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

Figure 4 Mechanisms underlying ceramide-induced and reactive oxygen species-induced insulin resistance in skeletal muscle involve multiple interconnected pathways. Ceramide impairs protein kinase B activity through inhibitory phosphorylation mediated by PKCζ and dephosphorylation facilitated by PP2A, thereby disrupting GLUT4 translocation. Concurrently, mitochondrial hydrogen peroxide (H₂O₂) activates IKKβ and JNK1, which promote inhibitory phosphorylation and subsequent degradation of insulin receptor substrate-1 (IRS-1). nuclear factor kappa-B suppresses IRS-1 gene transcription. Reactive oxygen species further stimulate the NLRP3 inflammasome, leading to interleukin-1β production that perpetuates inflammatory signaling. Nutrient excess activates the mechanistic target of rapamycin complex 1. PKCζ-mediated activation of p70S6K induces feedback phosphorylation of IRS-1. These coordinated molecular events convert skeletal muscle from an efficient glucose-utilizing tissue into one characterized by chronic insulin resistance and metabolic dysfunction. TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; AKT: Protein kinase B; FOXO: Forkhead box O transcription factors; SOD: Superoxide dismutase; IRS-1: Insulin receptor substrate-1; TSC: Tuberous sclerosis complex; mTORC1: Mechanistic target of rapamycin complex 1.