The article reviews the insulin signaling pathway, its critical nodes, and how these are perturbed in insulin-resistant states. Insulin and IGF-1 control various biological processes through their receptors, which initiate a cascade of phosphorylation events leading to the activation of enzymes that regulate metabolism and growth. The insulin signaling network includes positive and negative modulators that ensure proper signal duration and intensity. Key components of the pathway include insulin receptor substrate (IRS) proteins, phosphatidylinositol 3-kinase (PI3K), Akt, and protein kinase C (PKC). The PI3K-Akt pathway is crucial for mediating insulin's metabolic effects, while the Grb2-SOS-Ras-MAPK pathway controls cellular proliferation and gene transcription. Negative regulators of insulin signaling include phosphoprotein phosphatases, lipid phosphatases, and inhibitory serine and threonine kinases. Genetic mutations, dephosphorylation events, posttranslational modifications, and inhibitory complexes can all contribute to insulin resistance.肥胖和糖尿病相关的炎症、脂毒性、高血糖、线粒体功能障碍和内质网应激等细胞扰动是导致胰岛素抵抗的主要原因。理解这些机制对于开发治疗2型糖尿病及其并发症的新药物至关重要。The article reviews the insulin signaling pathway, its critical nodes, and how these are perturbed in insulin-resistant states. Insulin and IGF-1 control various biological processes through their receptors, which initiate a cascade of phosphorylation events leading to the activation of enzymes that regulate metabolism and growth. The insulin signaling network includes positive and negative modulators that ensure proper signal duration and intensity. Key components of the pathway include insulin receptor substrate (IRS) proteins, phosphatidylinositol 3-kinase (PI3K), Akt, and protein kinase C (PKC). The PI3K-Akt pathway is crucial for mediating insulin's metabolic effects, while the Grb2-SOS-Ras-MAPK pathway controls cellular proliferation and gene transcription. Negative regulators of insulin signaling include phosphoprotein phosphatases, lipid phosphatases, and inhibitory serine and threonine kinases. Genetic mutations, dephosphorylation events, posttranslational modifications, and inhibitory complexes can all contribute to insulin resistance.肥胖和糖尿病相关的炎症、脂毒性、高血糖、线粒体功能障碍和内质网应激等细胞扰动是导致胰岛素抵抗的主要原因。理解这些机制对于开发治疗2型糖尿病及其并发症的新药物至关重要。