Pathophysiological mechanisms and risk factors linking type 2 diabetes mellitus and sarcopenia: A narrative review

Figure 3 Reactive oxygen species contribute to insulin resistance and muscle atrophy in skeletal muscle through several molecular mechanisms. Specifically, hydrogen peroxide (H₂O₂) directly oxidizes cysteine residue 296 on insulin receptor substrate-1, thereby inhibiting the recruitment of phosphoinositide 3-kinase. Reactive oxygen species (ROS)-mediated activation of JNK and p38 MAPK leads to the inhibitory phosphorylation of insulin receptor substrate-1 at serine residues 307 and 636, which facilitates its ubiquitination and subsequent proteasomal degradation. Peroxynitrite (ONOO^-) nitrates cysteine 296 on protein kinase B, resulting in diminished kinase activity and impaired translocation of GLUT4. Furthermore, ROS induces oxidation of the transcriptional coactivators CBP/p300, causing epigenetic repression of GLUT4 gene expression. Concurrently, ROS activates the p38 MAPK- forkhead box O transcription factors signaling axis, which upregulates the expression of muscle-specific E3 ubiquitin ligases MAFbx and MuRF1, thereby promoting proteasomal protein degradation. Moreover, ROS triggers calcium release through oxidation of IP3R, which activates the Ca²⁺/CaMKKβ/AMP-AMP-activated protein kinase pathway. This activation inhibits mechanistic target of rapamycin complex 1 and stimulates ULK1-mediated autophagy, collectively contributing to a reduction in muscle fiber cross-sectional area. ROS: Reactive oxygen species; IRS-1: Insulin receptor substrate-1; PI3K: Phosphoinositide 3-kinase; AKT: Protein kinase B; FOXO: Forkhead box O transcription factors; mTORC1: Mechanistic target of rapamycin complex 1.