Bariatric Surgery, Hypoglycemia, Hypoglycemia, Reactive
Conditions
Keywords
glucagon sensitivity
Brief summary
In this study, the investigators will determine (a) whether metabolism (secretion and turnover) of glucagon is altered in patients with PBH, (b) whether this is affected by a meal, (c) whether PBH affects the ability of the body to produce glucose (endogenous glucose production), and (d) whether PBH affects the amount of glycogen in the liver (storage form of glucose) when fasting and after a meal. The investigators will determine the effect of glucagon to raise glucose levels after a meal. To answer these questions, participants will receive an infusion of a stable (nonradioactive) isotope of glucose and glucagon, and a meal containing a stable isotope of glucose. Glycogen will be measured by magnetic resonance imaging (MRI) of the liver before and after the meal. This information will be used to develop computer models for the glucagon pump system.
Detailed description
The purpose of this study is to assess post-prandial carbohydrate, hormone, and hepatic glycogen metabolism comparing individuals with post-bariatric surgery hypoglycemia (PBH+) to individuals post-bariatric surgery without hypoglycemia (PBH-). There will be 3 visits to the study center in total. In this study, the investigators will determine (a) whether metabolism (secretion and turnover) of glucagon is altered in patients with PBH, (b) whether this is affected by a meal, (c) whether PBH affects the ability of the body to produce glucose (endogenous glucose production), and (d) whether PBH affects the amount of glycogen in the liver (storage form of glucose) when fasting and after a meal. The investigators will determine the effect of glucagon to raise glucose levels after a meal. To answer these questions, participants will receive an infusion of a stable (nonradioactive) isotope of glucose and glucagon, and a meal containing a stable isotope of glucose. Glycogen will be measured by magnetic resonance imaging (MRI) of the liver before and after the meal. This information will be used to develop computer models for the glucagon pump system. During Visit 1, the participants will undergo a medical history, physical examination, vital signs, and ECG; inclusion/exclusion criteria will be assessed. Participants will also be advised to complete food log entries and to follow a low glycemic index diet. At Visit 2, a continuous glucose monitor (CGM sensor) in masked mode will be placed on the participant. During Visit 3, participants will undergo infusions of glucose, glucagon, and their respective isotope tracers, and will consume a triple tracer mixed meal containing labeled glucose. The participants will complete C13 MRS scans to estimate liver glycogen content. Participants at Joslin Diabetes Center will not have MRS; response to an exogenous subcutaneous glucagon injection in the post-prandial state will be assessed instead. Blood samples will be processed and stored for subsequent analysis.
Interventions
The investigators are assessing glucagon metabolism in individuals with and without PBH in fasting and post-prandial states.
DRUG[6,6-2H2] glucose
The investigators are using a stable isotope glucose tracer to assess glucose metabolism in individuals with and without PBH in fasting and post-prandial states.
DRUG[13C9, 15N1]-glucagon
The investigators are assessing the metabolism of glucagon in individuals with and without PBH in fasting and post-prandial states.
DRUG[1-13C] glucose
The investigators are assessing the metabolism of glucose in individuals with and without PBH in fasting and post-prandial states.
DRUG[2-13C] glucose
The investigators assessing the metabolism of glucose in individuals with and without PBH in fasting and post-prandial states.
Sponsors
Joslin Diabetes Center
University of Alabama at Birmingham
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
Yes
Inclusion criteria
* Age 18-70 years of age, inclusive, at screening. * Willingness to provide informed consent and follow all study procedures, including attending all scheduled visits. * Males or females at least 2 years following Roux-en-Y gastric bypass (RYGB) * For patients recruited to PBH group: diagnosed with ongoing PBH, with documented episodes of hypoglycemia, and history of fulfillment of Whipple's triad.
