Effect of sirolimus on insulin dynamics in horses.
Authors: de Tonnerre Demia J, Medina Torres Carlos E, Stefanovski Darko, Robinson Mary A, Kemp Kate L, Bertin François-René, van Eps Andrew W
Journal: Journal of veterinary internal medicine
Summary
Hyperinsulinemia represents a significant clinical challenge in equine practice, and sirolimus—an mTOR inhibitor already used therapeutically in other species—offers a potentially valuable pharmacological approach to managing insulin dysregulation in horses. Researchers at this institution conducted a two-phase investigation: first establishing the pharmacokinetics of oral sirolimus in healthy Standardbreds (finding rapid peak concentrations around 277 ng/mL within 5 minutes but modest bioavailability of 9.5%, with a notably prolonged half-life of approximately 59 hours), then evaluating its effects on insulin dynamics via oral glucose tolerance testing in both healthy horses and those with dexamethasone-induced insulin dysregulation. A single sirolimus dose produced clinically meaningful reductions in post-glucose insulin concentrations at 24 hours post-administration—approximately 37% lower at 60 minutes and 28% lower at 120 minutes compared to placebo—whilst glucose concentrations remained essentially unchanged, indicating a selective effect on insulin secretion rather than glucose metabolism. Seven days of continuous sirolimus treatment further reduced insulinemic responses in dysregulated horses, suggesting potential therapeutic benefit in chronic management. Given these encouraging results, practitioners managing horses with insulin dysregulation should anticipate further clinical trials; however, the low oral bioavailability and lengthy half-life will require careful consideration regarding dosing schedules and cost-effectiveness in practice settings.
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Practical Takeaways
- •Sirolimus shows promise as a potential therapeutic agent for managing hyperinsulinemia in horses, with measurable reductions in post-glucose insulin responses within 24 hours of administration
- •The drug's long half-life (approximately 2.5 days) supports feasibility for practical clinical dosing schedules
- •Further investigation with longer treatment periods and larger sample sizes is needed before clinical implementation; this preliminary evidence warrants monitoring for potential application in horses with metabolic syndrome and insulin dysregulation
Key Findings
- •Sirolimus achieved peak concentration of 277.0 ng/mL within 5 minutes with a half-life of 3552 minutes and oral bioavailability of 9.5%
- •24 hours after a single sirolimus dose, insulin concentration at 60 minutes was 37% lower than placebo (5.0 vs 8.7 μIU/mL, P=0.03)
- •Insulin response at 120 minutes post-glucose was 28% lower with sirolimus than placebo 24 hours after dosing (10.2 vs 14.9 μIU/mL, P=0.02)
- •In insulin dysregulation horses, insulin responses decreased toward baseline after 7 days of sirolimus treatment with minimal effect on glucose concentration