<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/NCT03241706</url>
  </required_header>
  <id_info>
    <org_study_id>2016-7982</org_study_id>
    <nct_id>NCT03241706</nct_id>
  </id_info>
  <brief_title>Liver Glycogen and Hypoglycemia in Humans</brief_title>
  <official_title>Effect of Liver Glycogen Content on Hypoglycemic Counterregulation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jason Winnick</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Cincinnati</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this research study is to learn more about how sugar levels in the liver&#xD;
      affect the ability of people both with and without type 1 diabetes. People with type 1&#xD;
      diabetes do not make their own insulin, and are therefore required to give themselves&#xD;
      injections of insulin in order to keep their blood sugar under control. However, very often&#xD;
      people with type 1 diabetes give themselves too much insulin and this causes their blood&#xD;
      sugar to become very low, which can have a negative impact on their health. When the blood&#xD;
      sugar becomes low, healthy people secrete hormones such as glucagon and epinephrine (i.e.,&#xD;
      adrenaline), which restore the blood sugar levels to normal by increasing liver glucose&#xD;
      production into the blood. However, in people with type 1 diabetes, the ability to release&#xD;
      glucagon and epinephrine is impaired and this reduces the amount of sugar the liver is able&#xD;
      to release.&#xD;
&#xD;
      People with type 1 diabetes also have unusually low stores of sugar in their livers. It has&#xD;
      been shown in animal studies that when the amount of sugar stored in the liver is increased,&#xD;
      it increases the release of glucagon and epinephrine during insulin-induced hypoglycemia. In&#xD;
      turn, this increase in hormone release boosts liver sugar production. However, it is not&#xD;
      known if increased liver sugar content can influence these responses in people with and&#xD;
      without type 1 diabetes. In addition, when people with type 1 diabetes do experience an&#xD;
      episode of low blood sugar, it impairs their responses to low blood sugar the next day. It is&#xD;
      also unknown whether this reduction in low blood sugar responses is caused by low liver sugar&#xD;
      levels.&#xD;
&#xD;
      The investigators want to learn more about how liver sugar levels affect the ability to&#xD;
      respond to low blood sugar.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      There is universal agreement that iatrogenic hypoglycemia is the single most prominent&#xD;
      barrier to the safe, effective management of blood sugar in people with type 1 diabetes&#xD;
      (T1D). The typical patient with T1D is required to &quot;count&quot; the number of carbohydrates they&#xD;
      consume, estimate their own insulin doses and deliver this insulin subcutaneously to manage&#xD;
      their own glycemic level. With these multiple degrees of freedom, it is not surprising that&#xD;
      people with T1D frequently over-insulinize, thereby putting themselves at increased risk of&#xD;
      developing hypoglycemia and its associated comorbidities.&#xD;
&#xD;
      As the glycemic level falls in people who are generally healthy (i.e., non-T1D), the first&#xD;
      response is an abatement of insulin secretion. This reduction is then followed by an increase&#xD;
      in the release of the counterregulatory hormones glucagon and epinephrine as glycemia&#xD;
      continues to fall. Collectively, this hormonal milieu causes an increase in liver glycogen&#xD;
      mobilization and gluconeogenesis such that hepatic glucose production (HGP) increases,&#xD;
      thereby preventing serious hypoglycemia from occurring. However, people with T1D are unable&#xD;
      to reduce their own insulin levels (due to subcutaneous insulin delivery) and often have a&#xD;
      diminished capacity to secrete both glucagon and epinephrine during insulin-induced&#xD;
      hypoglycemia. Predictably, the HGP response to hypoglycemia in people with T1D is a fraction&#xD;
      of that seen in non-T1D controls, thereby increasing the depth and duration of the&#xD;
      hypoglycemic episode.&#xD;
&#xD;
      Liver glycogen is the first substrate used to defend against hypoglycemia. Interestingly,&#xD;
      hepatic glycogen levels in people with T1D are lower than those of non-T1D controls and their&#xD;
      ability to mobilize liver glycogen to combat insulin-induced hypoglycemia is also diminished.&#xD;
      Because of this, we carried out experiments in dogs to determine whether hepatic glycogen&#xD;
      content is a determinant of the HGP response to insulin-induced hypoglycemia. Results of&#xD;
      those studies showed that a 75% increase in liver glycogen (such as occurs in a non-T1D&#xD;
      individual over the course of a day) generated a signal in the liver that was transmitted to&#xD;
      the brain via afferent nerves which, in turn, led to an increase in the secretion of both&#xD;
      epinephrine and glucagon. As expected, this increase in counterregulatory hormone secretion&#xD;
      caused a 2.4-fold rise in HGP, despite insulin levels that were ~ 400 µU/mL at the liver.&#xD;
&#xD;
      The finding that an acute increase in hepatic glycogen can augment hypoglycemic&#xD;
      counterregulation has important clinical implications. However, despite the potential of this&#xD;
      therapeutic avenue to reduce the risk of iatrogenic hypoglycemia, it remains unclear at this&#xD;
      point if such a strategy translates to humans with T1D. Therefore, the overarching theme of&#xD;
      this proposal is to determine whether an acute increase in liver glycogen content can augment&#xD;
      the hepatic and hormonal responses to insulin-induced hypoglycemia in humans with and without&#xD;
      T1D. Herein we are proposing studies that will advance the field, with the specific aims&#xD;
      being as follows:&#xD;
&#xD;
      Specific Aim #1: To determine the effect of increasing liver glycogen deposition on&#xD;
      insulin-induced hypoglycemic counterregulation in humans with and without T1D.&#xD;
&#xD;
      The discovery of ways by which the risk of iatrogenic hypoglycemia can be reduced in people&#xD;
      with T1D is a priority. The proposed experiments will improve our understanding of the&#xD;
      mechanisms by which increased glycogen improves hypoglycemic counterregulation. If&#xD;
      hypoglycemia is reduced by increased glycogen, it will focus attention on the ways in which&#xD;
      liver glycogen levels can be normalized in people with T1D. This would be a significant step&#xD;
      forward in the ongoing effort to reduce the risk of iatrogenic hypoglycemia in people with&#xD;
      T1D.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">August 2, 2018</start_date>
  <completion_date type="Anticipated">May 31, 2022</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Single (Participant)</masking>
