Mechanisms of Hypoglycemia in Patients Without Diabetes

Study Overview
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Brief Summary
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The goal of this study is to identify physiologic and molecular mechanisms that underlie hypoglycemia in the absence of diabetes (or medications that can cause hypoglycemia) and to investigate potential genetic and microbiome differences which contribute to hypoglycemia. We will test the hypothesis that hypoglycemia in the absence of diabetes is linked to genetic variation or the microbiome, and identify whether additional medical history or diagnoses are enriched in the population of patients with hypoglycemia.

Detailed Description
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Although there are several conditions which have been identified that cause, or contribute to hypoglycemia, diagnosis can be challenging, as the physiologic, and molecular mechanisms are incompletely understood. Additionally, treatment options are relatively limited, and often incompletely effective and/or not well tolerated. Investigating the causative factors and mechanisms of hypoglycemia is important therefore in improving our understanding in order to develop new and more effective approaches to treatment. The current study aims to: more fully characterize clinical history and demographics in patients with diverse forms of hypoglycemia by creating and analyzing a patient database; for a subset of patients, characterize metabolic and hormonal responses to a standard meal; analyze DNA variants in individuals with hypoglycemia; analyze differences in the intestinal microbiome in individuals with hypoglycemia.

Official Title
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Mechanisms of Hypoglycemia in Patients Without Diabetes

