Exendin-(9-39) Effects on Glucose and Insulin in Children With Congenital Hyperinsulinism During Fasting and During a Meal and a Protein Challenge

Abstract

Objective: The aim of this study was to assess whether exendin-(9-39) will increase fasting and postprandial plasma glucose and decrease the incidence of hypoglycemia in children with hyperinsulinism (HI).

Research design and methods: This was an open-label, four-period crossover study. In periods 1 and 2, the effect of three different dosing regimens of exendin-(9-39) (group 1, 0.28 mg/kg; group 2, 0.44 mg/kg; group 3, 0.6 mg/kg) versus vehicle on fasting glucose was assessed in 16 children with HI. In periods 3 and 4, a subset of eight subjects received either vehicle or exendin-(9-39) (0.6 mg/kg) during a mixed-meal tolerance test (MMTT) and an oral protein tolerance test (OPTT).

Results: Treatment group 2 showed 20% (P = 0.037) increase in the area under the curve (AUC) of fasting glucose. A significant increase in AUC of glucose was also observed during the MMTT and OPTT; treatment with exendin-(9-39) resulted in 28% (P ≤ 0.001) and 30% (P = 0.01) increase in AUC of glucose, respectively. Fasting AUC of insulin decreased by 57% (P = 0.009) in group 3. In contrast, AUC of insulin was unchanged during the MMTT and almost twofold higher (P = 0.004) during the OPTT with exendin-(9-39) treatment. In comparison with vehicle, infusion of exendin-(9-39) resulted in significant reduction in likelihood of hypoglycemia in group 2, by 76% (P = 0.009), and in group 3, by 84% (P = 0.014). Administration of exendin-(9-39) during the OPTT resulted in 82% (P = 0.007) reduction in the likelihood of hypoglycemia.

Conclusions: These results support a therapeutic potential of exendin-(9-39) to prevent fasting and protein-induced hypoglycemia in children with HI.

Trial registration: ClinicalTrials.gov NCT00897676.

© 2022 by the American Diabetes Association.

Figures

Figure 1

Study protocol. Vertical arrows indicate when samples were taken. Horizontal lines indicate infusion of vehicle and exendin-(9-39) (Ex-9).

Figure 2

Graphical depiction of mathematical model of concurrent secretion and subsequent elimination of insulin and C-Peptide.

Figure 3

Average temporal fasting profile of plasma glucose (A), insulin (B), C-peptide (C), and glucagon (D) during infusion of vehicle; exendin-(9-39) with infusion rate 300 pmol/kg/min for 2 h, then 100 pmol/kg/min for 2 h, and then 300 pmol/kg/min for 2 h (group 1); exendin-(9-39) with infusion rate 300 pmol/kg/min for 2 h, then 500 pmol/kg/min for 2 h, and then 300 pmol/kg/min for 2 h (group 2); and exendin-(9-39) with infusion rate 500 pmol/kg/min for 6 h (group 3).

Figure 4

Average (with SE bars) temporal profiles of plasma glucose (A), insulin (B), and C-peptide (C) during MMTT for treatment with vehicle (●) and exendin-(9-39) at a rate of 500 pmol/kg/min (0.1 mg/kg/h) i.v. for 6 h (solid line, ▴). The lines in A and B represent the mathematical model fit for the vehicle (dashed line) and exendin-(9-39) (solid line) groups.

Figure 5

Average (with SE bars) temporal profiles of plasma glucose (A), insulin (B), and C-peptide (C) during OPTT for treatment with vehicle (dashed line, ●) and exendin-(9-39) at a rate of 500 pmol/kg/min (0.1 mg/kg/h) i.v. for 6 h (solid line, ▴). The lines in B represent the mathematical model fit for the vehicle (dashed line) and exendin-(9-39) (solid line) groups.