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Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia

This study has been completed.
Sponsor:
Collaborator:
Lester and Liesel Baker Foundation
Information provided by (Responsible Party):
Diva De Leon, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier:
NCT01162499
First received: May 4, 2010
Last updated: September 22, 2016
Last verified: September 2016
  Purpose

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.


Condition Intervention
Postprandial Hypoglycemia
Drug: Exendin-(9-39)
Other: Vehicle

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Open Label
Official Title: Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia After Nissen Fundoplication: Studies With the GLP-1 Receptor Antagonist Exendin-(9-39)

Resource links provided by NLM:


Further study details as provided by Children's Hospital of Philadelphia:

Primary Outcome Measures:
  • Mean Plasma Glucose Area Under the Curve (AUC 0-3h) [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Mean Plasma Insulin Area Under the Curve (AUC 0-3h) [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
    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.

  • Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h) [ Time Frame: 3 hours ] [ Designated as safety issue: No ]
    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.

  • Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During Infusion [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.

  • Peak Glucagon Concentration During Infusion [ Time Frame: 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 ] [ Designated as safety issue: No ]
    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.


Enrollment: 7
Study Start Date: April 2010
Study Completion Date: December 2014
Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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 Name: Normal Saline

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.
  Eligibility

Ages Eligible for Study:   6 Months to 18 Years   (Child, Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT01162499

Locations
United States, Pennsylvania
The Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, United States, 19104
Sponsors and Collaborators
Diva De Leon
Lester and Liesel Baker Foundation
Investigators
Principal Investigator: Diva De Leon, MD Children's Hospital of Philadelphia
  More Information

Responsible Party: Diva De Leon, M.D. Assistant Professor of Pediatrics, Children's Hospital of Philadelphia
ClinicalTrials.gov Identifier: NCT01162499     History of Changes
Other Study ID Numbers: 09-007372 
Study First Received: May 4, 2010
Results First Received: July 29, 2016
Last Updated: September 22, 2016
Health Authority: United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by Children's Hospital of Philadelphia:
Post prandial hypoglycemia
hypoglycemia
Nissen fundoplication
Dumping

Additional relevant MeSH terms:
Hypoglycemia
Glucose Metabolism Disorders
Metabolic Diseases
Glucagon-Like Peptide 1
Glucagon
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Gastrointestinal Agents

ClinicalTrials.gov processed this record on December 02, 2016