    <masking_description>The subjects will not be informed which treatment they will receive for a given trial.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Epinephrine</measure>
    <time_frame>2 hours</time_frame>
    <description>Hormone</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Glucagon</measure>
    <time_frame>2 hours</time_frame>
    <description>Hormone</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Glucose Infusion Rate</measure>
    <time_frame>2 hours</time_frame>
    <description>Whole-body responses</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Liver Glycogen</measure>
    <time_frame>2 hours</time_frame>
    <description>Amount of sugar stored in the liver</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hepatic Glucose Production</measure>
    <time_frame>2 hours</time_frame>
    <description>Amount of glucose released</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Peripheral Glucose Uptake</measure>
    <time_frame>2 hours</time_frame>
    <description>Amount of glucose being metabolized</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Hypoglycemia; Iatrogenic</condition>
  <arm_group>
    <arm_group_label>Controls-saline</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Each subject from Group 1 will undergo a metabolic study where saline is infused so as to not stimulate liver glucose uptake and glycogen deposition.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls-high fructose</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>A second group of control subjects will undergo a single metabolic study using a higher dose of fructose (6.5 mg/kg/min).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Controls-low fructose</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Each subject from Group 1 will undergo another metabolic study where fructose (1.3 mg/kg/min) is infused so as to stimulate liver glucose uptake and glycogen deposition.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Fructose</intervention_name>
    <description>IV fructose (1.3 mg/kg/min)</description>
    <arm_group_label>Controls-high fructose</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Saline</intervention_name>
    <description>Saline given as a comparison to fructose.</description>
    <arm_group_label>Controls-saline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Somatostatin</intervention_name>
    <description>IV infusion of somatostatin (60 ng/kg/min)</description>
    <arm_group_label>Controls-high fructose</arm_group_label>
    <arm_group_label>Controls-low fructose</arm_group_label>
    <arm_group_label>Controls-saline</arm_group_label>
    <other_name>SRIF</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Insulin</intervention_name>
    <description>IV infusion of insulin between 20-60 mU/m2/min.</description>
    <arm_group_label>Controls-high fructose</arm_group_label>
    <arm_group_label>Controls-low fructose</arm_group_label>
    <arm_group_label>Controls-saline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Glucagon</intervention_name>
    <description>IV glucagon (0.65 ng/kg/min).</description>
    <arm_group_label>Controls-high fructose</arm_group_label>
    <arm_group_label>Controls-low fructose</arm_group_label>
    <arm_group_label>Controls-saline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dextrose solution</intervention_name>
    <description>IV dextrose to clamp the plasma glucose at the desired level.</description>
    <arm_group_label>Controls-high fructose</arm_group_label>
    <arm_group_label>Controls-low fructose</arm_group_label>
    <arm_group_label>Controls-saline</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>High Fructose</intervention_name>
    <description>IV-fructose (6.5 mg/kg/min)</description>
    <arm_group_label>Controls-low fructose</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Males and females of any race or ethnicity.&#xD;
&#xD;
          -  Aged 21-40 years.&#xD;
&#xD;
          -  Non-obese (BMI &lt;28 kg/m2).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant women.&#xD;
&#xD;
          -  Cigarette smoking.&#xD;
&#xD;
          -  Taking inflammation-targeting steroids (e.g., prednisone).&#xD;
&#xD;
          -  Taking medications targeting adrenergic signaling (e.g., beta-blockers,&#xD;
             bronchodilators).&#xD;
&#xD;
          -  Abnormal hematocrit or electrolyte levels.&#xD;
&#xD;
          -  The presence of cardiovascular or peripheral vascular disease.&#xD;
&#xD;
          -  The presence of neuropathy, retinopathy or nephropathy.&#xD;
&#xD;
          -  Any metal in the body that would make magnetic resonance spectroscopy dangerous.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>21 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Jason Winnick, PhD</last_name>
    <phone>5135584437</phone>
    <email>jason.winnick@uc.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Rebecca Nelson, BS</last_name>
    <phone>5135583427</phone>
    <email>nelsonr8@ucmail.uc.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>University of Cincinnati</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45267</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Rebecca Cason, BS</last_name>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>May 2020</verification_date>
  <study_first_submitted>August 4, 2017</study_first_submitted>
  <study_first_submitted_qc>August 4, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 7, 2017</study_first_posted>
  <last_update_submitted>May 1, 2020</last_update_submitted>
  <last_update_submitted_qc>May 1, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">May 5, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Cincinnati</investigator_affiliation>
    <investigator_full_name>Jason Winnick</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>hypoglycemia</keyword>
  <keyword>type 1 diabetes</keyword>
  <keyword>liver glucose metabolism</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypoglycemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glucagon</mesh_term>
    <mesh_term>Somatostatin</mesh_term>
  </intervention_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/NCT03241706
org study id: 2016-7982
nct id: NCT03241706
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this research study is to learn more about how sugar levels in the liver
      affect the ability of people both with and without type 1 diabetes. People with type 1
      diabetes do not make their own insulin, and are therefore required to give themselves
      injections of insulin in order to keep their blood sugar under control. However, very often
      people with type 1 diabetes give themselves too much insulin and this causes their blood
      sugar to become very low, which can have a negative impact on their health. When the blood
      sugar becomes low, healthy people secrete hormones such as glucagon and epinephrine (i.e.,
      adrenaline), which restore the blood sugar levels to normal by increasing liver glucose
      production into the blood. However, in people with type 1 diabetes, the ability to release
      glucagon and epinephrine is impaired and this reduces the amount of sugar the liver is able
      to release.

