<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/NCT02971202</url>
  </required_header>
  <id_info>
    <org_study_id>161504</org_study_id>
    <nct_id>NCT02971202</nct_id>
  </id_info>
  <brief_title>Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance in Type 1 Diabetes and Maturity Onset Diabetes of the Young, Type 2 (MODY2)</brief_title>
  <official_title>A Novel Cross-sectional Analysis of Insulin Sensitivity Among Adolescents and Young Adults With Type 1 Diabetes, MODY2, and Normal Controls: the Contribution of Hyperinsulinemia vs. Hyperglycemia to Insulin Resistance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Vanderbilt University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Vanderbilt University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to determine the key factors influencing insulin sensitivity in&#xD;
      type 1 diabetes (T1DM) and maturity onset diabetes of the young, type 2 (MODY2).&#xD;
&#xD;
      Our study tests the hypothesis that decreased insulin sensitivity is primarily driven by&#xD;
      chronically elevated insulin levels in the blood rather than chronic elevations in blood&#xD;
      sugar.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research will determine whether insulin resistance (IR) in T1DM is predominantly an&#xD;
      effect of chronic hyperglycemia, as is commonly accepted, or a consequence of iatrogenic&#xD;
      hyperinsulinemia in the peripheral circulation, as alternatively hypothesized. IR is a&#xD;
      consistent but under-recognized finding in T1DM. Despite its independent contribution to&#xD;
      micro- and macrovascular disease, its underlying cause has not been established nor have&#xD;
      strategies to mitigate it been developed. This research will also characterize IR in maturity&#xD;
      onset diabetes of the young, type 2 (MODY2), a population for whom IR has been inadequately&#xD;
      studied to date.&#xD;
&#xD;
      Insulin therapy in T1DM attempts to achieve euglycemia but does so in an &quot;unphysiologic&quot; way,&#xD;
      by delivering insulin into the subcutaneous tissue as compared to physiologic delivery&#xD;
      directly into the hepatic portal circulation. Although life-saving, peripheral insulin&#xD;
      delivery in T1DM results in a loss of the normal insulin distribution; the physiologic state&#xD;
      maintains insulin at 3-fold higher concentrations in the portal circulation compared with the&#xD;
      peripheral circulation. IR in T1DM could therefore occur in response to peripheral&#xD;
      hyperinsulinemia, a mechanism that would protect against hypoglycemia and ensure adequate&#xD;
      glucose delivery to the central nervous system.&#xD;
&#xD;
      MODY2 is a condition that results a mutation in the gene encoding glucokinase (GCK), which in&#xD;
      turn causes a defect in β-cell sensitivity to glucose due to reduced glucose phosphorylation.&#xD;
      This effectively raises the &quot;set point&quot; for insulin secretion in response to increased&#xD;
      glycemia. Because MODY2 patients retain pancreatic insulin secretion, they usually require no&#xD;
      insulin therapy and have a normal insulin distribution between the portal and peripheral&#xD;
      circulations.&#xD;
&#xD;
      We therefore hypothesize that IR in T1DM 1) is a homeostatic response to increased peripheral&#xD;
      insulin concentrations resulting from peripheral insulin delivery and not significantly&#xD;
      attributable to hyperglycemia and 2) results primarily from peripheral tissue IR (especially&#xD;
      muscle) and not primarily from hepatic IR. Further, we anticipate that patients with MODY2, a&#xD;
      population that has hyperglycemia without hyperinsulinemia, will have insulin sensitivity&#xD;
      similar to that of otherwise healthy, nondiabetic individuals.&#xD;
&#xD;
      To test this hypothesis, the hyperinsulinemic, euglycemic clamp will be used to assess IR in&#xD;
      a cross-sectional study of 3 groups of subjects:&#xD;
&#xD;
        1. non-diabetic control subjects,&#xD;
&#xD;
        2. patients with well controlled T1DM, and&#xD;
&#xD;
        3. patients with MODY2&#xD;
&#xD;
      Key metabolic differences between these 3 groups will enable us to parse out the relative&#xD;
      contributions of peripheral hyperinsulinemia vs. hyperglycemia to IR in T1DM and MODY2.&#xD;
      Further, the proposed research will provide information on whether novel therapeutic&#xD;
      strategies to restore the normal portal to peripheral insulin distribution can normalize&#xD;
      insulin sensitivity (e.g. hepatopreferential insulin analogs, intraperitoneal insulin&#xD;
