Congenital Hyperinsulinism
Conditions
Keywords
hyperinsulinism, hypoglycemia, KATP channel, Kir6.2
Brief summary
The purpose of this study is to determine if Exendin-(9-39), an antagonist of the glucagon-like peptide-1 (GLP-1) receptor with effects on the pancreatic beta cell, increases fasting blood glucose levels in subjects with congenital hyperinsulinism.
Detailed description
This is an open-label, pilot study , to determine if Exendin-(9-39), an antagonist of the glucagon-like peptide-1 (GLP-1) receptor with effects on the pancreatic beta cells, increases fasting blood glucose levels in subjects with congenital hyperinsulinism. Our overall hypothesis is that abnormal GLP-1 secretion resulting from dysfunctional nutrient sensing in intestinal L-cells plays a role in the dysregulated insulin secretion characteristic of this disorder, and that antagonism of the GLP-1 receptor will increase fasting blood glucose levels. Aim 1. To evaluate the dose of exendin-(9-39) required to elevate fasting blood glucose levels in subjects with congenital hyperinsulinism due to KATP channel mutations. Aim 2. To determine therapeutic plasma levels, plasma half-life and pharmacokinetics of exendin-(9-39) during an intravenous short-term infusion in subjects with congenital hyperinsulinism due to Adenosine triphosphate (ATP)-sensitive potassium channel (KATP) mutations.
Interventions
DRUGExendin-(9-39)
A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.
OTHERVehicle
A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.
Sponsors
National Institutes of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Diva De Leon
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
7 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Subjects with congenital hyperinsulinism
Exclusion criteria
* Acute medical illness * History of other systemic chronic disease such as cardiac failure, renal insufficiency, hepatic insufficiency, chronic obstructive pulmonary disease, anemia, or uncontrolled hypertension * Pregnancy * Diabetes mellitus * Use of medications that affect glucose metabolism, such as glucocorticoids, beta agonists, diazoxide and octreotide. * Subjects will be eligible to participate 48 hrs after the last dose of octreotide and 72 hrs after last dose of diazoxide
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mean Blood Glucose Area Under the Curve (AUC 0-6h) | 6 hours | To examine the effect of Exendin-(9-39) on fasting blood 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean blood glucose area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Plasma Insulin Area Under the Curve (AUC 0-6h) | 6 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma insulin area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. |
| Mean Plasma Glucagon Area Under the Curve (AUC 0-6h) | 6 hours | To examine the effect of Exendin-(9-39) on plasma glucagon 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma glucagon area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. |
| Mean Plasma Intact Glucagon-Like Peptide-1 (GLP-1) Area Under the Curve (AUC 0-6h) | 6 hours | To examine the effect of Exendin-(9-39) on plasma intact glucagon-like Peptide-1 (GLP-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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean intact GLP-1 area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared. |
Countries
United States
Participant flow
Recruitment details
Subjects with confirmed genetic and clinical diagnosis of Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) hyperinsulinism were recruited from the Hyperinsulinism Center at the Children's Hospital of Philadelphia
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. | 9 |
| Total | 9 |
Baseline characteristics
| Characteristic | Subject Population |
|---|---|
| Age, Categorical <=18 years | 4 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 5 Participants |
| Mutation (ABCC8) Compound heterozygous recessive ABCC8 mutations | 1 participants |
| Mutation (ABCC8) Heterozygous dominant ABCC8 mutations | 6 participants |
| Mutation (ABCC8) Homozygous common recessive Ashkenazi mutation | 2 participants |
| Pancreatectomy 85% Pancreatectomy | 1 participants |
| Pancreatectomy 95% Pancreatectomy | 2 participants |
| Pancreatectomy None | 6 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 | 9 Participants |
| Region of Enrollment United States | 9 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 9 | 4 / 9 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 |
Outcome results
Primary
Mean Blood Glucose Area Under the Curve (AUC 0-6h)
To examine the effect of Exendin-(9-39) on fasting blood 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean blood glucose area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.
Time frame: 6 hours
Population: Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exendin-(9-39) | Mean Blood Glucose Area Under the Curve (AUC 0-6h) | 2,096 mmol*min/L | Standard Error 454 |
| Vehicle | Mean Blood Glucose Area Under the Curve (AUC 0-6h) | 1,678 mmol*min/L | Standard Error 281 |
Secondary
Mean Plasma Glucagon Area Under the Curve (AUC 0-6h)
To examine the effect of Exendin-(9-39) on plasma glucagon 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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma glucagon area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.
Time frame: 6 hours
Population: Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Exendin-(9-39) | Mean Plasma Glucagon Area Under the Curve (AUC 0-6h) | 21,243 pg*min/dL |
| Vehicle | Mean Plasma Glucagon Area Under the Curve (AUC 0-6h) | 21,867 pg*min/dL |
Secondary
Mean Plasma Insulin Area Under the Curve (AUC 0-6h)
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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean plasma insulin area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.
Time frame: 6 hours
Population: Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Exendin-(9-39) | Mean Plasma Insulin Area Under the Curve (AUC 0-6h) | 21,016 pmol*min/L |
| Vehicle | Mean Plasma Insulin Area Under the Curve (AUC 0-6h) | 25,842 pmol*min/L |
Secondary
Mean Plasma Intact Glucagon-Like Peptide-1 (GLP-1) Area Under the Curve (AUC 0-6h)
To examine the effect of Exendin-(9-39) on plasma intact glucagon-like Peptide-1 (GLP-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 20 minutes until 6 hours after the start of the infusion. Using this information, the mean intact GLP-1 area under the curve (AUC) from the start of the infusion to the end of the infusion (360 minutes) was calculated for each both Exendin-(9-39) and vehicle and compared.
Time frame: 6 hours
Population: Subjects served as their own control for comparison between effects of Exendin-(9-39) and the normal saline vehicle.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Exendin-(9-39) | Mean Plasma Intact Glucagon-Like Peptide-1 (GLP-1) Area Under the Curve (AUC 0-6h) | 1,970 pmol*min/L |
| Vehicle | Mean Plasma Intact Glucagon-Like Peptide-1 (GLP-1) Area Under the Curve (AUC 0-6h) | 1,992 pmol*min/L |