Drug could help horses with insulin problems, researchers report

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The medication, used in humans, reduced plasma insulin levels in horses after an oral sugar test.
File image by pasja1000

A type of medication used in people with type 2 diabetes may have therapeutic value in horses affected by insulin dysregulation, researchers report.

The study, carried out in the experimental herd at the New Bolton Center, part of the School of Veterinary Medicine at the University of Pennsylvania, investigated the effects of a synthetic GLP-1 analog called exenatide. It is a medication that exerts an effect on hormones called incretins.

Researchers Darko Stefanovski, Mary Robinson and Andrew Van Eps, writing in the journal BMC Veterinary Research, said insulin dysregulation is the most important risk factor for the development of laminitis in horses. Therapies are needed to control it.

In affected horses and ponies, hyperinsulinemia is most pronounced after carbohydrate ingestion. Therefore, understanding and controlling the insulin response following meals is critical to developing effective laminitis prevention and management strategies for affected horses.

Consumption of nutrients stimulates the secretion of gut-originating hormones such as the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Both have been termed incretin hormones for their ability to promote insulin secretion and thus potentially lead to high blood insulin levels in humans.

The authors said GLP-1 analogs have been at the forefront of therapy for type 2 diabetes in humans, because of their observed incretin effect: augmentation of glucose-dependent insulin secretion after meals.

GLP-1 analogs might be expected to exacerbate post-meal hyperinsulinemia in horses with insulin dysregulation, they said. However, a recent study revealed the presence of GLP-1 receptors in a wide range of equine tissues, suggesting that it is likely GLP-1 also has incretin-independent actions in the horse.

In addition, the same study showed that exenatide (in contrast to the effects of human GLP-1) did not stimulate the secretion of insulin in equine isolated pancreatic islets. In humans, it has been shown that GLP-1 analogs can slow gastric emptying, decrease the rate of glucose absorption, and subsequently blunt the post-meal insulin response.

“It is therefore unclear what effects synthetic GLP-1 agonists may have when administered to horses; however their therapeutic potential warrants investigation.”

The study team set out to assess the effect of a single dose of exenatide on insulin and glucose dynamics in horses after being given sugar by mouth. They hypothesized that, in horses, exenatide would improve insulin sensitivity and reduce hyperinsulinemia.

The study involved three mares and three geldings. Two were assessed as having normal insulin regulation and four were affected by mild insulin dysregulation.

The authors used a randomized, crossover experimental study, in which the insulin response from an oral sugar test on all horses was assessed twice – once after an injection of exenatide 30 minutes beforehand, and once without exenatide (the control). Blood samples were taken over a four-hour period to monitor the response. The sugar was given as Karo syrup, at a rate of 0.15 milligrams per kilogram of body weight.

The study team found that the exenatide resulted in a post-meal decrease in plasma insulin levels of 20%.

For the four horses classified as affected mildly by insulin dysregulation, the treatment resulted in the normalization of their plasma insulin concentrations during the oral sugar test.

The observed reduction in glucose and insulin in the current study both suggest that exenatide augmented the uptake of insulin and nutrients in the periphery (muscle tissue), and as such had enhanced whole-body insulin sensitivity.

This was also consistent with the findings that exenatide treatment in horses improved insulin sensitivity.

The authors acknowledged several limitations in their study, including the small number of horses and the fact that those with insulin dysregulation were only mildly affected. Concerns over possible exacerbation of hyperinsulinemia with exenatide use meant that horses with severe insulin dysregulation were not specifically recruited for the study. Also, only a single dose was given and it is unclear what effects chronic dosing might have on insulin dynamics.

Further studies are needed to evaluate the effects of exenatide, including its effects on gastric emptying, they said.

Regardless of the mechanism of action, the results show that post-meal hyperinsulinemia may be reduced using a synthetic GLP-1 agonist. This, they said, may ultimately prove to be a useful therapy for insulin dysregulation in horses.

“No ill effects from a single dose of exenatide were noted and this treatment may potentially be useful for reducing hyperinsulinemia in response to ingested carbohydrates in horses.

“Further research evaluating the safety and efficacy of GLP-1 analogs specifically in insulin dysregulated horses, is warranted.”

Stefanovski, D., Robinson, M.A. & Van Eps, A. Effect of a GLP-1 mimetic on the insulin response to oral sugar testing in horses. BMC Vet Res 18, 294 (2022). https://doi.org/10.1186/s12917-022-03394-2

The study, published under a Creative Commons License, can be read here

 

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