      delivery).&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">February 2019</completion_date>
  <primary_completion_date type="Actual">February 2019</primary_completion_date>
  <phase>Phase 1</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>Whole-body Glucose Utilization (Rd)</measure>
    <time_frame>End of clamp study (the study will last 8 hours)</time_frame>
    <description>The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Hepatic Insulin Sensitivity</measure>
    <time_frame>4 1/2 hours into clamp study</time_frame>
    <description>Glucose production (Ra) will be determined using stable isotopic tracer techniques. The extent to which Ra is suppressed at the end of 4 1/2 hours (when glucose Ra by liver has been submaximally suppressed) compared to basal (ΔRa) is directly proportional to hepatic insulin sensitivity.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adipose Tissue Insulin Sensitivity</measure>
    <time_frame>4 1/2 hours into clamp study</time_frame>
    <description>Insulin sensitivity at fat is directly proportional to insulin's ability to suppress lipolysis. Thus, we will determine the extent to which submaximal insulin stimulation (4 1/2 hours into the study) suppresses glycerol and non-esterified free fatty acids (NEFAs) compared to baseline. The extent to which these two metabolites are suppressed is directly proportional to insulin sensitivity in adipose tissue. Here the suppression of NEFA is taken as the secondary outcome parameter.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Type 1 Diabetes Mellitus</condition>
  <condition>Maturity-Onset Diabetes of the Young, Type 2</condition>
  <condition>MODY2</condition>
  <condition>Insulin Resistance</condition>
  <arm_group>
    <arm_group_label>Hyperinsulinemic, euglycemic clamp: T1DM</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hyperinsulinemic, euglycemic clamp:MODY2</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Hyperinsulinemic euglycemic clamp:Control</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Hyperinsulinemic, euglycemic clamp</intervention_name>
    <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.</description>
    <arm_group_label>Hyperinsulinemic euglycemic clamp:Control</arm_group_label>
    <arm_group_label>Hyperinsulinemic, euglycemic clamp: T1DM</arm_group_label>
    <arm_group_label>Hyperinsulinemic, euglycemic clamp:MODY2</arm_group_label>
    <other_name>glucose clamp</other_name>
    <other_name>pancreatic clamp</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>20% dextrose</intervention_name>
    <description>A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
    <arm_group_label>Hyperinsulinemic euglycemic clamp:Control</arm_group_label>
    <arm_group_label>Hyperinsulinemic, euglycemic clamp: T1DM</arm_group_label>
    <arm_group_label>Hyperinsulinemic, euglycemic clamp:MODY2</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion criteria for all subjects:&#xD;
&#xD;
        - BMI 19-28 kg/m^2&#xD;
&#xD;
        Additional inclusion criteria for T1DM subjects:&#xD;
&#xD;
          -  Age 13-51&#xD;
&#xD;
          -  T1DM duration 1-20 years&#xD;
&#xD;
          -  HbA1c 5.9-8.0%&#xD;
&#xD;
        Additional inclusion criteria for MODY2 subjects:&#xD;
&#xD;
          -  age 13-51&#xD;
&#xD;
          -  positive GCK genetic sequencing&#xD;
&#xD;
          -  HbA1c 5.9-8.0%&#xD;
&#xD;
        Additional inclusion criteria for control subjects:&#xD;
&#xD;
          -  age 18-5.1&#xD;
&#xD;
          -  HbA1c &lt; 5.5%&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Exclusion criteria for all subjects:&#xD;
&#xD;
          -  severe hypoglycemia (&gt;= 1 episode in the past 3 months or diagnosis of hypoglycemia&#xD;
             unawareness)&#xD;
&#xD;
          -  diabetes comorbidities (&gt;= 1 trip to emergency department for poor glucose control in&#xD;
             the past 6 months, New York Heart Association Class II-IV cardiac functional status,&#xD;
             systolic blood pressure &gt; 140 and diastolic blood pressure &gt; 100 mmHg, fasting&#xD;
             triglycerides &gt; 400 mg/dL, liver transaminases &gt; 2 times the upper limit of normal,&#xD;
             renal transplantation or serum creatinine &gt; 1.5 mg/dL)&#xD;
&#xD;
          -  confounding medications (any systemic glucocorticoid, any antipsychotic, atenolol,&#xD;
             metoprolol, propranolol, niacin, any thiazide diuretic, any oral contraceptive pill&#xD;
             with &gt; 35 mcg ethinyl estradiol, growth hormone, any immunosuppressant, any&#xD;
             anti-hypertensive, any-antilipidemic)&#xD;
&#xD;
          -  pregnancy&#xD;
&#xD;
          -  Tanner stage &lt; 5&#xD;
