<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/NCT04428866</url>
  </required_header>
  <id_info>
    <org_study_id>STUDY00000074</org_study_id>
    <nct_id>NCT04428866</nct_id>
  </id_info>
  <brief_title>Mechanisms of Post-Bariatric Hypoglycemia</brief_title>
  <official_title>Mechanisms of Post-Bariatric Hypoglycemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Joslin Diabetes Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Michigan</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Joslin Diabetes Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Post-bariatric hypoglycemia (PBH) is an increasingly recognized syndrome that is incompletely&#xD;
      understood.&#xD;
&#xD;
      The purpose of this study is to increase our level of understanding by investigating&#xD;
      mechanisms contributing to this condition.&#xD;
&#xD;
      Participation in this study will take place over four visits, which will include the&#xD;
      following:&#xD;
&#xD;
        -  Wearing of a continuous glucose monitoring device;&#xD;
&#xD;
        -  Providing a stool sample (collected at home);&#xD;
&#xD;
        -  Measuring glucose and hormone levels in response to a meal;&#xD;
&#xD;
        -  Measuring glucose and hormone levels in response to an injection of glucagon;&#xD;
&#xD;
        -  Measuring hormone levels while glucose levels are gradually lowered, and during a&#xD;
           controlled period of a low glucose level (hypoglycemic clamp).&#xD;
&#xD;
      Investigators will test the hypothesis that counterregulatory hormone responses are impaired&#xD;
      in individuals with PBH, and that differences in the intestinal bacteria (microbiome) may&#xD;
      contribute to this condition.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Bariatric surgery is increasingly recognized as a potent tool for the treatment of type 2&#xD;
      diabetes (T2D), yielding not only weight loss but also rapid improvements in glycemia&#xD;
      allowing discontinuation of diabetes-related medication within days after surgery. However,&#xD;
      along with this metabolic success comes an increased incidence of severe hypoglycemia (termed&#xD;
      post-bariatric hypoglycemia; PBH) for a subset of individuals.&#xD;
&#xD;
      The goal of these studies is to identify physiological and molecular mechanisms that underlie&#xD;
      PBH, to determine whether these changes also contribute to surgery-induced improvements in&#xD;
      glucose regulation (homeostasis), and to define potential new therapeutic interventions for&#xD;
      PBH.&#xD;
&#xD;
      Participation in this study will take place over four visits, which will include the&#xD;
      following:&#xD;
&#xD;
        -  Detailed history, physical exam, and laboratory testing to determine study eligibility&#xD;
&#xD;
        -  Assessment of glucose patterns using a masked continuous glucose monitor;&#xD;
&#xD;
        -  Analysis of a stool sample (collected at home);&#xD;
&#xD;
        -  Measuring glucose and hormone levels in response to a meal;&#xD;
&#xD;
        -  Measuring glucose and hormone levels in response to an injection of glucagon;&#xD;
&#xD;
        -  Measuring hormone levels while glucose levels are gradually lowered, and during a&#xD;
           controlled period of a low glucose level (hypoglycemic clamp).&#xD;
&#xD;
      Investigators will test the hypothesis that counterregulatory hormone responses are impaired&#xD;
      in individuals with PBH, and that differences in the intestinal bacteria (microbiome) and&#xD;
      hormones produced in response to a meal may contribute to this condition.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">February 26, 2020</start_date>
  <completion_date type="Anticipated">September 2024</completion_date>
  <primary_completion_date type="Anticipated">September 2024</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Case-Control</observational_model>
    <time_perspective>Cross-Sectional</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Metabolic responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing</measure>
    <time_frame>July 2023</time_frame>
    <description>Metabolites will be measured at set time points after the start of insulin or mixed meal. For the hypoglycemic clamp, a time-trend analysis will be performed to identify the glucose level at which each metabolite rises significantly above the linear average of its preceding values. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in metabolite responses. Data will be checked to ensure variables conform to assumptions of the analysis. Sensitivity analysis will determine whether missing data are randomly associated with clinical or experimental phenotypes, and assess the impact of missing data on conclusions. Relationships between clinical and metabolic variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Hormonal responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing</measure>
    <time_frame>July 2023</time_frame>