Exclusion criteria
* Documented hypoglycemia occurring only in the fasting state (\>12 hours fast); * Current diabetes, defined as hemoglobin A1c \>6.5% or use of diabetes medications, except for acarbose or miglitol; * Chronic kidney disease stage 4 or 5 (including end-stage renal disease); * Hepatic disease, including serum ALT or AST greater than 2 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, NYHA class II, III or IV; * History of myocardial infarction, unstable angina or revascularization within the past 6 months. * Two or more risk factors for coronary artery disease including diabetes, uncontrolled hypertension, uncontrolled hyperlipidemia, and active tobacco use. * History of recurrent syncope (unrelated to hypoglycemia) or active diagnosis of a cardiac arrhythmia; * Current administration of β-blocker therapy; * History of a cerebrovascular accident; * Seizure disorder (other than with suspect or documented hypoglycemia); * Active treatment with long-acting (LAR) octreotide or pasireotide; * 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; * Clinically significant anemia as defined as a hematocrit \< 33%; * 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 persons of childbearing potential: there is a requirement for a negative urine pregnancy test before any procedures. * Not enrolled in another study that uses an investigational drug for this condition.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Between-group differences in iAUC for postprandial EGP | During Visit 2, within 10 days of the baseline visit | Between-group differences in endogenous glucose production (EGP) in the postprandial state, as quantified by iAUC for postprandial EGP. These measurements will be taken at baseline and after mixed-meal consumption, specifically at minutes 10, 20, 30, 60, 90, 120, 150, and 180. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Between-group differences in the integrated postprandial response (iAUC) of Ra glucagon | During Visit 2, within 10 days of the baseline visit | Between-group differences in glucagon secretion (Ra glucagon) in the postprandial state during mixed meal testing, as quantified by integrated postprandial response (iAUC) of Ra glucagon. These measurements will be taken at baseline and after mixed-meal consumption, specifically at minutes 10, 20, 30, 60, 90, 120, 150, and 180. |
| Between-group differences in EGP in the fasting state | During Visit 2, within 10 days of the baseline visit | Between-group differences in EGP in the fasting state, as quantified by fasting EGP. Samples will be collected at baseline before consumption of a mixed meal. This will be measured at baseline. |
| Between-group differences in iAUC for glucose levels for 60 minutes after postprandial glucagon administration | During Visit 2, within 10 days of the baseline visit | Between-group differences in glycemic response to exogenous glucagon administration in the postprandial state, following mixed meal testing, as quantified by iAUC glucose for 60 minutes after postprandial glucagon administration. This will be measured at the end of mixed meal testing (180 minutes) and then every 10 minutes for up to 60 minutes. |
| Between-group differences in insulin sensitivity, as estimated by postprandial SI derived from oral glucose minimal model | During Visit 2, within 10 days of the baseline visit | Between-group differences in insulin sensitivity, as estimated by postprandial SI derived from oral glucose minimal model. This will be measured after mixed-meal consumption (timepoints 0 minutes). |
| Between-group differences in insulin secretion, as estimated by postprandial phi total | During Visit 2, within 10 days of the baseline visit | Between-group differences in insulin secretion, as estimated by postprandial phi total, derived from oral glucose minimal model. This will be measured after mixed-meal consumption (timepoint 0 minutes). |
| Between-group differences in disposition index derived from oral glucose minimal model | During Visit 2, within 10 days of the baseline visit | Between group differences in disposition index, as estimated by postprandial DI, derived from oral glucose minimal model. This will be measured after mixed-meal consumption (timepoint 0 minutes). |
| Between-group differences in basal glycogen content, measured by MRI | During Visit 2, within 10 days of the baseline visit. | Glycogen content will be measured using magnetic resonance imaging (MRI). Spectroscopy will be performed using a 3-Tesla whole-body MR imager/spectrometer. Absolute glycogen concentrations will be calculated from the integrated area of the C1-glycogen signal at 100.1 parts per million referenced to a glycogen phantom, corrected for receiver gain and reception sensitivity. This measurement by MRI will only occur at the University of Alabama at Birmingham. |
| Between-group differences in meal-stimulated changes in glycogen content, measured by change from baseline | During Visit 2, within 10 days of the baseline visit | Glycogen content will be measured using magnetic resonance imaging (MRI). Spectroscopy will be performed using a 3-Tesla whole-body MR imager/spectrometer. Absolute glycogen concentrations will be calculated from the integrated area of the C1-glycogen signal at 100.1 parts per million referenced to a glycogen phantom, corrected for receiver gain and reception sensitivity. This measurement by MRI will only occur at the University of Alabama at Birmingham. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORAnanda Basu, MD
University of Alabama at Birmingham
PRINCIPAL_INVESTIGATORMary-Elizabeth Patti, MD
Joslin Diabetes Center
Outcome results
None listed