Effect of Exendin-(9-39) on Glycemic Control in Subjects With Congenital Hyperinsulinism

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open Label Pilot Study of the Effects of the Glucagon-like Peptide-1 Receptor Antagonist, Exendin-(9-39) on Glycemic Control in Subjects With Congenital Hyperinsulinism

Conditions
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Congenital Hyperinsulinism

Intervention / Treatment
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* Drug: Exendin-(9-39)
* Other: Vehicle


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 7 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exendin-(9-39) first, the Vehicle<br>Exendin-(9-39) will be administered intravenously (IV) after an overnight fast. Exendin-(9-39) will be infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. The following day, after another overnight fast, normal saline (control) vehicle infusion will be administered intravenously (IV) over 6 hours. During both infusions, blood glucose levels will be measured every 20 minutes. | Drug: Exendin-(9-39)<br>* A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.<br>Other: Vehicle<br>* A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.<br>* Other names: Placebo;|
| Placebo Comparator: Vehicle first, then Exendin-(9-39)<br>Normal saline vehicle infusion will be administered intravenously (IV) after an overnight fast. The infusion will be given over 6 hours. The following day, after another overnight fast, Exendin-(9-39) will be infused over 6 hours with the dose slowly escalating from 100pmol/kg/min for 2 hours, then 300pmol/kg/min for another 2 hours followed by 500pmol/kg/min for the last 2 hours of the infusion. During both infusions, blood glucose levels will be measured every 20 minutes. | Drug: Exendin-(9-39)<br>* A short term intravenous infusion of the study drug, exendin-(9-39), will be given over 6 hours.<br>Other: Vehicle<br>* A short term intravenous infusion of normal saline, or the vehicle, will be given over 6 hours.<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 6 hours | 
| 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. | 6 hours | 
| 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. | 6 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hyperinsulinism, hypoglycemia, KATP channel, Kir6.2