    <description>Counterregulatory hormones will be measured at set time points after the start of insulin or mixed meal. For the hypoglycemic clamp, a time-trend analysis will be performed to identify the glucose level at which each hormone rises significantly above the linear average of its preceding values. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in counterregulatory hormone responses. Data will be checked to ensure variables conform to assumptions of the analysis. Sensitivity analysis will determine whether missing data are randomly associated with clinical or experimental phenotypes, and assess the impact of missing data on conclusions. Relationships between clinical and hormonal variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of glucagon responsiveness during glucagon stimulation testing</measure>
    <time_frame>July 2023</time_frame>
    <description>Glucose response to glucagon will be assessed by measurement of glucose levels at baseline, and at set time points after glucagon injection. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in glucose response to glucagon. Relationships between clinical variables and glucose levels in response to glucagon will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Assessment of hormonal responses during glucagon stimulation testing</measure>
    <time_frame>July 2023</time_frame>
    <description>Hormonal response to glucagon will be assessed by measurement of hormone levels at baseline, and at a set time point after glucagon injection. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in hormonal response to glucagon. Relationships between clinical variables, glucose levels, and hormonal levels in response to glucagon will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Analysis of microbiome differences in patients with PBH</measure>
    <time_frame>July 2023</time_frame>
    <description>Microbiome will be characterized by sequencing to obtain metagenomic data and pathway analysis; all data will be adjusted for multiple comparisons.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Correlation between counterregulatory hormone response to experimental hypoglycemia and magnitude of hypoglycemia as determined by continuous glucose monitoring (CGM)</measure>
    <time_frame>July 2023</time_frame>
    <description>CGM data will be analyzed to assess mean, median, peak, and nadir sensor glucose values, glycemic variability (GV), severity and length of hypoglycemia (% time glucose &lt;70, &lt;60, &lt;54 mg/dL), and number and duration of severe hypoglycemia (sensor glucose &lt;54, duration &gt;15 minutes) will be quantified. Metrics will be assessed over 24 hours and during daytime (6 AM to midnight) and nighttime (midnight to 6 AM) independently. Magnitude of hypoglycemia will be correlated with counterregulatory hormone levels during experimental hypoglycemia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between hypoglycemia frequency (as determined by CGM) and microbiome</measure>
    <time_frame>July 2023</time_frame>
    <description>Metagenomic data will be correlated with hypoglycemia frequency determined by CGM.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Correlation between hypoglycemia frequency (as determined by CGM) and counterregulatory hormones.</measure>
    <time_frame>July 2023</time_frame>
    <description>Hypoglycemia data (from CGM) will be correlated with counterregulatory hormone response to experimental hypoglycemia.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Safety Outcome - Hyper - and hypoglycemia during the study.</measure>
    <time_frame>July 2023</time_frame>
    <description>Participants will be closely monitored and glucose levels will be checked regularly at set time points during study visits. Symptoms of hypoglycemia will also be assessed at set time points during visits, and as needed.</description>
  </other_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Hypoglycemia</condition>
  <arm_group>
    <arm_group_label>Participants with post-bariatric hypoglycemia</arm_group_label>
    <description>Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)</arm_group_label>
    <description>Individuals with history of RYGB, without a history of or symptoms of hypoglycemia will be recruited from local postoperative surgical clinics and from the community.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Control group</arm_group_label>
    <description>Individuals without a history of bariatric surgery will be recruited by local advertisement.</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Continuous Glucose Monitoring</intervention_name>
    <description>A CGM sensor (Dexcom G4 or other professional version available at onset of study) will be placed during visit 1 in blinded (masked) mode, and will be worn for 10 days. Data will be analyzed to determine patterns of glucose during both day and night intervals.</description>
    <arm_group_label>Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)</arm_group_label>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Participants with post-bariatric hypoglycemia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>activity monitor</intervention_name>
    <description>The activity monitor (Fitbit Charge 2) will be worn by participants for 10 days to assess activity, concurrent with CGM sensor wear.</description>
