
      minutes of this infusion period blood samples will be collected from the retrograde IV line.&#xD;
      The infusion will then be discontinued the IV lines removed, and the participants will be&#xD;
      served breakfast/lunch and discharged to home.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date>October 2002</start_date>
  <completion_date type="Anticipated">October 2025</completion_date>
  <primary_completion_date type="Anticipated">October 2025</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Improvements in insulin sensitivity</measure>
    <time_frame>up to 6 months intervention to examine whether insulin sensitivity has improved significantly after the moderate weight reduction</time_frame>
    <description>Insulin sensitivity will be assessed using the insulin/glucose clamp, liver and muscle fat will be measured using 1H magnetic resonance spectroscopy (MRS) and both results from the clamp and MRS compared to baseline values before the weight reduction intervention.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">100</enrollment>
  <condition>Insulin Resistance</condition>
  <condition>NAFLD</condition>
  <arm_group>
    <arm_group_label>Lifestyle Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Caloric Restriction to reverse lipid-induced insulin resistance.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Baseline Assessment of Hepatic Mitochondrial Fat Oxidation</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Tracer study to assess hepatic mitochondrial fat oxidation (PINTA).</description>
  </arm_group>
  <intervention>
    <intervention_type>Behavioral</intervention_type>
    <intervention_name>Caloric Restriction</intervention_name>
    <description>Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss. Weekly visits for measurements of body weight, body composition, blood glucose and MRS measurements of liver and muscle lipid.</description>
    <arm_group_label>Baseline Assessment of Hepatic Mitochondrial Fat Oxidation</arm_group_label>
    <arm_group_label>Lifestyle Intervention</arm_group_label>
    <other_name>Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss.</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy, sedentary, non-smoking and not taking any medications other than birth&#xD;
             control pills.&#xD;
&#xD;
          -  Hematocrit &gt;35%&#xD;
&#xD;
          -  Subjects will have no systemic or organ disease including diabetes.&#xD;
&#xD;
          -  Subjects will have no history eating disorders.&#xD;
&#xD;
          -  Women must be using a form of birth control (sexual abstinence, birth control pills,&#xD;
             Norplant, IUD or condoms) and will be studied between day 0 and 7 of their menstrual&#xD;
             cycle.&#xD;
&#xD;
          -  Those who are taking birth control pills or have had a hysterectomy may be studied at&#xD;
             any time.&#xD;
&#xD;
          -  Physical activity will be assessed using a standard questionnaire with an activity&#xD;
             index cut off at 2.3.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Any subject, who does not fit the inclusion criteria. Including history of eating&#xD;
             disorders, any systemic and organ disease including diabetes.&#xD;
&#xD;
        Lactose intolerance Any blood count, clotting abnormalities HYpertriglyceridemeia (TG over&#xD;
        100 mg/dL)&#xD;
&#xD;
          -  Hematocrit &lt;35%.&#xD;
&#xD;
          -  Women of childbearing potential, who are not using contraception (as mentioned above)&#xD;
             or who are not abstinent.&#xD;
&#xD;
          -  Subjects who have a regular exercise regimen will not be enrolled.&#xD;
&#xD;
          -  Metal implants and/or body piercing, which cannot be removed before the MR studies.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kitt Petersen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Yale University</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Kitt Petersen, MD</last_name>
    <phone>203-688-4106</phone>
    <email>kitt.petersen@yale.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Yale Center for Clinical Investigation HRU</name>
      <address>
        <city>New Haven</city>
        <state>Connecticut</state>
        <zip>06520</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Kitt Petersen, MD</last_name>
      <phone>203-688-4106</phone>
    </contact>
    <investigator>
      <last_name>Kitt Petersen, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 25, 2014</study_first_submitted>
  <study_first_submitted_qc>July 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 17, 2014</study_first_posted>
  <last_update_submitted>August 21, 2023</last_update_submitted>
  <last_update_submitted_qc>August 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 23, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Weight Reduction</keyword>
  <keyword>Caloric Restriction</keyword>
  <keyword>Euglycemic Hyperinsulinemic Clamp</keyword>
  <keyword>Magnetic Resonance Spectroscopy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Insulin Resistance</mesh_term>
  </condition_browse>
  <!-- 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/NCT02193295
org study id: 02029020997_a
secondary id: R01DK113984
secondary id: R01DK124272
nct id: NCT02193295
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study is to examine whether weight reduction decreases intramyocellular
      (IMCL) and hepatic lipid content, and improves insulin sensitivity of muscle and fat tissue
      in people who are insulin resistant and have a family history of type 2 diabetes.

