Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia

Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia After Nissen Fundoplication: Studies With the GLP-1 Receptor Antagonist Exendin-(9-39)

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.

Study Overview

• Status: Completed
• Conditions: Postprandial Hypoglycemia
• Intervention / Treatment: Drug: Exendin-(9-39); Other: Vehicle

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.

• Study Type: Interventional
• Enrollment (Actual): 7
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 18 years (ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: OTHER
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: 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.	Drug: Exendin-(9-39); IV infusion of exendin-(9-39) for 5 hours; Other: Vehicle; Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr; Other Names: Normal Saline
ACTIVE_COMPARATOR: 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.	Drug: Exendin-(9-39); IV infusion of exendin-(9-39) for 5 hours; Other: Vehicle; Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr; Other Names: Normal Saline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Plasma Glucose Area Under the Curve (AUC 0-3h)	To examine the effect of Exendin-(9-39) on plasma glucose levels samples were collected at various time points before and during the infusion [Exendin-(9-39) or vehicle] including: 60 minutes before the start of the infusion, again at the start of the infusion (time 0), and then every 30 minutes until 3 hours after the start of the meal. Using this information, the mean plasma glucose area under the curve (AUC) from the start of the infusion to the end of the infusion (3 hours) was calculated for both doses of Exendin-(9-39) [300pmol/kg/min & 500pmol/kg/min] and compared with the vehicle.	3 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Plasma Insulin Area Under the Curve (AUC 0-3h)	To examine the effect of Exendin-(9-39) on plasma insulin levels, samples were collected at various time points before and during the infusion [Exendin-(9-39) or vehicle] including: 60 minutes before the start of the infusion, again at the start of the infusion (time 0), and then every 30 minutes until 3 hours after the start of the meal. Using this information, the mean plasma insulin area under the curve (AUC) from the start of the infusion to the end of the infusion (3 hours) was calculated for both doses of Exendin-(9-39) [300pmol/kg/min & 500pmol/kg/min] and compared with the vehicle.	3 hours
Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h)	The effect of gastric emptying was examined using the acetaminophen method whereby acetaminophen (30mg/kg or maximum of 1500mg) was mixed into the Pediasure/formula during the meal tolerance testing. Blood samples were collected every 30 minutes and the absorption of acetaminophen was determined by the gastric emptying rate, as the serum concentrations correlate with gastric emptying of liquids. Mean acetaminophen levels for each group at each time point were used to calculate the Area Under the Concentration versus Time Curve (AUC expressed in μg*min/l) after the consumption of formula for each of the two Exendin-(9-39) dose levels and normal saline vehicle.	3 hours
Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During Infusion	To examine the effect of Exendin-(9-39) on plasma glucagon-like peptide-1 levels, samples were collected at various time points before and during the infusion [Exendin-(9-39) or vehicle] including: 60 minutes before the start of the infusion, again at the start of the infusion (time 0), and then every 30 minutes until 3 hours after the start of the infusion. The mean peak glucagon-like peptide-1 concentration for both Exendin-(9-39) doses were compared with the peak glucagon-like peptide-1 during vehicle infusion.	60 minutes before the start of the infusion, again at the start of the infusion (time 0), and then every 30 minutes until 3 hours after the start of the infusion
Peak Glucagon Concentration During Infusion	To examine the effect of Exendin-(9-39) on plasma glucagon levels, samples were collected at various 3 hours after the start of the infusion. The mean peak glucagon concentration for both Exendin-(9-39) doses were compared with the peak glucagon during vehicle infusion.	60 minutes before the start of the infusion, again at the start of the infusion (time 0), and then every 30 minutes until 3 hours after the start of the infusion

Collaborators and Investigators

• Sponsor: Diva De Leon
• Collaborators: Lester and Liesel Baker Foundation

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ACTUAL): December 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: May 4, 2010
• First Submitted That Met QC Criteria: July 13, 2010
• First Posted (ESTIMATE): July 14, 2010

Study Record Updates

• Last Update Posted (ACTUAL): October 23, 2017
• Last Update Submitted That Met QC Criteria: September 21, 2017
• Last Verified: September 1, 2017

More Information

Terms related to this study

• Keywords: hypoglycemia; Nissen fundoplication; Post prandial hypoglycemia; Dumping
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hypoglycemia
• Other Study ID Numbers: 09-007372