    <arm_group_label>Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)</arm_group_label>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Participants with post-bariatric hypoglycemia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Mixed meal tolerance test</intervention_name>
    <description>After an overnight fast, participants will be given a standard liquid mixed meal; blood samples will be collected at baseline (fasting) and at defined time points after a meal for metabolic and hormonal analyses.</description>
    <arm_group_label>Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)</arm_group_label>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Participants with post-bariatric hypoglycemia</arm_group_label>
    <other_name>meal test</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Glucagon Sensitivity Testing</intervention_name>
    <description>After baseline blood sampling, glucagon will be administered by injection, and blood samples will be collected for analysis of glucose and hormone responses. This will allow us to assess whether sensitivity to glucagon is altered in PBH.</description>
    <arm_group_label>Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)</arm_group_label>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Participants with post-bariatric hypoglycemia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>Hypoglycemic Hyperinsulinemic Clamp</intervention_name>
    <description>This test will assess hormonal responses to hypoglycemia. Participants will arrive after an overnight fast. After baseline blood sampling, an infusion of insulin and glucose will be started, and infusions will be adjusted to allow glucose levels to drop very gradually. Blood samples will be collected for measurement of hormonal responses to lowering of glucose. This test will allow us to determine whether secretion of hormones which counteract hypoglycemia (counterregulatory hormones) is reduced in patients with PBH as compared with other groups.</description>
    <arm_group_label>Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)</arm_group_label>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Participants with post-bariatric hypoglycemia</arm_group_label>
    <other_name>Hyperinsulinemic Hypoglycemic Clamp</other_name>
  </intervention>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>analysis of fecal microbiome</intervention_name>
    <description>Participants will be asked to provide a fecal sample, collected at home, which will be analyzed to determine the types of bacteria present in the feces.</description>
    <arm_group_label>Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)</arm_group_label>
    <arm_group_label>Control group</arm_group_label>
    <arm_group_label>Participants with post-bariatric hypoglycemia</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood, urine, and fecal samples will be stored for up to 5 years for future analyses. DNA&#xD;
      will be stored for additional expanded genotyping. Fecal samples and /or cultures from them&#xD;
      may be used for mouse transfer experiments in the future.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Individuals with post-bariatric hypoglycemia will be recruited from the the Joslin&#xD;
        Hypoglycemia Clinic.&#xD;
&#xD;
        Individuals who have had RYGB but have no symptoms of hypoglycemia will be recruited from&#xD;
        local bariatric programs and via advertisement.&#xD;
&#xD;
        Control individuals will be recruited via advertisement locally.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. For PBH group only: Males or females diagnosed with ongoing post-bariatric&#xD;
             hypoglycemia with prior episodes of neuroglycopenia, unresponsive to dietary&#xD;
             intervention (low glycemic index, controlled carbohydrate portions) and trial of&#xD;
             acarbose therapy at the maximally tolerated dose.&#xD;
&#xD;
          2. For post-RYGB group without PBH: Males or females with history of RYGB and no history&#xD;
             of symptomatic hypoglycemia.&#xD;
&#xD;
          3. For non-surgical controls only: Males or females with no history of upper&#xD;
             gastrointestinal surgery and no history of hypoglycemia or diabetes.&#xD;
&#xD;
          4. Age 18-70 years of age, inclusive, at screening.&#xD;
&#xD;
          5. Willingness to provide informed consent and follow all study procedures, including&#xD;
             attending all scheduled visits.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Documented hypoglycemia occurring in the fasting state (&gt; 12 hours fast);&#xD;
&#xD;
          2. Chronic kidney disease stage 4 or 5 (including end-stage renal disease);&#xD;
&#xD;
          3. Hepatic disease, including serum alanine aminotransferase (ALT) or aspartate&#xD;
             aminotransferase (AST) greater than or equal to 3 times the upper limit of normal;&#xD;
             hepatic synthetic insufficiency as defined as serum albumin &lt; 3.0 g/dL; or serum&#xD;
             bilirubin &gt; 2.0;&#xD;
&#xD;
          4. Congestive heart failure, New York Heart Association class II, III or IV;&#xD;
