Mechanisms of Post-Bariatric Hypoglycemia

NCT ID: NCT04428866

Last Updated: 2024-01-05

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

ACTIVE_NOT_RECRUITING

Total Enrollment

105 participants

Study Classification

OBSERVATIONAL

Study Start Date

2020-02-26

Study Completion Date

2024-09-30

Brief Summary

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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.

Detailed Description

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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.

Conditions

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Hypoglycemia

Study Design

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Observational Model Type

CASE_CONTROL

Study Time Perspective

CROSS_SECTIONAL

Study Groups

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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.

Continuous Glucose Monitoring

Intervention Type 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.

activity monitor

Intervention Type DIAGNOSTIC_TEST

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

Mixed meal tolerance test

Intervention Type 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.

Glucagon Sensitivity Testing

Intervention Type 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.

Hypoglycemic Hyperinsulinemic Clamp

Intervention Type 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.

analysis of fecal microbiome

Intervention Type 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)

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.

Continuous Glucose Monitoring

Intervention Type 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.

activity monitor

Intervention Type DIAGNOSTIC_TEST

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

Mixed meal tolerance test

Intervention Type 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.

Glucagon Sensitivity Testing

Intervention Type 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.

Hypoglycemic Hyperinsulinemic Clamp

Intervention Type 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.

analysis of fecal microbiome

Intervention Type 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.

Control group

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

Continuous Glucose Monitoring

Intervention Type 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.

activity monitor

Intervention Type DIAGNOSTIC_TEST

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

Mixed meal tolerance test

Intervention Type 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.

Glucagon Sensitivity Testing

Intervention Type 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.

Hypoglycemic Hyperinsulinemic Clamp

Intervention Type 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.

analysis of fecal microbiome

Intervention Type 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.

Interventions

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Continuous Glucose Monitoring

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.

Intervention Type DIAGNOSTIC_TEST

activity monitor

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

Intervention Type DIAGNOSTIC_TEST

Mixed meal tolerance 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.

Intervention Type DIAGNOSTIC_TEST

Glucagon Sensitivity Testing

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.

Intervention Type DIAGNOSTIC_TEST

Hypoglycemic Hyperinsulinemic Clamp

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.

Intervention Type DIAGNOSTIC_TEST

analysis of fecal microbiome

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.

Intervention Type DIAGNOSTIC_TEST

Other Intervention Names

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meal test Hyperinsulinemic Hypoglycemic Clamp

Eligibility Criteria

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Inclusion Criteria

1. 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.
2. For post-RYGB group without PBH: Males or females with history of RYGB and no history of symptomatic hypoglycemia.
3. For non-surgical controls only: Males or females with no history of upper gastrointestinal surgery and no history of hypoglycemia or diabetes.
4. Age 18-70 years of age, inclusive, at screening.
5. Willingness to provide informed consent and follow all study procedures, including attending all scheduled visits.

Exclusion Criteria

1. Documented hypoglycemia occurring in the fasting state (\> 12 hours fast);
2. Chronic kidney disease stage 4 or 5 (including end-stage renal disease);
3. 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;
4. Congestive heart failure, New York Heart Association class II, III or IV;
5. 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.
6. History of syncope (unrelated to hypoglycemia) or diagnosed cardiac arrhythmia
7. Concurrent administration of β-blocker therapy;
8. History of a cerebrovascular accident;
9. Seizure disorder (other than with suspect or documented hypoglycemia);
10. Active treatment with any diabetes medications except for acarbose;
11. Active malignancy, except basal cell or squamous cell skin cancers;
12. Personal or family history of pheochromocytoma or disorder with increased risk of pheochromocytoma (MEN 2, neurofibromatosis, or Von Hippel-Lindau disease);
13. Known insulinoma;
14. Major surgical operation within 30 days prior to screening;
15. Hematocrit \< 33% (women) or \<36% (men);
16. Bleeding disorder, treatment with warfarin, or platelet count \<50,000;
17. Blood donation (1 pint of whole blood) within the past 2 months;
18. Active alcohol abuse or substance abuse;
19. Current administration of oral or parenteral corticosteroids;
20. Pregnancy and/ or Lactation: For women of childbearing potential: there is a requirement for a negative urine pregnancy test and for agreement to use contraception during the study and for at least 1 month after participating in the study. Acceptable contraception includes birth control pill / patch / vaginal ring, Depo-Provera, Norplant, an intrauterine device, the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence.
21. Use of an investigational drug within 30 days prior to screening.

There will be no involvement of special vulnerable populations such as fetuses, neonates, pregnant women, children, prisoners, institutionalized or incarcerated individuals, or others who may be considered vulnerable populations.
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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University of Michigan

OTHER

Sponsor Role collaborator

Joslin Diabetes Center

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Mary Elizabeth Patti, MD

Role: PRINCIPAL_INVESTIGATOR

Joslin Diabetes Center

Locations

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Joslin Diabetes Center

Boston, Massachusetts, United States

Site Status

Countries

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United States

Related Links

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https://www.joslin.org/research/clinical-research/clinical-trials/mechanisms-post-bariatric-hypoglycemia

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

Other Identifiers

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STUDY00000074

Identifier Type: -

Identifier Source: org_study_id

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