Postprandial Hypoglycemia
Conditions
Keywords
Post prandial hypoglycemia, hypoglycemia, Nissen fundoplication, Dumping
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.
Interventions
DRUGExendin-(9-39)
IV infusion of exendin-(9-39) for 5 hours
OTHERVehicle
Normal saline (vehicle) infusion for 5 hours at 0.06 mL/kg/hr
Sponsors
Lester and Liesel Baker Foundation
Diva De Leon
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
6 Months to 18 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
Children were recruited from the Division of Endocrinology and Diabetes at The Children's Hospital of Philadelphia.
Pre-assignment details
One subject signed consent but they were excluded from study participation after the study team was unable to establish IV access.
Participants by arm
| Arm | Count |
|---|---|
| Subject Population All subjects enrolled and treated in the protocol served as their own control. Because of this and the small sample size, baseline characteristic data is presented together. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Intervention 1 (4 Hours) | Unable to establish IV access | 0 | 1 |
Baseline characteristics
| Characteristic | Subject Population |
|---|---|
| Age at Post-Prandial Hypoglycemia Diagnosis Between 1-2 years | 1 participants |
| Age at Post-Prandial Hypoglycemia Diagnosis Between 2-3 years | 1 participants |
| Age at Post-Prandial Hypoglycemia Diagnosis Between 3-4 years | 3 participants |
| Age at Post-Prandial Hypoglycemia Diagnosis Less than 1 year | 1 participants |
| Age, Categorical <=18 years | 6 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Feeding Regimen Both Oral & Gastrostomy | 3 participants |
| Feeding Regimen Gastrostomy Only | 1 participants |
| Feeding Regimen Oral Only | 2 participants |
| Post-Prandial Hypoglycemia Treatment Acarbose | 4 participants |
| Post-Prandial Hypoglycemia Treatment Feeding | 2 participants |
| Post-Prandial Hypoglycemia Treatment Frequency Frequent | 3 participants |
| Post-Prandial Hypoglycemia Treatment Frequency Intermittent | 3 participants |
| Previous Surgery Gastric pull-through | 1 participants |
| Previous Surgery Nissen fundoplication | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 3 | 0 / 3 | 2 / 6 |
| serious Total, serious adverse events | 0 / 3 | 0 / 3 | 0 / 6 |
Outcome results
Primary
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.
Time frame: 3 hours
Population: Changes were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Exendin-(9-39) 300pmol/kg/Min Dose | Mean Plasma Glucose Area Under the Curve (AUC 0-3h) | 22,192.5 mg*min/dl |
| Exendin-(9-39) 500pmol/kg/Min Dose | Mean Plasma Glucose Area Under the Curve (AUC 0-3h) | 25,207.1 mg*min/dl |
| Vehicle | Mean Plasma Glucose Area Under the Curve (AUC 0-3h) | 21,715.9 mg*min/dl |
Secondary
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.
Time frame: 3 hours
Population: AUC were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exendin-(9-39) 300pmol/kg/Min Dose | Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h) | 3,387.5 μg*min/l | Standard Error 898 |
| Exendin-(9-39) 500pmol/kg/Min Dose | Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h) | 3,742.8 μg*min/l | Standard Error 124.3 |
| Vehicle | Mean Acetaminophen Plasma Concentration Area Under the Curve (AUC 0-3h) | 3,436.6 μg*min/l | Standard Error 465.2 |
Secondary
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.
Time frame: 3 hours
Population: Changes were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Exendin-(9-39) 300pmol/kg/Min Dose | Mean Plasma Insulin Area Under the Curve (AUC 0-3h) | 14,695.85 pmol*min/l |
| Exendin-(9-39) 500pmol/kg/Min Dose | Mean Plasma Insulin Area Under the Curve (AUC 0-3h) | 9,058.5 pmol*min/l |
| Vehicle | Mean Plasma Insulin Area Under the Curve (AUC 0-3h) | 19,435.4 pmol*min/l |
Secondary
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.
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
Population: Differences in peak glucagon concentration were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exendin-(9-39) 300pmol/kg/Min Dose | Peak Glucagon Concentration During Infusion | 127.5 pg/ml | Standard Error 75.7 |
| Exendin-(9-39) 500pmol/kg/Min Dose | Peak Glucagon Concentration During Infusion | 145.7 pg/ml | Standard Error 33.6 |
| Vehicle | Peak Glucagon Concentration During Infusion | 114.0 pg/ml | Standard Error 50.1 |
Secondary
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.
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
Population: Differences were compared between the two dose levels of Exendin-(9-39) of 300pmol/kg/min (3 subjects) and 500pmol/kg/min (3 subjects) were compared to the vehicle infusion (all 6 subjects).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exendin-(9-39) 300pmol/kg/Min Dose | Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During Infusion | 65.8 pmol/l | Standard Error 33.3 |
| Exendin-(9-39) 500pmol/kg/Min Dose | Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During Infusion | 75.2 pmol/l | Standard Error 5.8 |
| Vehicle | Peak Plasma Glucagon-like Peptide-1 (GLP-1) Concentration During Infusion | 72.8 pmol/l | Standard Error 26.1 |