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Background <p>Patients with insulin resistance exhibit reduced cardiorespiratory fitness (CRF), assessed by peak oxygen consumption (VO₂peak), compared with healthy age-matched individuals. Although high-intensity interval training (HIIT) can substantially improve VO₂peak, there is considerable interindividual variability in this response. Therefore, further research is needed to elucidate the molecular mechanisms underlying the heterogeneous response of VO₂peak to HIIT in individuals with prediabetes.</p> Methods <p>Proteomic analyses of serum samples, along with fecal metagenomic and targeted metabolomic profiling, were conducted in medication-naïve, overweight and obese Chinese men with prediabetes (<i>n</i> = 35; aged 24–62 years). All participants underwent a 12-week HIIT intervention, and biological samples were collected both before and after the intervention to evaluate exercise-induced alterations in circulating proteins, gut microbial composition, and metabolite profiles.</p> Results <p>After 12 weeks of HIIT, mean VO₂peak increased by 0.47&#xa0;L/min with individual responses ranging from 0 to 1.7&#xa0;L/min. Baseline levels of short-chain fatty acid (SCFA)-producing genera, including <i>Prevotella</i> (β = 105.65, <i>P</i> = &lt; 0.001, FDR = 0.034), <i>Coprococcus</i> (β = 50.22, <i>P</i> = 0.01, FDR = 0.39), and <i>Hungatella</i> (β = 40.72, <i>P</i> = 0.025, FDR = 0.50), were positively associated with ΔVO₂ peak. In contrast, baseline levels of the erythropoiesis-stimulating hormone erythropoietin (EPO) (β = −279.03, <i>P</i> = 0.024, FDR = 0.99) were negatively associated with ΔVO₂ peak. Exercise-induced changes in growth hormone 1 (β = 63.97, <i>P</i> = 0.04, FDR = 0.99) were positively associated with ΔVO₂ peak, whereas exercise-induced changes in BTB and CNC Homology 1 (β = −250.82, <i>P</i> = 0.01, FDR = 0.99), a repressor of heme oxygenase-1, were negatively associated with ΔVO₂ peak. In multiple linear regression analysis including clinical variables, percentage lean mass (β = 64.17, <i>P</i> = 0.0005) was the strongest variable associated with <b>Δ</b>VO₂peak. The clinical model explained 27% of the variance which increased to 37% (<i>P</i> = 0.002) upon inclusion of exercise-associated circulating factors such as EPO.</p> Conclusions <p>Our findings reveal that baseline proteomic and metagenomic signatures are associated with VO₂peak adaptations. These multi-omics signatures may support the clinical implementation of personalized exercise interventions to improve CRF in individuals with prediabetes.</p>

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Multi-omics signatures of circulating factors associated with cardiorespiratory fitness adaptations in individuals with prediabetes

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  • 发表日期：

    2026年7月12日

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  • Candela Diaz-Canestro,
  • Kit Cheung,
  • Enrique Roche,
  • Jose Manuel Sarabia,
  • Michael Andrew Tse,
  • Aimin Xu

摘要

Background

Patients with insulin resistance exhibit reduced cardiorespiratory fitness (CRF), assessed by peak oxygen consumption (VO₂peak), compared with healthy age-matched individuals. Although high-intensity interval training (HIIT) can substantially improve VO₂peak, there is considerable interindividual variability in this response. Therefore, further research is needed to elucidate the molecular mechanisms underlying the heterogeneous response of VO₂peak to HIIT in individuals with prediabetes.

Methods

Proteomic analyses of serum samples, along with fecal metagenomic and targeted metabolomic profiling, were conducted in medication-naïve, overweight and obese Chinese men with prediabetes (n = 35; aged 24–62 years). All participants underwent a 12-week HIIT intervention, and biological samples were collected both before and after the intervention to evaluate exercise-induced alterations in circulating proteins, gut microbial composition, and metabolite profiles.

Results

After 12 weeks of HIIT, mean VO₂peak increased by 0.47 L/min with individual responses ranging from 0 to 1.7 L/min. Baseline levels of short-chain fatty acid (SCFA)-producing genera, including Prevotella (β = 105.65, P = < 0.001, FDR = 0.034), Coprococcus (β = 50.22, P = 0.01, FDR = 0.39), and Hungatella (β = 40.72, P = 0.025, FDR = 0.50), were positively associated with ΔVO₂ peak. In contrast, baseline levels of the erythropoiesis-stimulating hormone erythropoietin (EPO) (β = −279.03, P = 0.024, FDR = 0.99) were negatively associated with ΔVO₂ peak. Exercise-induced changes in growth hormone 1 (β = 63.97, P = 0.04, FDR = 0.99) were positively associated with ΔVO₂ peak, whereas exercise-induced changes in BTB and CNC Homology 1 (β = −250.82, P = 0.01, FDR = 0.99), a repressor of heme oxygenase-1, were negatively associated with ΔVO₂ peak. In multiple linear regression analysis including clinical variables, percentage lean mass (β = 64.17, P = 0.0005) was the strongest variable associated with ΔVO₂peak. The clinical model explained 27% of the variance which increased to 37% (P = 0.002) upon inclusion of exercise-associated circulating factors such as EPO.

Conclusions

Our findings reveal that baseline proteomic and metagenomic signatures are associated with VO₂peak adaptations. These multi-omics signatures may support the clinical implementation of personalized exercise interventions to improve CRF in individuals with prediabetes.