New Drug for Lowering Insulin Levels in Horses Shows Promise

A medication called Exendin-3 (9-39) blocks the receptors to a hormone called glucagon-like peptide-1 (GLP-1), which inhibits insulin production. When used in ponies, Exendin-3 (9-39) partially reduced insulin levels following a high-starch meal. Medications blocking GLP-1 receptors could therefore prove to be suitable therapeutic agents to include in a multidrug treatment protocol for hyperinsulinemia-associated laminitis.

Horse and ponies with insulin dysregulation, a central feature of equine metabolic syndrome, have high circulating insulin levels. Hyperinsulinemia is a known trigger for laminitis, a painful, life-threatening hoof condition. According to nutritionists, managing horses and ponies with insulin dysregulation and laminitis should focus on improving insulin levels and inducing weight loss when needed.

“The main dietary strategy for managing horses with insulin dysregulation is to reduce the intake of nonstructural carbohydrates (NSC). Ideally, owners should look for hay that contains no more than 10% NSC on an as-fed basis. If low-NSC hay cannot be sourced, owners can soak the hay to reduce the NSC concentration,” recommended Ashley Fowler, Ph.D., a nutritionist for Kentucky Equine Research.

Some patients, however, fail to respond to diet alone or cannot be exercised due to severe laminitis. In such cases, many veterinarians are reaching for sodium-glucose co-transporter-2 inhibitors (SGLT2i) to improve insulin dysregulation and laminitis, often with much success.

Nonetheless, researchers are still looking for other ways to approach insulin dysregulation and hyperinsulinemia-associated laminitis, including the GLP-1 receptor antagonists.^* Such medications, including Exendin-3 (9-39), inhibit the production of GLP-1 that stimulates the insulin secretion following a meal.

To determine if Exendin-3 (9-39) decreases the magnitude of the insulin response following a high sugar meal, five ponies were used in a study. All ponies underwent a standard oral sugar test, and three were diagnosed with insulin dysregulation.

Starting three weeks prior to the study, the ponies were adapted to a diet high in hydrolysable carbohydrates using a feed that provided 2.2 g NSC/kg body weight daily. The remainder of the diet consisted of a vitamin-mineral supplement, soybean hulls, lucerne chaff, and grass hay restricted to 1% of body weight (26 g NSC/100 g hay). The diet was designed to provide highly available nonstructural carbohydrates to stimulate insulin, so the effects of the drug, if any, could be evaluated.

All ponies were then administered a dose of Exendin-3 (9-39) intravenously on two consecutive days before a morning serving of the highly hydrolysable carbohydrate meal. Blood samples were obtained immediately prior to feeding and treatment and again at 30-minute intervals for six hours. Insulin, glucose, and GLP-1 levels were measured. The study was then repeated using an intravenous injection of sterile water for a control.

Insulin responses to a highly hydrolysable carbohydrate meal were decreased following Exendin-3 (9-39). This study also found no change in glucose levels following the meal, and GLP-1 levels were not altered with treatment.

Thus, blocking GLP-1 receptors partially reduced insulin production following the highly hydrolysable carbohydrate meal.

“This is promising news as we currently have no medications licensed for the management of hyperinsulinemia in horses. Medications that lower insulin secretion following a meal would play a vital role in reducing hyperinsulinemia-associated laminitis,” Fowler says.

Additional studies such as dose optimization and using Exendin-3 (9-39) in conjunction with diets low in NSC are needed.

Until then, owners are encouraged to offer feeds containing less than 10% NSC in conjunction with an exercise program when appropriate. If weight loss is needed, hay can be restricted to 1.5% of body weight and slow-feeders can be used to prolong eating time throughout the day.

“In addition, offering a balancer pellet or vitamin and mineral supplement helps meet the requirements for essential minerals and vitamins that may be lacking in hay. Adding a high-quality protein source may also be beneficial as some hays contain low crude protein. If the hay is soaked to lower the NSC, adding these additional nutrients to the ration becomes even more important,” advised Fowler.

^*de Laat, M.A., D.M. Fitzgerald, P.A. Harris, and S.R. Bailey. 2023. A glucagon-like peptide-1 receptor antagonist reduces the insulin response to a glycemic meal in ponies. Journal of Animal Science 101:skad389.