Effects of high-intensity interval training on metabolic impairments in liver tissue of rats with type 2 diabetes: a metabolomics-based approach

Abstract

Our aim was to study the metabolic effects of eight weeks of high-intensity interval training (HIIT) on the liver of rats with type 2 diabetes (T2D) using untargeted metabolomics. Twenty male Wistar rats, were divided into four groups (n = 5 per group): control (CTL), type 2 diabetes (DB), HIIT (EX), and type 2 diabetes + HIIT (DTX). A two months of a high-fat diet followed by a single dose of streptozotocin (35 mg/kg body weight) was used to induce T2D. Animals in the EX and DTX groups were trained for eight weeks (5 times per week, 4-10 running intervals at 80-100% of their maximum velocity). Metabolomic data were collected using proton nuclear magnetic resonance (¹H-NMR) to assess metabolic changes in the liver after training. Data were then pre-processed using ProMetab (MATLAB) for baseline correction, normalisation and binning. Fasting blood glucose (FBG) levels were analysed using a repeated-measures mixed ANOVA [i.e., time as the within-subject factor (Baseline - Month 0, Post-induction - Month 2, and Post-intervention - Month 4) and gruop (CTL, DB, HIIT, DTX) as the between-subject factor]. A one-way ANOVA with Tukey's post hoc test (p < 0.05) was applied to assess differences in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR). Multivariate analysis - using sparse partial least squares discriminant analysis (sPLS-DA) - was performed to identify key metabolites, followed by pathway analysis (MetaboAnalyst) to determine significantly affected metabolic pathways. DB group showed higher HOMA-IR than CTL and DTX groups (p < 0.05). Furthermore, distinct clustering patterns was shown for metabolites by multivariate analysis. Key altered metabolic pathways included valine, leucine, and isoleucine biosynthesis; glutathione metabolism; pantothenate and coenzyme A biosynthesis; fructose and mannose metabolism; glycine, serine, and threonine metabolism; cysteine and methionine metabolism; arginine biosynthesis; tyrosine metabolism; histidine metabolism; beta-alanine metabolism; propanoate metabolism; glycolysis/gluconeogenesis; phenylalanine, tyrosine, and tryptophan biosynthesis; arginine and proline metabolism; and thiamine metabolism. These results suggest that eight weeks of HIIT may reverse metabolic changes induced by T2D in the rat liver, potentially contributing to reduced FBG and HOMA-IR levels. Clinical trial number: Not applicable.

Keywords: High-intensity interval training; Liver metabolism; Metabolomics; Type 2 diabetes.