Human alpha cell transcriptomic signatures of types 1 and 2 diabetes highlight disease-specific dysfunction pathways

Area of Science:

• Endocrinology
• Molecular Biology
• Genomics

Background:

• Glucagon secretion is altered in both type 1 diabetes (T1D) and type 2 diabetes (T2D).
• The specific pathophysiological changes within individual pancreatic alpha cells in these diabetes types remain unclear.

Purpose of the Study:

• To investigate the transcriptomic alterations in pancreatic alpha cells from donors with T1D and T2D compared to controls.
• To identify common and disease-specific gene expression signatures in alpha cells associated with T1D and T2D.

Main Methods:

• Analysis of curated single-cell RNA sequencing (scRNASeq) data from T1D, T2D, and control donors.
• Comparative transcriptomic analysis to identify differentially expressed genes in alpha cells.

Main Results:

• Conserved alterations in alpha cell identity genes (e.g., ARX, MAFB) were observed.
• T1D alpha cells showed upregulated cytokine-regulated and glucagon biosynthesis genes, alongside immune-induced ER stress genes.
• T2D alpha cells exhibited dysregulated mitochondrial genes (e.g., COX7B, NQO2) and altered expression of glycolytic/citrate cycle genes.

Conclusions:

• Alpha cells display conserved alterations related to loss of function across T1D and T2D.
• Distinct disease-specific gene signatures in alpha cells suggest pathways influenced by immune-mediated stress (T1D) or metabolism-mediated stress (T2D).