Mechanisms of Post-Bariatric Hypoglycemia

Active, not recruiting

• Conditions: Hypoglycemia
• Interventions: 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

• Registration Number: NCT04428866
• Lead Sponsor: Joslin Diabetes Center

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.

Detailed Description

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.

Study Timeline

• Study First Submitted: 2019-11-14
• Study Start: 2020-02-26
• Study First Submitted QC: 2020-06-10
• Study First Posted: 2020-06-11
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-04
• Last Update Posted: 2024-01-05
• Primary Completion: 2024-09
• Study Completion: 2024-09

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 105

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.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)	Glucagon Sensitivity Testing	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.
Participants with post-bariatric hypoglycemia	Glucagon Sensitivity Testing	Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.
Control group	Glucagon Sensitivity Testing	Individuals without a history of bariatric surgery will be recruited by local advertisement.
Participants with post-bariatric hypoglycemia	activity monitor	Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.
Participants with post-bariatric hypoglycemia	Mixed meal tolerance test	Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.
Participants with post-bariatric hypoglycemia	Continuous Glucose Monitoring	Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.
Participants with post-bariatric hypoglycemia	Hypoglycemic Hyperinsulinemic Clamp	Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.
Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)	activity monitor	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.
Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)	Mixed meal tolerance test	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.
Participants with post-bariatric hypoglycemia	analysis of fecal microbiome	Individuals with history of Roux-en-Y gastric bypass surgery, who have a history of hypoglycemia will be recruited from the Joslin Hypoglycemia Clinic.
Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)	Continuous Glucose Monitoring	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.
Control group	activity monitor	Individuals without a history of bariatric surgery will be recruited by local advertisement.
Control group	Hypoglycemic Hyperinsulinemic Clamp	Individuals without a history of bariatric surgery will be recruited by local advertisement.
Control group	analysis of fecal microbiome	Individuals without a history of bariatric surgery will be recruited by local advertisement.
Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)	Hypoglycemic Hyperinsulinemic Clamp	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.
Asymptomatic participants with Roux-en-Y gastric bypass (RYGB)	analysis of fecal microbiome	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.
Control group	Continuous Glucose Monitoring	Individuals without a history of bariatric surgery will be recruited by local advertisement.
Control group	Mixed meal tolerance test	Individuals without a history of bariatric surgery will be recruited by local advertisement.

Primary Outcome Measures

Name	Time	Method
Metabolic responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing	July 2023	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.
Assessment of glucagon responsiveness during glucagon stimulation testing	July 2023	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.
Analysis of microbiome differences in patients with PBH	July 2023	Microbiome will be characterized by sequencing to obtain metagenomic data and pathway analysis; all data will be adjusted for multiple comparisons.
Hormonal responses during experimental hypoglycemia induced by hypoglycemic clamp and/or mixed meal testing	July 2023	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.
Assessment of hormonal responses during glucagon stimulation testing	July 2023	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.

Secondary Outcome Measures

Name	Time	Method
Correlation between counterregulatory hormone response to experimental hypoglycemia and magnitude of hypoglycemia as determined by continuous glucose monitoring (CGM)	July 2023	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.
Correlation between hypoglycemia frequency (as determined by CGM) and microbiome	July 2023	Metagenomic data will be correlated with hypoglycemia frequency determined by CGM.
Correlation between hypoglycemia frequency (as determined by CGM) and counterregulatory hormones.	July 2023	Hypoglycemia data (from CGM) will be correlated with counterregulatory hormone response to experimental hypoglycemia.

Trial Locations

Locations (1)

Joslin Diabetes Center; 🇺🇸 Boston, Massachusetts, United States