Identification of a pancreatic stellate cell gene signature and lncRNA interactions associated with type 2 diabetes...

Type 2 diabetes (T2D) has become a significant global health threat, yet its precise causes and mechanisms remain unclear. This study aims to identify gene expression patterns specific to T2D pancreatic islet cells and to explore the potential role of pancreatic stellate cells (PSCs) in T2D progression through regulatory networks involving lncRNA-mRNA interactions.

In this study, we screened for upregulated genes in T2D pancreatic islet samples using bulk sequencing (bulkseq) datasets and mapped these gene expression profiles onto three T2D single-cell RNA sequencing (scRNAseq) datasets. The identified T2D-specific gene features were further validated in an additional T2D scRNAseq dataset, a T1D scRNAseq dataset, and a T2D bulkseq dataset. To investigate regulatory networks, we analyzed the potential lncRNA-mRNA interactions within T2D peripheral blood mononuclear cell (PBMC) bulkseq data.

Our analysis identified a specific gene panel-COL1A2, VCAN, and SULF1-that was consistently upregulated in T2D pancreatic islet samples. Expression of this gene panel was strongly associated with the activation of pancreatic stellate cells (PSCs), suggesting a unique T2D-specific signature characterized by COL1A2^hi/VCAN^hi/SULF1^hi PSCs. This signature was exclusive to T2D and was not observed in Type 1 diabetes (T1D) samples, indicating a distinct role for activated PSCs in T2D progression. Furthermore, we identified six long non-coding RNAs (lncRNAs) that potentially interact with the COL1A2^hi/VCAN^hi/SULF1^hi PSCs. These lncRNAs were mapped to a lncRNA-mRNA network, suggesting they may modulate immune responses and potentially reshape the immune microenvironment in T2D.

Our findings highlight the potential immune-regulatory role of PSCs in T2D and suggest that PSC-related lncRNA-mRNA networks could serve as novel therapeutic targets for T2D treatment. This research provides insights into PSCs as a modulator in T2D progression, paving the way for innovative treatment strategies.