&#xD;
          5. History of myocardial infarction, unstable angina or revascularization within the past&#xD;
             6 months or 2 or more risk factors for coronary artery disease including diabetes,&#xD;
             uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use.&#xD;
&#xD;
          6. History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia&#xD;
&#xD;
          7. Concurrent administration of β-blocker therapy;&#xD;
&#xD;
          8. History of a cerebrovascular accident;&#xD;
&#xD;
          9. Seizure disorder (other than with suspect or documented hypoglycemia);&#xD;
&#xD;
         10. Active treatment with any diabetes medications except for acarbose;&#xD;
&#xD;
         11. Active malignancy, except basal cell or squamous cell skin cancers;&#xD;
&#xD;
         12. Personal or family history of pheochromocytoma or disorder with increased risk of&#xD;
             pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);&#xD;
&#xD;
         13. Known insulinoma;&#xD;
&#xD;
         14. Major surgical operation within 30 days prior to screening;&#xD;
&#xD;
         15. Hematocrit &lt; 33% (women) or &lt;36% (men);&#xD;
&#xD;
         16. Bleeding disorder, treatment with warfarin, or platelet count &lt;50,000;&#xD;
&#xD;
         17. Blood donation (1 pint of whole blood) within the past 2 months;&#xD;
&#xD;
         18. Active alcohol abuse or substance abuse;&#xD;
&#xD;
         19. Current administration of oral or parenteral corticosteroids;&#xD;
&#xD;
         20. Pregnancy and/ or Lactation: For women of childbearing potential: there is a&#xD;
             requirement for a negative urine pregnancy test and for agreement to use contraception&#xD;
             during the study and for at least 1 month after participating in the study. Acceptable&#xD;
             contraception includes birth control pill / patch / vaginal ring, Depo-Provera,&#xD;
             Norplant, an intrauterine device, the double barrier method (the woman uses a&#xD;
             diaphragm and spermicide and the man uses a condom), or abstinence.&#xD;
&#xD;
         21. Use of an investigational drug within 30 days prior to screening.&#xD;
&#xD;
        There will be no involvement of special vulnerable populations such as fetuses, neonates,&#xD;
        pregnant women, children, prisoners, institutionalized or incarcerated individuals, or&#xD;
        others who may be considered vulnerable populations.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Mary Elizabeth Patti, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Joslin Diabetes Center</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Mary-Elizabeth Patti, MD</last_name>
    <phone>6173092635</phone>
    <email>MaryElizabeth.Patti@joslin.harvard.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Amanda L Sheehan, MSN</last_name>
    <phone>6173092695</phone>
    <email>amanda.sheehan@joslin.harvard.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Joslin Diabetes Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Mary E Patti, MD</last_name>
      <phone>617-309-2635</phone>
      <email>mary.elizabeth.patti@joslin.harvard.edu</email>
    </contact>
    <investigator>
      <last_name>Mary E. Patti, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Amanda L. Sheehan, NP</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.joslin.org/research/clinical-research/clinical-trials/mechanisms-post-bariatric-hypoglycemia</url>
    <description>Joslin Diabetes Center: Mechanisms of PBH recruitment website with contact information</description>
  </link>
  <verification_date>September 2023</verification_date>
  <study_first_submitted>November 14, 2019</study_first_submitted>
  <study_first_submitted_qc>June 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 11, 2020</study_first_posted>
  <last_update_submitted>September 5, 2023</last_update_submitted>
  <last_update_submitted_qc>September 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">September 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Post-Bariatric Hypoglycemia</keyword>
  <keyword>Roux-en-Y gastric bypass</keyword>
  <keyword>Bariatric Surgery</keyword>
  <keyword>Hypoglycemic clamp</keyword>
  <keyword>Hormones</keyword>
  <keyword>Microbiome</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>Hypoglycemic Agents</mesh_term>
    <mesh_term>Glucagon</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Deidentified participant data may be shared with other researchers with permission of local institutional review boards.</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>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>6 months after publication of study results</ipd_time_frame>
    <ipd_access_criteria>Data will be shared with academic investigators with approval of local institutional review boards.</ipd_access_criteria>
  </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/NCT04428866
org study id: STUDY00000074
nct id: NCT04428866
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Post-bariatric hypoglycemia (PBH) is an increasingly recognized syndrome that is incompletely
      understood.

