A glucagon-like peptide-1 receptor antagonist reduces the insulin response to a glycemic meal in ponies.

Abstract: High plasma concentrations of insulin can cause acute laminitis. Ponies and horses with insulin dysregulation (ID) exhibit marked hyperinsulinemia in response to dietary hydrolyzable carbohydrates. Glucagon-like peptide-1 (GLP-1), an incretin hormone released from the gastrointestinal tract, enhances insulin release, and is increased postprandially 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 glycemic meal. Five adult ponies were adapted to a cereal meal and then given two feed challenges 24 h apart of a meal containing 3 g/kg BW micronized maize. Using a randomized 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 h 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 glycemic 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. Horses and ponies are prone to suffer from laminitis if they produce too much insulin after eating a high-sugar/starch meal. Laminitis associated with high insulin is very painful and can result in the affected animals having to be put down. The reason why some ponies over-produce insulin is not known. However, we do know that small molecules produced in the upper intestine contribute to the problem. In this study we blocked the action of these molecules, to see if we could reduce the insulin released after a meal that was high in soluble carbohydrate (starch and sugar) content, in ponies. Using a specially designed drug, we were able to reduce insulin responses to the meal by over 20%. None of the ponies had any clinical problems in this study. This study helped us to explain why some animals produce excessive insulin; this compound may even have potential as a future therapy. However, whilst a promising finding, this effect was not as strong as it needs to be to help prevent laminitis in all animals. The next step is to test the drug at different doses, and under varying conditions, to see whether we can improve its performance.