&#xD;
        Additional exclusion criteria for T1DM subjects&#xD;
&#xD;
          -  any diabetes medication except insulin&#xD;
&#xD;
          -  fasting c-peptide &gt; 0.7 ng/mL&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>13 Years</minimum_age>
    <maximum_age>51 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Justin M Gregory, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Vanderbilt University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Vanderbilt University Medical Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>July 2019</verification_date>
  <study_first_submitted>October 27, 2016</study_first_submitted>
  <study_first_submitted_qc>November 18, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 22, 2016</study_first_posted>
  <results_first_submitted>May 30, 2019</results_first_submitted>
  <results_first_submitted_qc>July 29, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">August 1, 2019</results_first_posted>
  <last_update_submitted>July 29, 2019</last_update_submitted>
  <last_update_submitted_qc>July 29, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Vanderbilt University</investigator_affiliation>
    <investigator_full_name>Justin Gregory</investigator_full_name>
    <investigator_title>Assistant Professor of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>o-glcnacylation</keyword>
  <keyword>hexosamine</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Diabetes Mellitus</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 1</mesh_term>
    <mesh_term>Insulin Resistance</mesh_term>
    <mesh_term>Hyperglycemia</mesh_term>
    <mesh_term>Hyperinsulinism</mesh_term>
    <mesh_term>Diabetes Mellitus, Type 2</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. No applicable resources were generated or analyzed during the current study.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 24, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/02/NCT02971202/Prot_SAP_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>September 20, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/02/NCT02971202/ICF_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Hyperinsulinemic, Euglycemic Clamp: T1DM</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
        <group group_id="P2">
          <title>Hyperinsulinemic, Euglycemic Clamp:MODY2</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
        <group group_id="P3">
          <title>Hyperinsulinemic Euglycemic Clamp:Control</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="12"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="11"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Started Study</title>
              <participants_list>
                <participants group_id="P1" count="11"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Pregnancy</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>screen fail after consent</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Hyperinsulinemic, Euglycemic Clamp: T1DM</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
        <group group_id="B2">
          <title>Hyperinsulinemic, Euglycemic Clamp:MODY2</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
        <group group_id="B3">
          <title>Hyperinsulinemic Euglycemic Clamp:Control</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="12"/>
            <count group_id="B2" value="10"/>
            <count group_id="B3" value="11"/>
            <count group_id="B4" value="33"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="28"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="8"/>
                    <measurement group_id="B4" value="24"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="33"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="12"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Whole-body Glucose Utilization (Rd)</title>
        <description>The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts.</description>
        <time_frame>End of clamp study (the study will last 8 hours)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hyperinsulinemic, Euglycemic Clamp: T1DM</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
          <group group_id="O2">
            <title>Hyperinsulinemic, Euglycemic Clamp:MODY2</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
          <group group_id="O3">
            <title>Hyperinsulinemic Euglycemic Clamp:Control</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Whole-body Glucose Utilization (Rd)</title>
          <description>The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts.</description>
