Role of Glucagon-Like Peptide-1 in Postprandial Hypoglycemia

Not Applicable

Completed

Conditions: Postprandial Hypoglycemia

Interventions: Drug: Exendin-(9-39)
Other: Vehicle

Registration Number: NCT01162499

Lead Sponsor: Diva De Leon

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 7

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 & Design

Study Type: INTERVENTIONAL

Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
Exendin-(9-39) first, then Vehicle	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.
Vehicle first, then Exendin-(9-39)	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.
Exendin-(9-39) first, then Vehicle	Exendin-(9-39)	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.
Vehicle first, then Exendin-(9-39)	Vehicle	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.

Primary Outcome Measures

Name	Time	Method
Mean Plasma Glucose Area Under the Curve (AUC 0-3h)	3 hours	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

Name	Time	Method
Mean Plasma Insulin Area Under the Curve (AUC 0-3h)	3 hours	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)	3 hours	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	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	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	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	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.