      The purpose of this study is to increase our level of understanding by investigating
      mechanisms contributing to this condition.

      Participation in this study will take place over four visits, which will include the
      following:

        -  Wearing of a continuous glucose monitoring device;

        -  Providing a stool sample (collected at home);

        -  Measuring glucose and hormone levels in response to a meal;

        -  Measuring glucose and hormone levels in response to an injection of glucagon;

        -  Measuring hormone levels while glucose levels are gradually lowered, and during a
           controlled period of a low glucose level (hypoglycemic clamp).

      Investigators will test the hypothesis that counterregulatory hormone responses are impaired
      in individuals with PBH, and that differences in the intestinal bacteria (microbiome) may
      contribute to this condition.
Bariatric surgery is increasingly recognized as a potent tool for the treatment of type 2
      diabetes (T2D), yielding not only weight loss but also rapid improvements in glycemia
      allowing discontinuation of diabetes-related medication within days after surgery. However,
      along with this metabolic success comes an increased incidence of severe hypoglycemia (termed
      post-bariatric hypoglycemia; PBH) for a subset of individuals.

      The goal of these studies is to identify physiological and molecular mechanisms that underlie
      PBH, to determine whether these changes also contribute to surgery-induced improvements in
      glucose regulation (homeostasis), and to define potential new therapeutic interventions for
      PBH.

      Participation in this study will take place over four visits, which will include the
      following:

        -  Detailed history, physical exam, and laboratory testing to determine study eligibility

        -  Assessment of glucose patterns using a masked continuous glucose monitor;

        -  Analysis of a stool sample (collected at home);

        -  Measuring glucose and hormone levels in response to a meal;

        -  Measuring glucose and hormone levels in response to an injection of glucagon;

        -  Measuring hormone levels while glucose levels are gradually lowered, and during a
           controlled period of a low glucose level (hypoglycemic clamp).