          <units>mg/kg FFM/min</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8.5" lower_limit="6.1" upper_limit="10.9"/>
                    <measurement group_id="O2" value="11.0" lower_limit="9.1" upper_limit="13.0"/>
                    <measurement group_id="O3" value="12.1" lower_limit="10.3" upper_limit="14.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Hepatic Insulin Sensitivity</title>
        <description>Glucose production (Ra) will be determined using stable isotopic tracer techniques. The extent to which Ra is suppressed at the end of 4 1/2 hours (when glucose Ra by liver has been submaximally suppressed) compared to basal (ΔRa) is directly proportional to hepatic insulin sensitivity.</description>
        <time_frame>4 1/2 hours into clamp study</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hyperinsulinemic, Euglycemic Clamp: T1DM</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
          <group group_id="O2">
            <title>Hyperinsulinemic, Euglycemic Clamp:MODY2</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
          <group group_id="O3">
            <title>Hyperinsulinemic Euglycemic Clamp:Control</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Hepatic Insulin Sensitivity</title>
          <description>Glucose production (Ra) will be determined using stable isotopic tracer techniques. The extent to which Ra is suppressed at the end of 4 1/2 hours (when glucose Ra by liver has been submaximally suppressed) compared to basal (ΔRa) is directly proportional to hepatic insulin sensitivity.</description>
          <units>mg/kg FFM/min</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.9" lower_limit="1.5" upper_limit="2.2"/>
                    <measurement group_id="O2" value="2.1" lower_limit="1.7" upper_limit="2.4"/>
                    <measurement group_id="O3" value="1.7" lower_limit="1.4" upper_limit="2.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Adipose Tissue Insulin Sensitivity</title>
        <description>Insulin sensitivity at fat is directly proportional to insulin's ability to suppress lipolysis. Thus, we will determine the extent to which submaximal insulin stimulation (4 1/2 hours into the study) suppresses glycerol and non-esterified free fatty acids (NEFAs) compared to baseline. The extent to which these two metabolites are suppressed is directly proportional to insulin sensitivity in adipose tissue. Here the suppression of NEFA is taken as the secondary outcome parameter.</description>
        <time_frame>4 1/2 hours into clamp study</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Hyperinsulinemic, Euglycemic Clamp: T1DM</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
          <group group_id="O2">
            <title>Hyperinsulinemic, Euglycemic Clamp:MODY2</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
          <group group_id="O3">
            <title>Hyperinsulinemic Euglycemic Clamp:Control</title>
            <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
          </group>
        </group_list>
        <measure>
          <title>Adipose Tissue Insulin Sensitivity</title>
          <description>Insulin sensitivity at fat is directly proportional to insulin's ability to suppress lipolysis. Thus, we will determine the extent to which submaximal insulin stimulation (4 1/2 hours into the study) suppresses glycerol and non-esterified free fatty acids (NEFAs) compared to baseline. The extent to which these two metabolites are suppressed is directly proportional to insulin sensitivity in adipose tissue. Here the suppression of NEFA is taken as the secondary outcome parameter.</description>
          <units>μmol/L</units>
          <param>Mean</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="122.4" lower_limit="-54.36" upper_limit="299.1"/>
                    <measurement group_id="O2" value="382.3" lower_limit="244.4" upper_limit="520.3"/>
                    <measurement group_id="O3" value="392.7" lower_limit="274.4" upper_limit="511.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>1 week</time_frame>
      <desc>per protocol, hyperglycemia and hypoglycemia are not considered adverse events unless serious</desc>
      <group_list>
        <group group_id="E1">
          <title>Hyperinsulinemic, Euglycemic Clamp: T1DM</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
        <group group_id="E2">
          <title>Hyperinsulinemic, Euglycemic Clamp:MODY2</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
        <group group_id="E3">
          <title>Hyperinsulinemic Euglycemic Clamp:Control</title>
          <description>Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:&#xD;
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)&#xD;
