Incretins May Not Play a Role in Insulin Dysregulation

A study found that the nonsteroidal anti-inflammatory drug phenylbutazone, or “bute,” decreased insulin and glucose concentrations following an oral glucose test (OGT).^*

This finding suggests a beneficial role of phenylbutazone in horses with hyperinsulinemia-associated laminitis (HAL). The mechanisms explaining the beneficial effects, however, were not explored. A follow-up study by the same researchers investigated the potential role of the enteroinsular axis as cause for the positive effects of phenylbutazone, yet this hypothesis was disproved.

Insulin dysregulation is characterized by high levels of insulin circulating in the bloodstream, known as hyperinsulinemia. Elevated insulin levels contribute to the development of HAL, which is believed to be responsible for over 90% of all laminitis cases. Horses with HAL suffer from chronic pain and are therefore often treated with phenylbutazone.

“The researchers suggested that the enteroinsular axis might be involved in the beneficial effects of phenylbutazone on hyperinsulinemia, decreasing the occurrence of HAL. This axis involves the gastrointestinal or enteric system and the pancreas as well as hormones called incretins. Specifically, incretins are released by the gastrointestinal system and stimulate insulin secretion,” explained Kathleen Crandell, Ph.D., a nutritionist for Kentucky Equine Research.

Examples of incretins include glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). Another peptide thought to be involved in glucose dynamics in horses is glucagon-like peptide 2 (GLP-2).

To determine if phenylbutazone affected the levels of GIP, GLP-1, and GLP-2, the researchers recruited 16 horses, seven with insulin dysregulation and nine without. Horses were treated with a standard 4.4 mg/kg intravenous dose of phenylbutazone once daily for nine days. An OGT was then performed, and GIP, GLP-1, and GLP-2 concentrations were measured at 0, 15, 30, 60, 90, and 120 minutes. Following a washout period, another OGT was performed in horses without phenylbutazone as a control.

“No clinically relevant changes in GIP, GLP-1, and GLP-2 were observed in the horses treated with phenylbutazone. These results suggest that the enteroinsular axis and incretins have a smaller role in insulin dysregulation than hypothesized,” summarized Crandell.

The fact that phenylbutazone appears to lower glucose and insulin levels in horses with insulin dysregulation is good news, as it suggests that phenylbutazone is safe in animals with HAL. Other ways of helping horses with insulin dysregulation include medications (specifically the sodium glucose cotransporter-2 inhibitors) and dietary modifications.

“Horses with insulin dysregulation benefit from a weight-loss program consisting of decreasing high-glycemic/calorie-dense feedstuffs while still meeting their nutrient requirements. Limiting grazing and feeding a lower sugar hay as well as high-fiber/low-starch feeds can meet a horse’s forage requirement. Supplementing with a ration balancer such as All-Phase or a concentrated vitamin and mineral supplement can also be used to assure proper nutrition and a balanced diet,” Crandell advised.

^*Kemp, K.L., J.E. Skinner, and F.-R. Bertin. 2025. Effect of phenylbutazone administration on the enteroinsular axis in horses with insulin dysregulation. Journal of Veterinary Internal Medicine. 39(1):e17256.