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

Ákos Kenéz,Karsten Feige,Korinna Huber,Tobias Warnken

doi:10.1186/s12917-018-1479-z

Abstract

BackgroundInsulin 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.ResultsOral glucose testing triggered alterations in serum insulin (26.28 ± 4.20 vs. 422.84 ± 88.86 μIU/mL, p < 0.001) and plasma glucose concentrations (5.00 ± 0.08 vs. 9.43 ± 0.44 mmol/L, p < 0.001) comparing basal and stimulated conditions after 180 min. Metabolome analyses indicated OGT-induced changes in short-chain acylcarnitines (6.00 ± 0.53 vs. 3.99 ± 0.23 μmol/L, p < 0.001), long-chain acylcarnitines (0.13 ± 0.004 vs. 0.11 ± 0.002 μmol/L, p < 0.001) and amino acids (2.18 ± 0.11 vs. 1.87 ± 0.08 μmol/L, p < 0.05). Kynurenine concentrations increased (2.88 ± 0.18 vs. 3.50 ± 0.19 μmol/L, p < 0.01), whereas spermidine concentrations decreased during OGT (0.09 ± 0.004 vs. 0.08 ± 0.002 μmol/L, p < 0.01), indicating proinflammatory conditions after oral glucose load. Insulin dysregulation was associated with lower concentrations of trans-4-hydroxyproline (4.41 ± 0.29 vs. 6.37 ± 0.71 μmol/L, p < 0.05) and methionine sulfoxide (0.40 ± 0.06 vs. 0.87 ± 0.13 μmol/L, p < 0.01; mean ± SEM in insulin-dysregulated vs. insulin-sensitive basal samples, respectively), two metabolites which are related to antioxidant defense mechanisms.ConclusionOral 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.

Highlights

Insulin dysregulation in horses is a metabolic condition defined by high insulin concentrations in the blood and peripheral insulin resistance
The clustering algorithm applied to these data divided the horses clearly into two groups, which was the basis to assign them to either the IS (n = 10) or ID (n = 10) group
The IS group consisted of horses that had low to medium insulin concentrations in response to oral glucose test (OGT), while the ID group consisted of horses that had high insulin concentrations in response to OGT

Summary

Introduction

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. New hypotheses concerning affected pathways can be established as a basis for new experimental designs by introducing novel associations between certain metabolites and phenotypic observations. These new scientific studies will help to identify pathophysiological causes or consequences of equine insulin dysregulation. The identification of potential biomarkers capturing the acute health status is another benefit of metabolomics approaches

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