Equine Internal Medicine Resident The Ohio State University Columbus, Ohio
Insulin dysregulation (ID), a hallmark of equine metabolic syndrome (EMS), is intrinsically related to the development of laminitis. 5’-Adenosine-monophoshpate-activated protein kinase (AMPK) agonists are used in humans to promote euglycemia and enhance systemic insulin sensitivity, representing a promising therapy for horses with EMS. This study investigated hepatic AMPK signaling in response to AMPK agonists (metformin [MET], aspirin [ASP], combination [MET/ASP]) in horses with experimentally-induced ID. Insulin dysregulation was induced in 14 adult light breed horses with dexamethasone (0.08 mg/kg PO q24h). The horses were assigned to groups, and each horse received either ASP (10 mg/kg PO q24h; n=7) or MET (30 mg/kg PO q12h; n=7) for 7 days. Seven horses then received MET/ASP for an additional 7 days. To assess AMPK regulation, liver biopsy samples were obtained at the following time points: baseline, ID, ID + monotherapy, and ID + combination therapy. Real-time polymerase chain reaction (qPCR) was performed to evaluate expression of AMPKα, peroxisome proliferator-activated receptor-γ (PPARγ), peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α), and phosphoenolpyruvate carboxykinase (PEPCK) at all timepoints. The expression of AMPKα was significantly increased with combination therapy compared to baseline (P = 0.0114). PPARγ expression was significantly decreased at ID + monotherapy (P = 0.0026) but not with combination therapy, suggesting a partial response to combination treatment. The expression of PGC1α was not significantly affected by any treatment. PEPCK expression was significantly decreased by administration of dexamethasone (P = 0.0114). These findings suggest that AMPK agonist therapy can alter hepatic AMPK-related gene expression in adult horses.