Conditions
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Hypoglycemia

Intervention / Treatment
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* Other: Entry of demographic and medical history data into a deidentified database
* Genetic: Blood sample for DNA analysis
* Diagnostic Test: Stool sample for microbiome analysis
* Diagnostic Test: Mixed meal tolerance test
* Diagnostic Test: Continuous glucose monitoring
* Diagnostic Test: activity monitor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: For hypoglycemia group without a history of bariatric surgery: Males or females diagnosed with hypoglycemia with prior episodes of neuroglycopenia. For hypoglycemia group with history of upper gastrointestinal surgery: Males or females diagnosed with ongoing hypoglycemia with prior episodes of neuroglycopenia. 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 attend one study visit, with option to attend a second visit with mixed meal test, and follow all study procedures Exclusion Criteria: Active treatment with any diabetes medications except for acarbose; Known insulinoma, gastrinoma, or other neuroendocrine tumor; Additional exclusion criteria for those participating in optional Visit 2 (meal testing): Chronic kidney disease stage 4 or 5 (including end-stage renal disease); Hepatic disease, including serum alanine transaminase (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 Hear Association (NYHA) 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 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); Major surgical operation within 30 days prior to screening; Hematocrit < 33% (women) or <36% (men); Bleeding disorder, treatment with warfarin, or platelet count <50,000; Blood donation (1 pint of whole blood) within the past 2 months; Active alcohol abuse or substance abuse; Current administration of oral or parenteral corticosteroids; 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 (IUD), the double barrier method (the woman uses a diaphragm and spermicide and the man uses a condom), or abstinence. 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Hypoglycemia, no upper gastrointestinal (GI) surgery<br>Males or females with hypoglycemia with neuroglycopenia, but no history of upper GI surgery, diabetes or prediabetes | Other: Entry of demographic and medical history data into a deidentified database<br>* Entry into repository for analysis.<br>Genetic: Blood sample for DNA analysis<br>* Targeted resequencing of DNA to identify variants associated with hypoglycemia, comparing participants with hypoglycemia (both surgical and non-surgical) and healthy controls.<br>Diagnostic Test: Stool sample for microbiome analysis<br>* 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.<br>Diagnostic Test: Mixed meal tolerance test<br>* For a subset of participants: 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.<br>* Other names: Meal Testing;Diagnostic Test: Continuous glucose monitoring<br>* A CGM sensor (Dexcom G4 or other professional version available at onset of study) will be placed 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.<br>Diagnostic Test: activity monitor<br>* The activity monitor (Fitbit Charge 2) will be worn by participants for 10 days, to assess activity, concurrent with CGM sensor wear.<br>|
| Hypoglycemia, with history of upper GI surgery<br>Males or females with hypoglycemia with neuroglycopenia, with history of upper GI surgery | Other: Entry of demographic and medical history data into a deidentified database<br>* Entry into repository for analysis.<br>Genetic: Blood sample for DNA analysis<br>* Targeted resequencing of DNA to identify variants associated with hypoglycemia, comparing participants with hypoglycemia (both surgical and non-surgical) and healthy controls.<br>Diagnostic Test: Stool sample for microbiome analysis<br>* 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.<br>Diagnostic Test: Mixed meal tolerance test<br>* For a subset of participants: 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.<br>* Other names: Meal Testing;Diagnostic Test: Continuous glucose monitoring<br>* A CGM sensor (Dexcom G4 or other professional version available at onset of study) will be placed 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.<br>Diagnostic Test: activity monitor<br>* The activity monitor (Fitbit Charge 2) will be worn by participants for 10 days, to assess activity, concurrent with CGM sensor wear.<br>|
| Controls, without hypoglycemia or upper GI surgery<br>Males or females with no history of upper gastrointestinal surgery, hypoglycemia, or diabetes. | Other: Entry of demographic and medical history data into a deidentified database<br>* Entry into repository for analysis.<br>Genetic: Blood sample for DNA analysis<br>* Targeted resequencing of DNA to identify variants associated with hypoglycemia, comparing participants with hypoglycemia (both surgical and non-surgical) and healthy controls.<br>Diagnostic Test: Stool sample for microbiome analysis<br>* 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.<br>Diagnostic Test: Mixed meal tolerance test<br>* For a subset of participants: 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.<br>* Other names: Meal Testing;Diagnostic Test: Continuous glucose monitoring<br>* A CGM sensor (Dexcom G4 or other professional version available at onset of study) will be placed 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.<br>Diagnostic Test: activity monitor<br>* The activity monitor (Fitbit Charge 2) will be worn by participants for 10 days, to assess activity, concurrent with CGM sensor wear.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Entry of medical history data into a deidentified database. | Medical history data will be entered into RedCap for analysis. | March 2020 through March 2025 | 
| Entry of physical exam data into a deidentified database. | Pertinent physical exam data will be entered into RedCap for analysis. | March 2020 through March 2025 | 
| Entry of laboratory data into a deidentified database. | Laboratory data will be entered into RedCap for analysis. | March 2020 through March 2025 | 
| Entry of demographic data into a deidentified database. | Demographic data will be entered into RedCap for analysis. | March 2020 through March 2025 | 
| Analysis of participant demographics and medical history, comparing the 3 study groups. | Demographic and medical history data will be summarized in RedCap and compared between groups using ANOVA or chi-square testing, depending on the variable analyzed. | March 2025 | 
| Targeted resequencing of DNA to identify variants associated with hypoglycemia, comparing patients with hypoglycemia (both surgical and non-surgical) and healthy controls. | Sequence variants identified during targeted resequencing will be summarized and prevalence will be compared between groups and with population databases. Depending on results of targeted resequencing, additional expanded genotyping may be performed. | March 2025 | 
| Analysis of microbiome, comparing study groups. | Microbiome will be characterized by sequencing to obtain metagenomic data and pathway analysis; all data will be adjusted for multiple comparisons. | March 2025 | 
| Analysis of glucose patterns during masked continuous glucose monitoring (CGM), including time in range, time in hypoglycemia, time in hyperglycemia, comparing the study groups. | For a subset of participants who consent to participate in optional Visit 2, 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. | March 2025 | 
| Analysis of metabolic responses during mixed meal testing. | For a subset of participants who consent to participate in optional Visit 2, magnitude of hypoglycemia will be correlated with metabolite levels during meal testing. Metabolites will be measured at set time points after the start of the mixed meal. Linear mixed effects modeling will be utilized to identify group- and time-dependent differences in metabolic 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. The relationship between clinical and metabolic variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing. | March 2025 | 
| Analysis of hormonal responses during mixed meal testing. | For a subset of participants who consent to participate in optional Visit 2, magnitude of hypoglycemia will be correlated with hormone levels during meal testing. Counterregulatory hormones will be measured at set time points after the start of the mixed meal. 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. The relationship between clinical and hormonal variables will be analyzed using Pearson correlation, and adjusted for multiple comparisons using Benjamini-Hochberg testing. | March 2025 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relationship between metabolic responses and magnitude of hypoglycemia as determined by CGM. | This is for a subset of participants (non-surgical hypoglycemia and controls) participating in optional Visit 2. Magnitude of hypoglycemia will be correlated with metabolite levels during meal testing. | March 2025 | 
| Relationship between hormonal responses and magnitude of hypoglycemia as determined by CGM. | This is for a subset of participants (non-surgical hypoglycemia and controls) participating in optional Visit 2. Magnitude of hypoglycemia will be correlated with counterregulatory hormone levels during meal testing. | March 2025 | 
| Relationship between metabolic responses and microbiome. | This is for a subset of participants (non-surgical hypoglycemia and controls) participating in optional Visit 2. Metagenomic data will be correlated with metabolic responses during meal testing. | March 2025 | 
| Relationship between hormonal responses and microbiome. | This is for a subset of participants (non-surgical hypoglycemia and controls) participating in optional Visit 2. Metagenomic data will be correlated with counterregulatory hormone responses during meal testing. | March 2025 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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DNA, Microbiome, Hormones, Genetics