An Early Islet Transcriptional Signature Is Associated With Local Inflammation in Autoimmune Diabetes

Area of Science:

• Immunology
• Endocrinology
• Genomics

Background:

• Identifying early autoimmune type 1 diabetes (T1D) processes is difficult due to asymptomatic stages and limited pancreatic access.
• Animal models offer a window into prediabetic events, crucial for understanding disease initiation.

Purpose of the Study:

• To investigate early transcriptional events and cellular changes in pancreatic islets during the prediabetic phase of autoimmune diabetes.
• To identify specific molecular signatures and spatial relationships between islet cells and immune infiltrates.

Main Methods:

• Transcriptional analysis using single-cell RNA-sequencing on islets from prediabetic LEW.1WR1 rats.
• Differential gene expression analysis to identify stressed cell populations and inflammatory markers.
• RNA-in situ hybridization to determine the spatial distribution of key genes and immune cells within pancreatic tissue.

Main Results:

• Subsets of beta- and alpha-cells exhibit stress signatures, including interferon-stimulated genes, chemokines (e.g., Cxcl10), MHC class I, and ubiquitin-proteasome system genes.
• Mononuclear phagocytes display elevated inflammatory markers.
• Cxcl10+ beta- and alpha-cells are spatially associated with CD8+ T cell infiltration (insulitis).

Conclusions:

• Early islet cell stress, characterized by specific transcriptional profiles, occurs during immune cell recruitment in prediabetic T1D.
• The spatial proximity of stressed islet cells and immune cells highlights critical early events in T1D pathogenesis.
• Understanding these early molecular and cellular interactions can inform the development of T1D prevention and treatment strategies.