Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia

NCT ID: NCT01162499

Last Updated: 2017-10-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 7 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-04-30
• Study Completion Date: 2014-12-31

Brief Summary

It has been proposed that the rapid gastric emptying of carbohydrate containing fluids into the intestine causes hyperglycemia followed by reactive hypoglycemia. The investigators have shown that glucagon-like peptide-1 (GLP-1) secretion in response to a glucose load is increased in children with Post-prandial hypoglycemia (PPH). This is a proof of concept study to investigate the causative role of GLP-1 in the pathophysiology of PPH after fundoplication by evaluating the effects of GLP-1 receptor antagonism on metabolic variables after a mixed meal.

Hypothesis: In children with post-prandial hypoglycemia after fundoplication, antagonism of the GLP-1 receptor by exendin-(9-39) will elevate nadir blood glucose levels after a meal challenge and prevent post-prandial hypoglycemia.

Detailed Description

PPH is a frequent complication of fundoplication in children. The mechanism responsible for the PPH is poorly understood, but involves an exaggerated insulin response to a meal and subsequent hypoglycemia. We have shown that children with PPH after Nissen fundoplication have abnormally exaggerated secretion of GLP-1, an incretin hormone with multiple glucose lowering effects including stimulation of insulin secretion and suppression of glucagon secretion. In this study we seek to examine the causal role of endogenous GLP-1 in PPH after fundoplication by evaluating the effects of antagonizing the GLP-1 receptor with exendin-(9-39) on key metabolic features of PPH.

Conditions

Postprandial Hypoglycemia

Keywords

Post prandial hypoglycemia; hypoglycemia; Nissen fundoplication; Dumping

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: NONE

Study Groups

Exendin-(9-39) first, then Vehicle

After an overnight fast, an intravenous (IV) infusion of Exendin-(9-39) will be started 1 hour prior to the meal challenge and continued for 5 hours. After the first hour of the infusion, subjects will undergo a mixed meal tolerance test in which Pediasure (10cc/kg) will be consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes (for infants under 12 months, Pediasure will be replaced by the infant's formula). Blood samples will be drawn at different time points during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1). The Exendin-(9-39) dose for the first 3 subjects will be 300pmol/kg/min and, if tolerated, the dose will be increased to 500pmol/kg/min for subsequent subjects.

The next day, all procedures will be repeated except subjects will receive an IV infusion of normal saline (vehicle) over 6 hours.

Group Type: EXPERIMENTAL

Exendin-(9-39)

Intervention Type: DRUG

IV infusion of exendin-(9-39) for 5 hours

Vehicle

Intervention Type: OTHER

Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr

Vehicle first, then Exendin-(9-39)

After an overnight fast, an intravenous (IV) infusion of normal saline (vehicle) will be started 1 hour prior to the meal challenge and continued for 5 hours. After the first hour of the infusion, subjects will undergo a mixed meal tolerance test in which Pediasure (10cc/kg) will be consumed by mouth or gastrostomy/nasogastric tube over a period of 15 minutes (for infants under 12 months, Pediasure will be replaced by the infant's formula). Blood samples will be drawn at different time points during the infusion to measure blood glucose, plasma insulin, glucagon and plasma glucagon-like-peptide-1 (GLP-1).

The next day, all procedures will be repeated except subjects will receive an IV infusion of Exendin-(9-39) which will be started 1 hour prior to the meal challenge and continue for 5 hours. The dose for the first 3 subjects will be 300pmol/kg/min and, if tolerated, the dose will be increased to 500pmol/kg/min for subsequent subjects.

Group Type: ACTIVE_COMPARATOR

Exendin-(9-39)

Intervention Type: DRUG

IV infusion of exendin-(9-39) for 5 hours

Vehicle

Intervention Type: OTHER

Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr

Interventions

Exendin-(9-39)

IV infusion of exendin-(9-39) for 5 hours

Intervention Type: DRUG

Vehicle

Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr

Intervention Type: OTHER

Other Intervention Names

Normal Saline

Eligibility Criteria

Inclusion Criteria

• Children (6 months-18 years) who have had fundoplication or other gastric surgeries, irrespective of duration of postoperative period
• Weight > 6.5 Kg
• Signs and/or symptoms of PPH: post-prandial blood glucose levels of < 70 mg/dL ; symptoms including but not limited to feeding difficulties, irritability, nausea, diarrhea, pallor, diaphoresis, weakness, and lethargy after meals

Exclusion Criteria

• Evidence of a medical condition that might alter results or compromise the elimination of the peptide, including, but not limited to: active infection, kidney failure (creatinine ≥ 2x above upper limit for age), severe liver dysfunction (AST or ALT ≥ 5x upper limit of normal for AST or ALT), severe respiratory or cardiac failure
• Other disorders of glucose regulation such as diabetes mellitus, congenital hyperinsulinism, glycogen storage disease
• Current use (within 1 week) of medications that may alter glucose homeostasis such as glucocorticoids, diazoxide, octreotide
• Use of antihistaminics within 10 days prior to the study
• Moderate and severe anemia defined as a hemoglobin < 10g/dL
• Pregnancy
• Milk and soy protein allergy

• Minimum Eligible Age: 6 Months
• Maximum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Lester and Liesel Baker Foundation

UNKNOWN

Sponsor Role: collaborator

Diva De Leon

OTHER

Sponsor Role: lead

Responsible Party

Diva De Leon

M.D. Assistant Professor of Pediatrics

Responsibility Role: SPONSOR_INVESTIGATOR

Principal Investigators

Diva De Leon, MD

Role: PRINCIPAL_INVESTIGATOR

Children's Hospital of Philadelphia

Locations

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Countries

United States

Other Identifiers

09-007372

Identifier Type: -

Identifier Source: org_study_id