Effect of Exendin-(9-39) on Fasting Adaptation and Protein Sensitivity

Role of GLP-1 in Congenital Hyperinsulinism:Effect of Exendin-(9-39) on Fasting Adaptation and Protein Sensitivity

The purpose of this study is to examine the effects of exendin-(9-39) on fasting blood glucose and protein induced hypoglycemia on subjects with Congenital Hyperinsulinism. Funding Source - FDA Office of Orphan Products Development (OODP).

Study Overview

• Status: Completed
• Conditions: Congenital Hyperinsulinism
• Intervention / Treatment: Drug: Exendin-(9-39); Drug: placebo

Detailed Description

This is a placebo controlled study with randomized crossover design to evaluate the effect of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin-(9-39), on fasting blood glucose levels, protein-induced hypoglycemia, and fasting tolerance of subjects with congenital hyperinsulinism due to mutations in the ATP- sensitive potassium channel (KATP) channel.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • The Children's Hospital of Philadelphia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Confirmed diagnosis of hyperinsulinism
• Mutation analysis results demonstrating KATP channel defect
• Age 6 months to 18 years with
• Persistent hypoglycemia

Exclusion Criteria:

• Current therapy with medications that may affect glucose metabolism such as octreotide, diazoxide, high dose glucocorticoids, adrenergic agents, etc. Subjects will be eligible to participate if the last dose of octreotide is given 48 hrs before study day 1 and the last dose of diazoxide is given 72 hours before study day 1
• Evidence of a medical condition that might alter results or compromised the elimination of the peptide, including active infection, kidney failure, severe liver dysfunction, severe respiratory or cardiac failure
• Pregnancy
• Subjects with milk protein allergy will be excluded for participating in studies involving protein tolerance test

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Vehicle first, then Exendin-(9-39); An infusion of vehicle (0.9%NaCl) will run for 60 minutes(time -60 to 0) before starting the study infusion of vehicle or exendin-(9-39). At time 0, vehicle (0.9%NaCl) will be started and will continue for 6 hours. The following day, at time 0, exendin-(9-39) at a dose ranging from 100-500pmol/kg/min will be started and continue for 6 hours. During both infusions, blood glucose, insulin, c-peptide, GLP-1, and glucagon will be measured every 30 minutes.	Drug: Exendin-(9-39); 100-500pmol/kg/min; Drug: placebo; placebo (0.9% NaCl); Other Names: (0.9% NaCl)
Other: Exendin-(9-39) first then Vehicle.; An infusion of vehicle (0.9%NaCl) will run for 60 minutes(time -60 to 0) before starting the study infusion of vehicle or exendin-(9-39). . At time 0, exendin-(9-39) at a dose ranging from 100-500pmol/kg/min will be started and continue for 6 hours. The following day, at time 0, vehicle (0.9%NaCl) will be started and will continue for 6 hours. During both infusions, blood glucose, insulin, c-peptide, GLP-1, and glucagon will be measured every 30 minutes. .	Drug: Exendin-(9-39); 100-500pmol/kg/min; Drug: placebo; placebo (0.9% NaCl); Other Names: (0.9% NaCl)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) Plasma Glucose	Area under the curve plasma glucose from the initiation of infusion of vehicle or exendin-(9-39) to end of the infusion	Time 0 min - time 360 min

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Curve (AUC) Plasma Insulin	Area under the curve plasma insulin from the initiation of infusion of vehicle or exendin-(9-39) to end of the infusion	time 0 min to time 360 min
Area Under the Curve (AUC) Plasma C-peptide	Area under the curve plasma C-peptide from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion	time 0 min to time 360 min
Area Under the Curve (AUC) Plasma Glucagon	Area under the curve plasma glucagon from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion	time 0 min to time 360 min
Area Under the Curve ( AUC) Plasma Total GLP-1 (Glucagon-like Peptide-1)	Area under the curve plasma total GLP-1 (glucagon-like peptide-1) from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion	time 0 to time 360 min
Area Under the Curve ( AUC) Plasma Active GLP-1 (Glucagon-like Peptide-1)	Area under the curve plasma active GLP-1 (glucagon-like peptide-1) from the beginning of the infusion of vehicle or exendin-(9-39) to the end of the infusion	time 0 min to time 360 min

Collaborators and Investigators

• Sponsor: Diva De Leon
• Investigators: Principal Investigator: Diva D DeLeon, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Stefanovski D, Vajravelu ME, Givler S, De Leon DD. Exendin-(9-39) Effects on Glucose and Insulin in Children With Congenital Hyperinsulinism During Fasting and During a Meal and a Protein Challenge. Diabetes Care. 2022 Jun 2;45(6):1381-1390. doi: 10.2337/dc21-2009.

Study record dates

Study Major Dates

• Study Start: May 1, 2009
• Primary Completion (Actual): August 26, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: May 8, 2009
• First Submitted That Met QC Criteria: May 8, 2009
• First Posted (Estimate): May 12, 2009

Study Record Updates

• Last Update Posted (Actual): March 13, 2020
• Last Update Submitted That Met QC Criteria: March 12, 2020
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: Hypoglycemia; Hyperinsulinism; KATP channel
• Additional Relevant MeSH Terms: Digestive System Diseases; Glucose Metabolism Disorders; Metabolic Diseases; Infant, Newborn, Diseases; Pancreatic Diseases; Hypoglycemia; Hyperinsulinism; Congenital Hyperinsulinism; Nesidioblastosis
• Other Study ID Numbers: 2008-10-6255; R01FD004905 (Other Grant/Funding Number: US Food and Drug Administration)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No