Post-Prandial Carbohydrate Metabolism in Individuals With and Without Post-Bariatric Surgery Hypoglycemia (PBH)

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.

Study Overview

• Status: Recruiting
• Conditions: Hypoglycemia; Bariatric Surgery; Hypoglycemia, Reactive
• Intervention / Treatment: Drug: Glucagon for Injection (Fresenius Kabi USA); Drug: [6,6-2H2] glucose; Drug: [13C9, 15N1]-glucagon; Drug: [1-13C] glucose; Drug: [2-13C] glucose

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.

• Study Type: Interventional
• Enrollment (Estimated): 40
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • University of Alabama
      • Contact: Ananda Basu, MD; Phone Number: 205-975-0471; Email: anandabasu@uabmc.edu
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Recruiting
      • Joslin Diabetes Center
      • Contact: Mary-Elizabeth Patti, MD; Phone Number: 617-309-2400; Email: mary.elizabeth.patti@joslin.harvard.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: RYGB non-hypoglycemia; Individuals that underwent Roux-en-y gastric bypass (RYGB) at least 2 years prior to recruitment and do not have a diagnosis of PBH.	Drug: Glucagon for Injection (Fresenius Kabi USA); 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.
Experimental: Post-Bariatric Hypoglycemia (PBH); Individuals that underwent RYGB at least 2 years prior to recruitment and have a diagnosis of PBH.	Drug: Glucagon for Injection (Fresenius Kabi USA); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group differences in iAUC for postprandial EGP	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.	During Visit 2, within 10 days of the baseline visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Between-group differences in the integrated postprandial response (iAUC) of Ra glucagon	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.	During Visit 2, within 10 days of the baseline visit
Between-group differences in EGP in the fasting state	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.	During Visit 2, within 10 days of the baseline visit
Between-group differences in iAUC for glucose levels for 60 minutes after postprandial glucagon administration	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.	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	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).	During Visit 2, within 10 days of the baseline visit
Between-group differences in insulin secretion, as estimated by postprandial phi total	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).	During Visit 2, within 10 days of the baseline visit
Between-group differences in disposition index derived from oral glucose minimal model	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).	During Visit 2, within 10 days of the baseline visit
Between-group differences in basal glycogen content, measured by MRI	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.	During Visit 2, within 10 days of the baseline visit.
Between-group differences in meal-stimulated changes in glycogen content, measured by change from baseline	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.	During Visit 2, within 10 days of the baseline visit

Collaborators and Investigators

• Sponsor: Joslin Diabetes Center
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); University of Alabama at Birmingham
• Investigators: Principal Investigator: Ananda Basu, MD, University of Alabama at Birmingham; Principal Investigator: Mary-Elizabeth Patti, MD, Joslin Diabetes Center

Study record dates

Study Major Dates

• Study Start (Actual): January 27, 2026
• Primary Completion (Estimated): January 1, 2027
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: August 6, 2026
• First Submitted That Met QC Criteria: September 9, 2026
• First Posted (Actual): September 14, 2026

Study Record Updates

• Last Update Posted (Actual): September 14, 2026
• Last Update Submitted That Met QC Criteria: September 9, 2026
• Last Verified: September 1, 2026

More Information

Terms related to this study

• Keywords: glucagon sensitivity
• Additional Relevant MeSH Terms: Metabolic Diseases; Glucose Metabolism Disorders; Nutritional and Metabolic Diseases; Hypoglycemia; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Peptide Hormones; Peptides; Amino Acids, Peptides, and Proteins; Therapeutics; Drug Administration Routes; Drug Therapy; Carbohydrates; Sugars; Pancreatic Hormones; Hexoses; Monosaccharides; Proglucagon; Glucagon; Injections; Glucose
• Other Study ID Numbers: STUDY00000341; R01DK137518 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified participant data may be shared with other researchers with permission of local institutional review boards.
• IPD Sharing Time Frame: 6 months after publication of study results
• IPD Sharing Access Criteria: Data will be shared with academic investigators with approval of local institutional review boards.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No