      People with type 1 diabetes also have unusually low stores of sugar in their livers. It has
      been shown in animal studies that when the amount of sugar stored in the liver is increased,
      it increases the release of glucagon and epinephrine during insulin-induced hypoglycemia. In
      turn, this increase in hormone release boosts liver sugar production. However, it is not
      known if increased liver sugar content can influence these responses in people with and
      without type 1 diabetes. In addition, when people with type 1 diabetes do experience an
      episode of low blood sugar, it impairs their responses to low blood sugar the next day. It is
      also unknown whether this reduction in low blood sugar responses is caused by low liver sugar
      levels.

      The investigators want to learn more about how liver sugar levels affect the ability to
      respond to low blood sugar.
There is universal agreement that iatrogenic hypoglycemia is the single most prominent
      barrier to the safe, effective management of blood sugar in people with type 1 diabetes
      (T1D). The typical patient with T1D is required to "count" the number of carbohydrates they
      consume, estimate their own insulin doses and deliver this insulin subcutaneously to manage
      their own glycemic level. With these multiple degrees of freedom, it is not surprising that
      people with T1D frequently over-insulinize, thereby putting themselves at increased risk of
      developing hypoglycemia and its associated comorbidities.

      As the glycemic level falls in people who are generally healthy (i.e., non-T1D), the first
      response is an abatement of insulin secretion. This reduction is then followed by an increase
      in the release of the counterregulatory hormones glucagon and epinephrine as glycemia
      continues to fall. Collectively, this hormonal milieu causes an increase in liver glycogen
      mobilization and gluconeogenesis such that hepatic glucose production (HGP) increases,
      thereby preventing serious hypoglycemia from occurring. However, people with T1D are unable
      to reduce their own insulin levels (due to subcutaneous insulin delivery) and often have a
      diminished capacity to secrete both glucagon and epinephrine during insulin-induced
      hypoglycemia. Predictably, the HGP response to hypoglycemia in people with T1D is a fraction
      of that seen in non-T1D controls, thereby increasing the depth and duration of the
      hypoglycemic episode.

