A glucagon-like peptide-1 receptor antagonist reduces the insulin response to a glycaemic meal in ponies1

Abstract

High plasma concentrations of insulin can cause acute laminitis. Ponies and horses with insulin dysregulation (ID) exhibit marked hyperinsulinaemia in response to dietary hydrolysable carbohydrates. Glucagon-like peptide-1 (GLP-1), an incretin hormone released from the gastrointestinal tract, enhances insulin release, and is increased post-prandially in ponies with ID. The aim of this study was to determine whether blocking the GLP-1 receptor reduces the insulin response to a high glycaemic meal. Five adult ponies were adapted to a cereal meal then given two feed challenges 24 h apart of a meal containing 3 g/kg BW micronized maize. Using a randomised cross-over design all ponies received both treatments, where one of the feeds was preceded by the IV administration of a GLP-1 receptor blocking peptide, Exendin-3 (9-39) amide (80 µg/kg), and the other feed by a sham treatment of peptide diluent only. Blood samples were taken before feeding and peptide administration, and then at 30 min intervals via a jugular catheter for 6 hours for the measurement of insulin, glucose and active GLP-1. The peptide and meal challenge caused no adverse effects, and the change in plasma glucose in response to the meal was not affected (P = 0.36) by treatment: peak concentration 9.24 ± 1.22 and 9.14 ± 1.08 mmol/L without and with the antagonist, respectively. Similarly, there was no effect (P = 0.35) on plasma active GLP-1 concentrations: peak concentration 14.3 ± 1.36 pM and 13.7 ± 1.97 pM without and with the antagonist, respectively. However, the antagonist caused a significant decrease in the area under the curve for insulin (P = 0.04), and weak evidence (P = 0.06) of a reduction in peak insulin concentration (456 ± 147 μIU/mL and 370 ± 146 μIU/mL without and with the antagonist, respectively). The lower overall insulin response to the maize meal after treatment with the antagonist demonstrates that blocking the GLP-1 receptor partially reduced insulin production in response to a high starch, high glycaemic index, diet. Using a different methodological approach to published studies, this study also confirmed that GLP-1 does contribute to the excessive insulin production in ponies with ID.