Mechanisms of IGF1R signaling in type 2 diabetes-related neurodegeneration and therapeutic implications of exercise.

BACKGROUND

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.

OBJECTIVES

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.

METHODS

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.

RESULTS

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.

CONCLUSIONS

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.