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

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.Electronic supplementary materialThe online version of this article (10.1186/s12917-018-1479-z) contains supplementary material, which is available to authorized users.

Metabolic changes induced by oral glucose tests in horses and their diagnostic use

“…The fold change of H1 can be used as a scale to interpret the shifts in other metabolites, because it should have the highest magnitude.Of the 14 amino acids that varied significantly over time, only Trp and Gly had a positive concentration gradient during the test, whereas all others were negative. The decrease in amino acids corroborates previous reports on the metabolome during the OGT in humans and horses and could be attributed to insulin-induced decreased proteolysis and enhanced cellular amino acid uptake 9,31,32. T A B L E 2 Indicators of model performance for the baseline and 120 minutes partial least-squares discriminant analysis (PLS-DA) as obtained by leave-one-out-cross-validation on all samples.…”

“…An increase of Trp during the OGT previously has been reported in ponies, 17 whereas kynurenine was shown to increase in horses 9 . In our study, both molecules and their ratio (kynurenine : tryptophan) exhibited a positive concentration gradient, which might be attributable to enhanced indoleamine 2,3‐dioxygenase (IDO) activity, considered to be induced by inflammatory processes and associated with metabolic syndrome in humans 33 .…”

Important roles of dietary taurine, creatine, carnosine, anserine and 4-hydroxyproline in human nutrition and health

“…4-Hydroxyproline oxidase is the rate-controlling enzyme in the conversion of 4-hydroxyproline into glycine (Wu et al 2011) and is induced by cortisol (Phang et al 2010). Thus, the circulating levels of hydroxylproline are reduced in animals with fatigue (caused by deprivation of rest and sleep; a physical stress condition) or oxidative stress (Kenéz et al 2018;Kume et al 2015).…”

Metabolomics window into the role of acute kidney injury after coronary artery bypass grafting in diabetic nephropathy progression

“…Its level in circulation has been correlated with the degree of fibrosis in chronic hepatitis (Attallah et al, 2007;Lawrence et al, 2019). Moreover, abnormal plasma trans-4-hydroxy-L-proline concentration was found in an insulin-dysregulated animal model (Kenez et al, 2018). Changes in trans-4-hydroxy-L-proline in circulation have been reported, along with collagen metabolism, fibrosis, and insulin-dysregulation.…”