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

Diva De Leon

Status and phase: Completed; Phase 2; Phase 1

Conditions: Congenital Hyperinsulinism

Treatments: Drug: Exendin-(9-39); Other: Vehicle

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT00571324

2007-1-5131

R03DK078535-01 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full 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.

Enrollment: 9 patients

Sex: All

Ages: 7 to 60 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Other

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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9 participants in 2 patient groups, including a placebo group

Exendin-(9-39) first, the Vehicle

Experimental group

Description:

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.

Treatment:

Other: Vehicle

Drug: Exendin-(9-39)

Vehicle first, then Exendin-(9-39)

Placebo Comparator group

Description:

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.

Treatment:

Other: Vehicle

Drug: Exendin-(9-39)