Hyperglycemia as driver of glioblastoma progression: Insights from Mendelian randomization and single-cell transcriptomics

Abstract

Background

Hyperglycemia and diabetes may influence GBM progression by altering tumor metabolism and the tumor microenvironment. However, the causal relationship between blood glucose levels and GBM remains unclear.

Methods

Mendelian randomization (MR) analysis was performed using GWAS data from the UK Biobank and FinnGen databases, with fasting blood glucose, plasma glucose, cerebrospinal fluid (CSF) glucose, and diabetes as exposures. Single-cell RNA sequencing of GBM mouse models on high-glucose and control diets was conducted to explore the cellular landscape of the tumor microenvironment under hyperglycemic conditions. Additionally, gene set enrichment analysis (GSEA) was performed on transcriptomic data from brain tissues of diabetic patients to assess the activity of GBM-related pathways.

Results

MR analysis demonstrated a significant genetic relationship between elevated fasting blood glucose and GBM risk, with an odds ratio (OR) of 40.991 (95 % CI: 2.066–813.447, p = 0.015). Type 2 diabetes (T2D) also showed a potential causal link with GBM, with the Weighted Median and Inverse Variance Weighted methods yielding ORs of 2.740 (95 % CI: 1.033–7.273, p = 0.043) and 2.100 (95 % CI: 1.029–4.287, p = 0.042), respectively. Single-cell transcriptomic analysis of GBM mouse models revealed an increased proportion of GBM tumor stem cells and pro-tumorigenic M2 macrophages in the high-glucose diet (HGD) group. GSEA of diabetic patient brain tissue revealed heightened activity of GBM-related pathways, particularly in astrocytes, endothelial cells, and neurons.

Conclusion

These findings suggest that hyperglycemia may actively contribute to GBM progression by promoting cellular changes within the tumor microenvironment and activating GBM-related pathways in brain tissues.