      Investigators will test the hypothesis that counterregulatory hormone responses are impaired
      in individuals with PBH, and that differences in the intestinal bacteria (microbiome) and
      hormones produced in response to a meal may contribute to this condition.
observational model: Case-Control
time perspective: Cross-Sectional
measure: Metabolic responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing
time frame: July 2023
description: Metabolites will be measured at set time points after the start of insulin or mixed meal. For the hypoglycemic clamp, a time-trend analysis will be performed to identify the glucose level at which each metabolite rises significantly above the linear average of its preceding values. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in metabolite responses. Data will be checked to ensure variables conform to assumptions of the analysis. Sensitivity analysis will determine whether missing data are randomly associated with clinical or experimental phenotypes, and assess the impact of missing data on conclusions. Relationships between clinical and metabolic variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.
measure: Hormonal responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing
time frame: July 2023
description: Counterregulatory hormones will be measured at set time points after the start of insulin or mixed meal. For the hypoglycemic clamp, a time-trend analysis will be performed to identify the glucose level at which each hormone rises significantly above the linear average of its preceding values. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in counterregulatory hormone responses. Data will be checked to ensure variables conform to assumptions of the analysis. Sensitivity analysis will determine whether missing data are randomly associated with clinical or experimental phenotypes, and assess the impact of missing data on conclusions. Relationships between clinical and hormonal variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.
measure: Assessment of glucagon responsiveness during glucagon stimulation testing
time frame: July 2023
description: Glucose response to glucagon will be assessed by measurement of glucose levels at baseline, and at set time points after glucagon injection. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in glucose response to glucagon. Relationships between clinical variables and glucose levels in response to glucagon will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.
measure: Assessment of hormonal responses during glucagon stimulation testing
time frame: July 2023
description: Hormonal response to glucagon will be assessed by measurement of hormone levels at baseline, and at a set time point after glucagon injection. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in hormonal response to glucagon. Relationships between clinical variables, glucose levels, and hormonal levels in response to glucagon will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing.
measure: Analysis of microbiome differences in patients with PBH
time frame: July 2023
description: Microbiome will be characterized by sequencing to obtain metagenomic data and pathway analysis; all data will be adjusted for multiple comparisons.
measure: Correlation between counterregulatory hormone response to experimental hypoglycemia and magnitude of hypoglycemia as determined by continuous glucose monitoring (CGM)
time frame: July 2023
description: CGM data will be analyzed to assess mean, median, peak, and nadir sensor glucose values, glycemic variability (GV), severity and length of hypoglycemia (% time glucose <70, <60, <54 mg/dL), and number and duration of severe hypoglycemia (sensor glucose <54, duration >15 minutes) will be quantified. Metrics will be assessed over 24 hours and during daytime (6 AM to midnight) and nighttime (midnight to 6 AM) independently. Magnitude of hypoglycemia will be correlated with counterregulatory hormone levels during experimental hypoglycemia.
measure: Correlation between hypoglycemia frequency (as determined by CGM) and microbiome
time frame: July 2023
description: Metagenomic data will be correlated with hypoglycemia frequency determined by CGM.
measure: Correlation between hypoglycemia frequency (as determined by CGM) and counterregulatory hormones.
time frame: July 2023
description: Hypoglycemia data (from CGM) will be correlated with counterregulatory hormone response to experimental hypoglycemia.
measure: Safety Outcome - Hyper - and hypoglycemia during the study.
time frame: July 2023
description: Participants will be closely monitored and glucose levels will be checked regularly at set time points during study visits. Symptoms of hypoglycemia will also be assessed at set time points during visits, and as needed.
arm group label: Participants with post-bariatric hypoglycemia
description: Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.
arm group label: Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)
description: Individuals with history of RYGB, without a history of or symptoms of hypoglycemia will be recruited from local postoperative surgical clinics and from the community.
arm group label: Control group
description: Individuals without a history of bariatric surgery will be recruited by local advertisement.
intervention type: Diagnostic Test
intervention name: Continuous Glucose Monitoring
description: A CGM sensor (Dexcom G4 or other professional version available at onset of study) will be placed during visit 1 in blinded (masked) mode, and will be worn for 10 days. Data will be analyzed to determine patterns of glucose during both day and night intervals.
arm group label: Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)
arm group label: Control group
arm group label: Participants with post-bariatric hypoglycemia
intervention type: Diagnostic Test
intervention name: activity monitor
description: The activity monitor (Fitbit Charge 2) will be worn by participants for 10 days to assess activity, concurrent with CGM sensor wear.
arm group label: Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)
arm group label: Control group
arm group label: Participants with post-bariatric hypoglycemia
intervention type: Diagnostic Test
intervention name: Mixed meal tolerance test
description: After an overnight fast, participants will be given a standard liquid mixed meal; blood samples will be collected at baseline (fasting) and at defined time points after a meal for metabolic and hormonal analyses.
arm group label: Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)
arm group label: Control group
arm group label: Participants with post-bariatric hypoglycemia
other name: meal test
intervention type: Diagnostic Test
intervention name: Glucagon Sensitivity Testing
description: After baseline blood sampling, glucagon will be administered by injection, and blood samples will be collected for analysis of glucose and hormone responses. This will allow us to assess whether sensitivity to glucagon is altered in PBH.
arm group label: Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)
arm group label: Control group
arm group label: Participants with post-bariatric hypoglycemia
intervention type: Diagnostic Test
intervention name: Hypoglycemic Hyperinsulinemic Clamp
description: This test will assess hormonal responses to hypoglycemia. Participants will arrive after an overnight fast. After baseline blood sampling, an infusion of insulin and glucose will be started, and infusions will be adjusted to allow glucose levels to drop very gradually. Blood samples will be collected for measurement of hormonal responses to lowering of glucose. This test will allow us to determine whether secretion of hormones which counteract hypoglycemia (counterregulatory hormones) is reduced in patients with PBH as compared with other groups.
arm group label: Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)
arm group label: Control group
arm group label: Participants with post-bariatric hypoglycemia
other name: Hyperinsulinemic Hypoglycemic Clamp
intervention type: Diagnostic Test
intervention name: analysis of fecal microbiome
description: Participants will be asked to provide a fecal sample, collected at home, which will be analyzed to determine the types of bacteria present in the feces.
arm group label: Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)
arm group label: Control group
arm group label: Participants with post-bariatric hypoglycemia
Blood, urine, and fecal samples will be stored for up to 5 years for future analyses. DNA
      will be stored for additional expanded genotyping. Fecal samples and /or cultures from them
      may be used for mouse transfer experiments in the future.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Mary Elizabeth Patti, MD
role: Principal Investigator
affiliation: Joslin Diabetes Center
last name: Mary-Elizabeth Patti, MD
phone: 6173092635
email: MaryElizabeth.Patti@joslin.harvard.edu
last name: Amanda L Sheehan, MSN
phone: 6173092695
email: amanda.sheehan@joslin.harvard.edu
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
country: United States
url: https://www.joslin.org/research/clinical-research/clinical-trials/mechanisms-post-bariatric-hypoglycemia
description: Joslin Diabetes Center: Mechanisms of PBH recruitment website with contact information
responsible party type: Sponsor
mesh term: Hypoglycemia
mesh term: Hypoglycemic Agents
mesh term: Glucagon
sharing ipd: Yes
ipd description: Deidentified participant data may be shared with other researchers with permission of local institutional review boards.
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)
ipd info type: Analytic Code
ipd time frame: 6 months after publication of study results
ipd access criteria: Data will be shared with academic investigators with approval of local institutional review boards.