      Hepatic mitochondrial oxidation will be assesses using a 3 hour triple tracer study (D7
      glucose, 3-13C lactate and 13C4 beta-hydroxybutyrate).
In this study, we will examine whether a small weight loss in lean, insulin-resistant
      offspring of type 2 diabetic patients will improve insulin resistance. The control group will
      consist of subjects matched for gender, age and body weight with no family history of
      diabetes. Before and after weight loss, rates of basal and insulin stimulated whole body
      glucose metabolism will be measured using [6,6-2H] glucose during a 3 hour basal period and a
      4 hour euglycemic hyperinsulinemic (20 mU/m2-min) clamp. Rates of whole body lipolysis will
      be determined using [2H5] glycerol, localized rates of lipolysis will be measured using the
      microdialysis technique and muscle PI 3-kinase activity will be assessed in muscle biopsies.
      FFA metabolites (fatty acyl CoA, ceramides, diacylglycerol) will be measured in fat tissue
      collected from the abdominal subcutaneous fat cell depot. Body composition will be determined
      with bioelectrical impedance and whole body MRI; IMCL will be measured with MRS. Before and
      after weight loss, insulin secretion will be measured with the hyperglycemic clamp (as
      described under Day 2 Hyperglycemic Clamp).

      Hepatic mitochondrial fat oxidation will be assessed in a separate study at baseline.
      Participants will be admitted to the Yale HRU at 7 AM after an overnight fast. An IV line
      will be placed in antecubital vein for tracer infusions and a retrograde IV line will be
      placed in a hand vein for blood collections. The hand will be warmed in a 'hot box' 37°C to
      approximate collection of 'arterial' blood samples. After collection of a baseline blood
      samples, infusions of 13C lactate (0.9 mM, 99% 13C, infusion rate: 8.7 micromol/(Kg-min)),
      D7glucose (25 mg/mL, 99% 13C, infusion rate: 0.84 mg/(m2-min)) and 13C-BHOB (2 mg/mL,
      99%rate: 0.01 mg/(Kg-min)) will be started and continued for 180 minutes. During the final 20
      minutes of this infusion period blood samples will be collected from the retrograde IV line.
      The infusion will then be discontinued the IV lines removed, and the participants will be
      served breakfast/lunch and discharged to home.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Improvements in insulin sensitivity
time frame: up to 6 months intervention to examine whether insulin sensitivity has improved significantly after the moderate weight reduction
description: Insulin sensitivity will be assessed using the insulin/glucose clamp, liver and muscle fat will be measured using 1H magnetic resonance spectroscopy (MRS) and both results from the clamp and MRS compared to baseline values before the weight reduction intervention.
arm group label: Lifestyle Intervention
arm group type: Experimental
description: Caloric Restriction to reverse lipid-induced insulin resistance.
arm group label: Baseline Assessment of Hepatic Mitochondrial Fat Oxidation
arm group type: Experimental
description: Tracer study to assess hepatic mitochondrial fat oxidation (PINTA).
intervention type: Behavioral
intervention name: Caloric Restriction
description: Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss. Weekly visits for measurements of body weight, body composition, blood glucose and MRS measurements of liver and muscle lipid.
arm group label: Baseline Assessment of Hepatic Mitochondrial Fat Oxidation
arm group label: Lifestyle Intervention
other name: Dietary intervention to reduce lipid content in liver and muscle with minimal overall weight loss.
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kitt Petersen, MD
role: Principal Investigator
affiliation: Yale University
last name: Kitt Petersen, MD
phone: 203-688-4106
email: kitt.petersen@yale.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
responsible party type: Sponsor
mesh term: Insulin Resistance