Faculty, Staff and Student Publications
Language
English
Publication Date
3-1-2023
Journal
Journal of Veterinary Internal Medicine
DOI
10.1111/jvim.16650
PMID
36840433
PMCID
PMC10061188
PubMedCentral® Posted Date
February 2023
PubMedCentral® Full Text Version
Post-print
Abstract
BACKGROUND: Sirolimus, a mechanistic target of rapamycin inhibitor, suppresses insulin production in other species and has therapeutic potential for hyperinsulinemia in horses.
HYPOTHESIS/OBJECTIVE: Determine the pharmacokinetics (PKs) of sirolimus and evaluate its effect on insulin dynamics in healthy and insulin dysregulation (ID) horses.
ANIMALS: Eight Standardbred geldings.
METHODS: A PK study was performed followed by a placebo-controlled, randomized, crossover study. Blood sirolimus concentrations were measured by liquid chromatography-mass-spectrometry. PK indices were estimated by fitting a 2-compartment model using nonlinear least squares regression. An oral glucose test (OGT) was conducted before and 4, 24, 72, and 144 hours after administration of sirolimus or placebo. Effects of time, treatment and animal on blood glucose and insulin concentrations were analyzed using mixed-effects linear regression. Sirolimus was then administered to 4 horses with dexamethasone-induced ID and an OGT was performed at baseline, after ID induction and after 7 days of treatment.
RESULTS: Median (range) maximum sirolimus concentration was 277.0 (247.5-316.06) ng/mL at 5 (5-10) min and half-life was 3552 (3248-4767) min. Mean (range) oral bioavailability was 9.5 (6.8-12.4)%. Sirolimus had a significant effect on insulin concentration 24 hours after a single dose: median (interquartile range) insulin at 60 min (5.0 [3.7-7.0] μIU/mL) was 37 (-5 to 54)% less than placebo (8.7 [5.8-13.7] μIU/mL, P = .03); and at 120 min (10.2 [8.4-12.2] μIU/mL) was 28 (-15 to 53)% less than placebo (14.9 [8.4-24.8] μIU/mL, P = .02). There was minimal effect on glucose concentration. Insulin responses decreased toward baseline in ID horses after 7 days of treatment.
CONCLUSION AND CLINICAL IMPORTANCE: Sirolimus decreased the insulinemic response to glucose and warrants further investigation.
Keywords
Horses, Animals, Male, Insulin, Glucose Tolerance Test, Cross-Over Studies, Blood Glucose, Glucose, Horse Diseases
Published Open-Access
yes
Recommended Citation
de Tonnerre, Demia J; Medina Torres, Carlos E; Stefanovski, Darko; et al., "Effect of Sirolimus On Insulin Dynamics In Horses" (2023). Faculty, Staff and Student Publications. 2590.
https://digitalcommons.library.tmc.edu/uthmed_docs/2590