Back to resultsRole of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia
Primary Purpose
Postprandial Hypoglycemia
Status
Completed
Phase
Not Applicable
Locations
United States
Study Type
Interventional
Intervention
Exendin-(9-39)
Vehicle
Sponsored by
About this trial
This is an interventional other trial for Postprandial Hypoglycemia focused on measuring Post prandial hypoglycemia, hypoglycemia, Nissen fundoplication, Dumping
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
Sites / Locations
- The Children's Hospital of Philadelphia
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Active Comparator
Arm Label
Exendin-(9-39) first, then Vehicle
Vehicle first, then Exendin-(9-39)
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
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.
Secondary Outcome Measures
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.
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.
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.
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.
Full Information
NCT ID
NCT01162499
First Posted
May 4, 2010
Last Updated
September 21, 2017
Sponsor
Diva De Leon
Collaborators
Lester and Liesel Baker Foundation
1. Study Identification
Unique Protocol Identification Number
NCT01162499
Brief Title
Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia
Official Title
Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia After Nissen Fundoplication: Studies With the GLP-1 Receptor Antagonist Exendin-(9-39)
Study Type
Interventional
2. Study Status
Record Verification Date
September 2017
Overall Recruitment Status
Completed
Study Start Date
April 2010 (undefined)
Primary Completion Date
December 2014 (Actual)
Study Completion Date
December 2014 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Diva De Leon
Collaborators
Lester and Liesel Baker Foundation
4. Oversight
Data Monitoring Committee
No
5. Study Description
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Postprandial Hypoglycemia
Keywords
Post prandial hypoglycemia, hypoglycemia, Nissen fundoplication, Dumping
7. Study Design
Primary Purpose
Other
Study Phase
Not Applicable
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
7 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Exendin-(9-39) first, then Vehicle
Arm Type
Experimental
Arm Description
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.
Arm Title
Vehicle first, then Exendin-(9-39)
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Exendin-(9-39)
Intervention Description
IV infusion of exendin-(9-39) for 5 hours
Intervention Type
Other
Intervention Name(s)
Vehicle
Other Intervention Name(s)
Normal Saline
Intervention Description
Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr
Primary Outcome Measure Information:
Title
Mean Plasma Glucose Area Under the Curve (AUC 0-3h)
Description
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.
Time Frame
3 hours
Secondary Outcome Measure Information:
Title
Mean Plasma Insulin Area Under the Curve (AUC 0-3h)
Description
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.
Time Frame
3 hours
Title
Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h)
Description
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.
Time Frame
3 hours
Title
Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During Infusion
Description
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.
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
Title
Peak Glucagon Concentration During Infusion
Description
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.
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Diva De Leon, MD
Organizational Affiliation
Children's Hospital of Philadelphia
Official's Role
Principal Investigator
Facility Information:
Facility Name
The Children's Hospital of Philadelphia
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia
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