Background <p>Type 2 diabetes (T2D) is a chronic metabolic disorder associated with an elevated risk of neurodegenerative diseases (NDs), notably Alzheimer’s disease (AD). The insulin-like growth factor 1 receptor (IGF1R) plays a key role in both T2D and ND pathogenesis by regulating neuroinflammation and neuronal survival. However, the precise molecular mechanisms linking T2D to NDs remain unclear.</p> Objectives <p>This study investigates how IGF1R-mediated immunomodulatory pathways could be leveraged for therapeutic purposes in T2D-related neurodegeneration. It further explores the combined effects of Traditional Chinese Medicine (TCM) and structured exercise on IGF1R signaling and their potential to mitigate T2D-induced neurodegenerative changes.</p> Methods <p>Bioinformatics analyses and in vitro experiments were conducted using SH-SY5Y neuronal cells and primary mouse cortical neurons exposed to amyloid-beta (Aβ) toxicity. IGF1R was overexpressed, and cells were treated with CS at varying concentrations. Cell viability, apoptosis, inflammatory cytokines, oxidative stress markers, and macrophage polarization were assessed using CCK-8, flow cytometry, ELISA, fluorescence microscopy, and related methods.</p> Results <p>Elevated IGF1R expression reduced Aβ-induced neuronal death and inflammation. CS administration increased IL-10 levels, suppressing pro-inflammatory cytokines (IL-1β, TNF-α), and promoted M2-like macrophage polarization, enhancing neurotrophic factors, such as brain-derived neurotrophic factor (BDNF) and anti-inflammatory responses.</p> Conclusions <p>IGF1R is pivotal in regulating neuroinflammation and neuronal apoptosis in T2D-associated neurodegeneration. Combined TCM and structured exercise may beneficially modulate IGF1R-dependent signaling and protect neurons. Further clinical studies are needed to validate these findings and assess their therapeutic potential.</p> Graphical Abstract <p></p>