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<p>Oxidative stress plays a pivotal role in the pathogenesis of diabetes mellitus, primarily triggered by hyperglycaemia-induced activation of various metabolic pathways such as glycolytic, hexosamine, PKC, polyol, and AGE pathways. A critical event in this process is the inhibition of GAPDH mediated by PARP-1, leading to the accumulation of glyceraldehyde-3-phosphate, which subsequently promotes the formation of AGE through methylglyoxal, augments PKC signalling, and enhances flux through the polyol and hexosamine pathways. This oxidative imbalance disrupts the IRS-PI3K-GLUT signalling axis, resulting in diminished glucose uptake and contributing to systemic insulin resistance and β-cell damage. Genetic and epigenetic variations, coupled with compromised antioxidant defences, exacerbate susceptibility to oxidative stress, while the Keap1-Nrf2-ARE pathway emerges as a crucial mechanism for reinstating redox equilibrium.</p> Graphical abstract <p></p>

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Molecular pathways of oxidative stress in diabetes: redox imbalance and insulin pathway dysregulation

  • 期刊论文

  • 发表日期：

    2025年12月29日

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  • Zahid Ahmad Wani,
  • Asvene Kumar Sharma,
  • Showkeen Muzamil,
  • Mehak Nasser Mir,
  • Ishfaq Ahmad Malik,
  • Rayees Ahmad Naik,
  • Shuja Shafi Malik,
  • Irfan Ashraf Badroo,
  • Aabid Rashid Hurra,
  • Yaqoob lone

摘要

Oxidative stress plays a pivotal role in the pathogenesis of diabetes mellitus, primarily triggered by hyperglycaemia-induced activation of various metabolic pathways such as glycolytic, hexosamine, PKC, polyol, and AGE pathways. A critical event in this process is the inhibition of GAPDH mediated by PARP-1, leading to the accumulation of glyceraldehyde-3-phosphate, which subsequently promotes the formation of AGE through methylglyoxal, augments PKC signalling, and enhances flux through the polyol and hexosamine pathways. This oxidative imbalance disrupts the IRS-PI3K-GLUT signalling axis, resulting in diminished glucose uptake and contributing to systemic insulin resistance and β-cell damage. Genetic and epigenetic variations, coupled with compromised antioxidant defences, exacerbate susceptibility to oxidative stress, while the Keap1-Nrf2-ARE pathway emerges as a crucial mechanism for reinstating redox equilibrium.

Graphical abstract