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)&#xD;
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.&#xD;
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="12"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>hypotension</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>nausea and vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>IV site pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Vasovagal Response</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>headache</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="12"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Surgical and medical procedures</title>
            <event_list>
              <event>
                <sub_title>Swelling at biopsy site</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
              <event>
                <sub_title>Redness at biopsy site</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="12"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="11"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Justin M. Gregory MD MSCI</name_or_title>
      <organization>Vanderbilt University Medical Center</organization>
      <phone>615-875-9669</phone>
      <email>justin.m.gregory.1@vumc.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT02971202
org study id: 161504
nct id: NCT02971202
lead sponsor: 
has dmc: Yes
The purpose of this study is to determine the key factors influencing insulin sensitivity in
      type 1 diabetes (T1DM) and maturity onset diabetes of the young, type 2 (MODY2).

      Our study tests the hypothesis that decreased insulin sensitivity is primarily driven by
      chronically elevated insulin levels in the blood rather than chronic elevations in blood
      sugar.
This research will determine whether insulin resistance (IR) in T1DM is predominantly an
      effect of chronic hyperglycemia, as is commonly accepted, or a consequence of iatrogenic
      hyperinsulinemia in the peripheral circulation, as alternatively hypothesized. IR is a
      consistent but under-recognized finding in T1DM. Despite its independent contribution to
      micro- and macrovascular disease, its underlying cause has not been established nor have
      strategies to mitigate it been developed. This research will also characterize IR in maturity
      onset diabetes of the young, type 2 (MODY2), a population for whom IR has been inadequately
      studied to date.

      Insulin therapy in T1DM attempts to achieve euglycemia but does so in an "unphysiologic" way,
      by delivering insulin into the subcutaneous tissue as compared to physiologic delivery
      directly into the hepatic portal circulation. Although life-saving, peripheral insulin
      delivery in T1DM results in a loss of the normal insulin distribution; the physiologic state
      maintains insulin at 3-fold higher concentrations in the portal circulation compared with the
      peripheral circulation. IR in T1DM could therefore occur in response to peripheral
      hyperinsulinemia, a mechanism that would protect against hypoglycemia and ensure adequate
      glucose delivery to the central nervous system.

      MODY2 is a condition that results a mutation in the gene encoding glucokinase (GCK), which in
      turn causes a defect in β-cell sensitivity to glucose due to reduced glucose phosphorylation.
      This effectively raises the "set point" for insulin secretion in response to increased
      glycemia. Because MODY2 patients retain pancreatic insulin secretion, they usually require no
      insulin therapy and have a normal insulin distribution between the portal and peripheral
      circulations.

      We therefore hypothesize that IR in T1DM 1) is a homeostatic response to increased peripheral
      insulin concentrations resulting from peripheral insulin delivery and not significantly
      attributable to hyperglycemia and 2) results primarily from peripheral tissue IR (especially
      muscle) and not primarily from hepatic IR. Further, we anticipate that patients with MODY2, a
      population that has hyperglycemia without hyperinsulinemia, will have insulin sensitivity
      similar to that of otherwise healthy, nondiabetic individuals.

      To test this hypothesis, the hyperinsulinemic, euglycemic clamp will be used to assess IR in
      a cross-sectional study of 3 groups of subjects:

        1. non-diabetic control subjects,

        2. patients with well controlled T1DM, and

        3. patients with MODY2

      Key metabolic differences between these 3 groups will enable us to parse out the relative
      contributions of peripheral hyperinsulinemia vs. hyperglycemia to IR in T1DM and MODY2.
