Lower plasma trans-4-hydroxyproline and methionine sulfoxide levels are associated with insulin dysregulation in horses.

Abstract

BACKGROUND: Insulin dysregulation in horses is a metabolic condition defined by high insulin concentrations in the blood and peripheral insulin resistance. This hyperinsulinemia is often associated with severe damage in the hooves, resulting in laminitis. However, we currently lack detailed information regarding the potential involvement of particular metabolic pathways in pathophysiological causes and consequences of equine insulin dysregulation. This study aimed to assess the dynamic metabolic responses given to an oral glucose test (OGT) in insulin-sensitive and insulin-dysregulated horses by a targeted metabolomics approach to identify novel metabolites associated with insulin dysregulation. RESULTS: Oral glucose testing triggered alterations in serum insulin (26.28&#x2009;&#xb1;&#x2009;4.20 vs. 422.84&#x2009;&#xb1;&#x2009;88.86 &#x3bc;IU/mL, p&#x2009;<&#x2009;0.001) and plasma glucose concentrations (5.00&#x2009;&#xb1;&#x2009;0.08 vs. 9.43&#x2009;&#xb1;&#x2009;0.44&#xa0;mmol/L, p&#x2009;<&#x2009;0.001) comparing basal and stimulated conditions after 180&#xa0;min. Metabolome analyses indicated OGT-induced changes in short-chain acylcarnitines (6.00&#x2009;&#xb1;&#x2009;0.53 vs. 3.99&#x2009;&#xb1;&#x2009;0.23&#xa0;&#x3bc;mol/L, p&#x2009;<&#x2009;0.001), long-chain acylcarnitines (0.13&#x2009;&#xb1;&#x2009;0.004 vs. 0.11&#x2009;&#xb1;&#x2009;0.002&#xa0;&#x3bc;mol/L, p&#x2009;<&#x2009;0.001) and amino acids (2.18&#x2009;&#xb1;&#x2009;0.11 vs. 1.87&#x2009;&#xb1;&#x2009;0.08&#xa0;&#x3bc;mol/L, p&#x2009;<&#x2009;0.05). Kynurenine concentrations increased (2.88&#x2009;&#xb1;&#x2009;0.18 vs. 3.50&#x2009;&#xb1;&#x2009;0.19&#xa0;&#x3bc;mol/L, p&#x2009;<&#x2009;0.01), whereas spermidine concentrations decreased during OGT (0.09&#x2009;&#xb1;&#x2009;0.004 vs. 0.08&#x2009;&#xb1;&#x2009;0.002&#xa0;&#x3bc;mol/L, p&#x2009;<&#x2009;0.01), indicating proinflammatory conditions after oral glucose load. Insulin dysregulation was associated with lower concentrations of trans-4-hydroxyproline (4.41&#x2009;&#xb1;&#x2009;0.29 vs. 6.37&#x2009;&#xb1;&#x2009;0.71&#xa0;&#x3bc;mol/L, p&#x2009;<&#x2009;0.05) and methionine sulfoxide (0.40&#x2009;&#xb1;&#x2009;0.06 vs. 0.87&#x2009;&#xb1;&#x2009;0.13&#xa0;&#x3bc;mol/L, p&#x2009;<&#x2009;0.01; mean&#x2009;&#xb1;&#x2009;SEM in insulin-dysregulated vs. insulin-sensitive basal samples, respectively), two metabolites which are related to antioxidant defense mechanisms. CONCLUSION: Oral glucose application during OGT resulted in profound metabolic and proinflammatory changes in horses. Furthermore, insulin dysregulation was predicted in basal samples (without OGT) by pathways associated with trans-4-hydroxyproline and methionine sulfoxide, suggesting that oxidative stress and oxidant-antioxidant disequilibrium are contributing factors to insulin dysregulation. The present findings provide new hypotheses for future research to better understand the underlying pathophysiology of insulin dysregulation in horses.