      Liver glycogen is the first substrate used to defend against hypoglycemia. Interestingly,
      hepatic glycogen levels in people with T1D are lower than those of non-T1D controls and their
      ability to mobilize liver glycogen to combat insulin-induced hypoglycemia is also diminished.
      Because of this, we carried out experiments in dogs to determine whether hepatic glycogen
      content is a determinant of the HGP response to insulin-induced hypoglycemia. Results of
      those studies showed that a 75% increase in liver glycogen (such as occurs in a non-T1D
      individual over the course of a day) generated a signal in the liver that was transmitted to
      the brain via afferent nerves which, in turn, led to an increase in the secretion of both
      epinephrine and glucagon. As expected, this increase in counterregulatory hormone secretion
      caused a 2.4-fold rise in HGP, despite insulin levels that were ~ 400 µU/mL at the liver.

      The finding that an acute increase in hepatic glycogen can augment hypoglycemic
      counterregulation has important clinical implications. However, despite the potential of this
      therapeutic avenue to reduce the risk of iatrogenic hypoglycemia, it remains unclear at this
      point if such a strategy translates to humans with T1D. Therefore, the overarching theme of
      this proposal is to determine whether an acute increase in liver glycogen content can augment
      the hepatic and hormonal responses to insulin-induced hypoglycemia in humans with and without
      T1D. Herein we are proposing studies that will advance the field, with the specific aims
      being as follows:

      Specific Aim #1: To determine the effect of increasing liver glycogen deposition on
      insulin-induced hypoglycemic counterregulation in humans with and without T1D.

      The discovery of ways by which the risk of iatrogenic hypoglycemia can be reduced in people
      with T1D is a priority. The proposed experiments will improve our understanding of the
      mechanisms by which increased glycogen improves hypoglycemic counterregulation. If
      hypoglycemia is reduced by increased glycogen, it will focus attention on the ways in which
      liver glycogen levels can be normalized in people with T1D. This would be a significant step
      forward in the ongoing effort to reduce the risk of iatrogenic hypoglycemia in people with
      T1D.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Basic Science
masking: Single (Participant)
masking description: The subjects will not be informed which treatment they will receive for a given trial.
measure: Epinephrine
time frame: 2 hours
description: Hormone
measure: Glucagon
time frame: 2 hours
description: Hormone
measure: Glucose Infusion Rate
time frame: 2 hours
description: Whole-body responses
measure: Liver Glycogen
time frame: 2 hours
description: Amount of sugar stored in the liver
measure: Hepatic Glucose Production
time frame: 2 hours
description: Amount of glucose released
measure: Peripheral Glucose Uptake
time frame: 2 hours
description: Amount of glucose being metabolized
arm group label: Controls-saline
arm group type: Placebo Comparator
description: Each subject from Group 1 will undergo a metabolic study where saline is infused so as to not stimulate liver glucose uptake and glycogen deposition.
arm group label: Controls-high fructose
arm group type: Active Comparator
description: A second group of control subjects will undergo a single metabolic study using a higher dose of fructose (6.5 mg/kg/min).
arm group label: Controls-low fructose
arm group type: Active Comparator
description: Each subject from Group 1 will undergo another metabolic study where fructose (1.3 mg/kg/min) is infused so as to stimulate liver glucose uptake and glycogen deposition.
intervention type: Drug
intervention name: Fructose
description: IV fructose (1.3 mg/kg/min)
arm group label: Controls-high fructose
intervention type: Drug
intervention name: Saline
description: Saline given as a comparison to fructose.
arm group label: Controls-saline
intervention type: Drug
intervention name: Somatostatin
description: IV infusion of somatostatin (60 ng/kg/min)
arm group label: Controls-high fructose
arm group label: Controls-low fructose
arm group label: Controls-saline
other name: SRIF
intervention type: Drug
intervention name: Insulin
description: IV infusion of insulin between 20-60 mU/m2/min.
arm group label: Controls-high fructose
arm group label: Controls-low fructose
arm group label: Controls-saline
intervention type: Drug
intervention name: Glucagon
description: IV glucagon (0.65 ng/kg/min).
arm group label: Controls-high fructose
arm group label: Controls-low fructose
arm group label: Controls-saline
intervention type: Drug
intervention name: Dextrose solution
description: IV dextrose to clamp the plasma glucose at the desired level.
arm group label: Controls-high fructose
arm group label: Controls-low fructose
arm group label: Controls-saline
intervention type: Drug
intervention name: High Fructose
description: IV-fructose (6.5 mg/kg/min)
arm group label: Controls-low fructose
criteria: 
gender: All
minimum age: 21 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Jason Winnick, PhD
phone: 5135584437
email: jason.winnick@uc.edu
last name: Rebecca Nelson, BS
phone: 5135583427
email: nelsonr8@ucmail.uc.edu
facility: 
status: Recruiting
contact: 
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Cincinnati
investigator full name: Jason Winnick
investigator title: Assistant Professor
mesh term: Hypoglycemia
mesh term: Glucagon
mesh term: Somatostatin
sharing ipd: No