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Journal of animal science2023; 101; doi: 10.1093/jas/skad389

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.
© The Author(s) 2023. Published by Oxford University Press on behalf of the American Society of Animal Science.
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Publication Date: 2023-12-09 PubMed ID: 38066683PubMed Central: PMC10724109DOI: 10.1093/jas/skad389Google Scholar: Lookup
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Summary

This research summary has been generated with artificial intelligence and may contain errors and omissions. Refer to the original study to confirm details provided. Submit correction.

This research provides evidence that blocking the GLP-1 receptor in ponies can decrease the insulin response to a high glycaemic meal. It confirms that GLP-1 contributes to excessive insulin production, a condition particularly problematic in ponies suffering from insulin dysregulation (ID).

Objective and Background

The study is a scientific investigation into how blocking the glucagon-like peptide-1 (GLP-1) receptor affects the insulin response to a high glycaemic meal in ponies. The background context relates to the fact that high insulin levels caused by diets rich in hydrolysable carbohydrates can lead to acute laminitis, a painful condition affecting the hooves of horses and ponies. For ponies with insulin dysregulation (ID), the problem is exacerbated.

Methodology

  • The research involved five adult ponies who were adapted to a cereal meal before being subjected to two different types of feed challenges. The tests take place 24 hours apart, with each meal containing 3 grams per kilogram of micronized maize.
  • The ponies received both an authentic and a sham treatment in a randomized crossover setting. For the authentic treatment, the feed was preceded by the intravenous (IV) administration of a GLP-1 receptor blocking peptide called Exendin-3. For the sham treatment, the ponies were administered only the peptide diluent without the active blocking peptide.
  • Blood samples from the ponies were taken at regular intervals before and after feeding and peptide administration. These samples were used to measure the levels of insulin, glucose, and active GLP-1.

Findings

  • The experiment showed that neither the peptide nor the meal challenge produced any adverse effects in the ponies. It was also found that the blocking peptide did not significant affect the plasma glucose response (P = 0.36) or the plasma active GLP-1 concentrations (P = 0.35).
  • A significant finding was that the use of the GLP-1 receptor antagonist led to a substantial decrease in the insulin response, reduced area under the curve for insulin (P = 0.04).
  • There was also weak evidence (P = 0.06) of a decrease in peak insulin concentration.

Conclusions

  • This study illustrates the effect of GLP-1 receptor antagonists in reducing insulin production in ponies, particularly in response to a high-starch, high glycaemic index diet.
  • The findings also reinforce the understanding that GLP-1 contributes to extreme insulin production andlaminitis risk in ponies with ID.

Cite This Article

APA
de Laat MA, Fitzgerald DM, Harris PA, Bailey SR. (2023). A glucagon-like peptide-1 receptor antagonist reduces the insulin response to a glycemic meal in ponies. J Anim Sci, 101. https://doi.org/10.1093/jas/skad389

Publication

Journal of animal science
ISSN: 1525-3163
NlmUniqueID: 8003002
Country: United States
Language: English
Volume: 101

Researcher Affiliations

de Laat, Melody A
  • Faculty of Science, Queensland University of Technology, Brisbane, QLD, Australia.
Fitzgerald, Danielle M
  • Faculty of Science, Queensland University of Technology, Brisbane, QLD, Australia.
Harris, Patricia A
  • Equine Studies Group, Waltham Petcare Science Institute, Melton Mowbray, UK.
Bailey, Simon R
  • Melbourne Veterinary School, The University of Melbourne, Parkville, VIC, Australia.

MeSH Terms

  • Horses
  • Animals
  • Insulin
  • Glucagon-Like Peptide-1 Receptor
  • Hyperinsulinism / veterinary
  • Glucagon-Like Peptide 1
  • Diet / veterinary
  • Blood Glucose
  • Horse Diseases

Conflict of Interest Statement

Patricia A Harris works for the Waltham Petcare Science Institute, which funded the study. The study was funded by Mars Petcare UK.

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