      Further, the proposed research will provide information on whether novel therapeutic
      strategies to restore the normal portal to peripheral insulin distribution can normalize
      insulin sensitivity (e.g. hepatopreferential insulin analogs, intraperitoneal insulin
      delivery).
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Whole-body Glucose Utilization (Rd)
time frame: End of clamp study (the study will last 8 hours)
description: The primary outcome is the degree to which Rd (determined using isotopic glucose tracer techniques) during maximal insulin stimulation differs between cohorts.
measure: Hepatic Insulin Sensitivity
time frame: 4 1/2 hours into clamp study
description: Glucose production (Ra) will be determined using stable isotopic tracer techniques. The extent to which Ra is suppressed at the end of 4 1/2 hours (when glucose Ra by liver has been submaximally suppressed) compared to basal (ΔRa) is directly proportional to hepatic insulin sensitivity.
measure: Adipose Tissue Insulin Sensitivity
time frame: 4 1/2 hours into clamp study
description: Insulin sensitivity at fat is directly proportional to insulin's ability to suppress lipolysis. Thus, we will determine the extent to which submaximal insulin stimulation (4 1/2 hours into the study) suppresses glycerol and non-esterified free fatty acids (NEFAs) compared to baseline. The extent to which these two metabolites are suppressed is directly proportional to insulin sensitivity in adipose tissue. Here the suppression of NEFA is taken as the secondary outcome parameter.
arm group label: Hyperinsulinemic, euglycemic clamp: T1DM
arm group type: Other
description: Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:
insulin (12 milliunit (mU)/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.
arm group label: Hyperinsulinemic, euglycemic clamp:MODY2
arm group type: Other
description: Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.
arm group label: Hyperinsulinemic euglycemic clamp:Control
arm group type: Other
description: Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.
intervention type: Drug
intervention name: Hyperinsulinemic, euglycemic clamp
description: Participants will undergo an 8-hour hyperinsulinemic, euglycemic clamp to quantify insulin sensitivity at whole-body and tissue-specific levels. The following hormones will be infused in the study:
insulin (12 mU/m^2/min [3x basal] for 150 minutes, then 40 mU/m^2/min [10x basal] for 180 minutes)
glucagon (0.65 ng/kg/min [1x basal] for 330 minutes)
somatostatin (60 ng/kg/min) These infusions will maintain a basal glucagon level and an increased insulin level in the blood that will be equal between all 3 cohorts.
arm group label: Hyperinsulinemic euglycemic clamp:Control
arm group label: Hyperinsulinemic, euglycemic clamp: T1DM
arm group label: Hyperinsulinemic, euglycemic clamp:MODY2
other name: glucose clamp
other name: pancreatic clamp
intervention type: Drug
intervention name: 20% dextrose
description: A variable infusion of 20% dextrose will be used to maintain plasma glucose within the euglycemic range throughout the hyperinsulinemic portion of the clamp. 6,6-H2 glucose will be infused at a low rate (0.033-0.22 µmol/kg/min) to determine glucose flux during the study.
arm group label: Hyperinsulinemic euglycemic clamp:Control
arm group label: Hyperinsulinemic, euglycemic clamp: T1DM
arm group label: Hyperinsulinemic, euglycemic clamp:MODY2
criteria: 
gender: All
minimum age: 13 Years
maximum age: 51 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Justin M Gregory, MD
role: Principal Investigator
affiliation: Vanderbilt University School of Medicine
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Vanderbilt University
investigator full name: Justin Gregory
investigator title: Assistant Professor of Pediatrics
mesh term: Diabetes Mellitus
mesh term: Diabetes Mellitus, Type 1
mesh term: Insulin Resistance
mesh term: Hyperglycemia
mesh term: Hyperinsulinism
mesh term: Diabetes Mellitus, Type 2
sharing ipd: Yes
ipd description: The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request. No applicable resources were generated or analyzed during the current study.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 