Divergent fasting lactate responses are associated with serum multi-omics remodelling after 14-week high-intensity interval training in type 2 diabetes

Fasting lactate responses after HIIT in T2DM patients show significant variability, indicating that individual metabolic adaptations can differ widely and may not align with conventional glycaemic improvements.

Summary and findings

This study investigated the fasting lactate response and its association with serum multi-omics remodeling in patients with type 2 diabetes mellitus (T2DM) after a 14-week high-intensity interval training (HIIT) intervention. Participants were classified into lactate-decreased, lactate-maintained, and lactate-increased groups based on their lactate changes. The findings indicated significant differences in fasting lactate levels and metabolic adaptations among these groups.

Abstract

<title>Abstract</title> <p> <bold>Background</bold> Type 2 diabetes mellitus (T2DM) is characterised by impaired glucose regulation, insulin resistance and altered substrate metabolism. Exercise training improves glycaemic control and cardiorespiratory fitness, but individual metabolic adaptation remains heterogeneous. We investigated whether fasting lactate response after chronic exercise identifies distinct clinical and serum multi-omics remodelling patterns in T2DM. <bold>Methods</bold> This study included an independent baseline validation cohort and a 14-week supervised exercise intervention cohort. In the baseline cohort, fasting lactate, clinical markers and serum metabolomic profiles were compared between non-T2DM controls and patients with T2DM. In the intervention cohort, patients with T2DM completed rowing-based high-intensity interval training (HIIT), with fasting lactate assessed at baseline, week 7 and week 14. Exercised participants were classified according to tertiles of 0–14-week lactate change into lactate-decreased (LD), lactate-maintained (LM) and lactate-increased (LI) groups. Clinical markers, continuous glucose monitoring (CGM) profiles, untargeted serum metabolomics and serum proteomics were analysed. <bold>Results</bold> At baseline, patients with T2DM had higher fasting lactate than non-T2DM controls (1.72 ± 0.70 vs. 1.06 ± 0.57 mmol/L; P < 0.001, false discovery rate < 0.001), accompanied by impaired glucose–insulin homeostasis and exploratory metabolomic differences. During training, fasting lactate showed marked inter-individual heterogeneity. From baseline to week 14, lactate decreased in LD (− 1.08 ± 1.20 mmol/L), remained relatively stable in LM (+ 0.09 ± 0.21 mmol/L) and increased in LI (+ 1.15 ± 0.60 mmol/L), whereas the non-exercise control group showed minimal change (− 0.04 ± 0.79 mmol/L). The 0–14-week lactate change differed markedly between LD and LI (P < 0.001), and baseline lactate was inversely associated with subsequent lactate change (ρ = −0.63, P < 0.001). Fasting glucose, CGM profiles and peak oxygen uptake improved across trained groups. However, LI showed unfavourable trends in fasting insulin, HOMA-IR and triglyceride responses. Exploratory serum metabolomics linked lactate response to lipid- and redox-related features, including phospholipid, sphingolipid, acylcarnitine and fatty-acid handling modules, with PI (17:0/14:1(9Z)) emerging as the strongest adjusted candidate. Exploratory proteomics further highlighted lipid/adipokine, immune/complement, extracellular remodelling and cellular stress/RNA-related features. <bold>Conclusions</bold> Fasting lactate was elevated in T2DM and showed heterogeneous adaptation after 14 weeks of HIIT. Lactate-response groups captured a metabolic dimension not fully reflected by conventional glycaemic improvement. Exploratory metabolomic and proteomic findings suggest multi-layered substrate-handling, redox-related and systemic remodelling signatures associated with divergent lactate responses, warranting targeted validation in larger cohorts. <bold>Trial registration:</bold> Chinese Clinical Trial Registry, ChiCTR-IOR-16008469. </p>

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