Mechanisms of Post-Bariatric Hypoglycemia

NCT04428866 | Unknown DMC

• 1 other identifier: STUDY00000074
• Study Type: observational
• Target: 105
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Hypoglycemia

Keywords

Post-Bariatric Hypoglycemia; Roux-en-Y gastric bypass; Bariatric Surgery; Hypoglycemic clamp; Hormones; Microbiome

Outcome Measures

Primary Outcomes (5)

• Metabolic responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing

  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.

  July 2023

• Hormonal responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing

  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.

  July 2023

• Assessment of glucagon responsiveness during glucagon stimulation testing

  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.

  July 2023

• Assessment of hormonal responses during glucagon stimulation testing

  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.

  July 2023

• Analysis of microbiome differences in patients with PBH

  Microbiome will be characterized by sequencing to obtain metagenomic data and pathway analysis; all data will be adjusted for multiple comparisons.

  July 2023

Secondary Outcomes (3)

• Correlation between counterregulatory hormone response to experimental hypoglycemia and magnitude of hypoglycemia as determined by continuous glucose monitoring (CGM)

  July 2023

• Correlation between hypoglycemia frequency (as determined by CGM) and microbiome

  July 2023

• Correlation between hypoglycemia frequency (as determined by CGM) and counterregulatory hormones.

  July 2023

Other Outcomes (1)

• Safety Outcome - Hyper - and hypoglycemia during the study.

  July 2023

Study Arms (3)

Participants with post-bariatric hypoglycemia

Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.

Diagnostic Test: Continuous Glucose Monitoring; Diagnostic Test: activity monitor; Diagnostic Test: Mixed meal tolerance test; Diagnostic Test: Glucagon Sensitivity Testing; Diagnostic Test: Hypoglycemic Hyperinsulinemic Clamp; Diagnostic Test: analysis of fecal microbiome

Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)

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.

Diagnostic Test: Continuous Glucose Monitoring; Diagnostic Test: activity monitor; Diagnostic Test: Mixed meal tolerance test; Diagnostic Test: Glucagon Sensitivity Testing; Diagnostic Test: Hypoglycemic Hyperinsulinemic Clamp; Diagnostic Test: analysis of fecal microbiome

Control group

Individuals without a history of bariatric surgery will be recruited by local advertisement.

Diagnostic Test: Continuous Glucose Monitoring; Diagnostic Test: activity monitor; Diagnostic Test: Mixed meal tolerance test; Diagnostic Test: Glucagon Sensitivity Testing; Diagnostic Test: Hypoglycemic Hyperinsulinemic Clamp; Diagnostic Test: analysis of fecal microbiome

Interventions

Continuous Glucose Monitoring DIAGNOSTIC_TEST

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.

Asymptomatic participants with Roux-en-Y gastric bypass (RYGB); Control group; Participants with post-bariatric hypoglycemia

activity monitor DIAGNOSTIC_TEST

The activity monitor (Fitbit Charge 2) will be worn by participants for 10 days to assess activity, concurrent with CGM sensor wear.

Asymptomatic participants with Roux-en-Y gastric bypass (RYGB); Control group; Participants with post-bariatric hypoglycemia

Mixed meal tolerance test DIAGNOSTIC_TEST

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.

Also known as: meal test

Asymptomatic participants with Roux-en-Y gastric bypass (RYGB); Control group; Participants with post-bariatric hypoglycemia

Glucagon Sensitivity Testing DIAGNOSTIC_TEST

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.

Asymptomatic participants with Roux-en-Y gastric bypass (RYGB); Control group; Participants with post-bariatric hypoglycemia

Hypoglycemic Hyperinsulinemic Clamp DIAGNOSTIC_TEST

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.

Also known as: Hyperinsulinemic Hypoglycemic Clamp

Asymptomatic participants with Roux-en-Y gastric bypass (RYGB); Control group; Participants with post-bariatric hypoglycemia

analysis of fecal microbiome DIAGNOSTIC_TEST

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.

Asymptomatic participants with Roux-en-Y gastric bypass (RYGB); Control group; Participants with post-bariatric hypoglycemia

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Individuals with post-bariatric hypoglycemia will be recruited from the the Joslin Hypoglycemia Clinic. Individuals who have had RYGB but have no symptoms of hypoglycemia will be recruited from local bariatric programs and via advertisement. Control individuals will be recruited via advertisement locally.

You may qualify if:

• For PBH group only: Males or females diagnosed with ongoing post-bariatric hypoglycemia with prior episodes of neuroglycopenia, unresponsive to dietary intervention (low glycemic index, controlled carbohydrate portions) and trial of acarbose therapy at the maximally tolerated dose.
• For post-RYGB group without PBH: Males or females with history of RYGB and no history of symptomatic hypoglycemia.
• For non-surgical controls only: Males or females with no history of upper gastrointestinal surgery and no history of hypoglycemia or diabetes.
• Age 18-70 years of age, inclusive, at screening.
• Willingness to provide informed consent and follow all study procedures, including attending all scheduled visits.

You may not qualify if:

• Documented hypoglycemia occurring in the fasting state (\> 12 hours fast);
• Chronic kidney disease stage 4 or 5 (including end-stage renal disease);
• Hepatic disease, including serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than or equal to 3 times the upper limit of normal; hepatic synthetic insufficiency as defined as serum albumin \< 3.0 g/dL; or serum bilirubin \> 2.0;
• Congestive heart failure, New York Heart Association class II, III or IV;
• History of myocardial infarction, unstable angina or revascularization within the past 6 months or 2 or more risk factors for coronary artery disease including diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use.
• History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia
• Concurrent administration of β-blocker therapy;
• History of a cerebrovascular accident;
• Seizure disorder (other than with suspect or documented hypoglycemia);
• Active treatment with any diabetes medications except for acarbose;
• Active malignancy, except basal cell or squamous cell skin cancers;
• Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);
• Known insulinoma;
• Major surgical operation within 30 days prior to screening;
• Hematocrit \< 33% (women) or \<36% (men);

Sponsors & Collaborators

• Joslin Diabetes Center: lead
• University of Michigan: collaborator

Study Sites (1)

Joslin Diabetes Center

Boston, Massachusetts, 02215, United States

Location

Related Links

• Joslin Diabetes Center: Mechanisms of PBH recruitment website with contact information

Biospecimen

Retention: SAMPLES WITH DNA

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.

MeSH Terms

Conditions

Hypoglycemia

Interventions

Continuous Glucose Monitoring

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Blood Chemical Analysis; Clinical Chemistry Tests; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Diagnostic Techniques, Endocrine; Monitoring, Physiologic; Investigative Techniques

Study Officials

• Mary Elizabeth Patti, MD

  Joslin Diabetes Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 14, 2019
• First Posted: June 11, 2020
• Study Start: February 26, 2020
• Primary Completion: September 1, 2024
• Study Completion: September 1, 2024
• Last Updated: January 5, 2024

Record last verified: 2024-01

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR, ANALYTIC CODE
• Time Frame: 6 months after publication of study results
• Access Criteria: Data will be shared with academic investigators with approval of local institutional review boards.

Locations

US (1)