Background

Type 2 diabetes (T2D) is a chronic disease characterized by insulin resistance and failure of β-cells to meet the metabolic demand for insulin. Recent advances in single-cell RNA sequencing (sc-RNA-Seq) have allowed for in depth studies to further understand the underlying cellular mechanisms of T2D. In β-cells, redox signaling is critical for insulin production. A meta-analysis of human pancreas islet sc-RNA-Seq data was conducted to evaluate how T2D may modify the transcriptomes of α-and β-cells.

Methods

Annotated sc-RNA-Seq data from 6 studies of human pancreatic islets from metabolically healthy and donors with T2D were collected. α- and β-cells, subpopulations of proliferating α-cells, immature, and senescent β-cells were identified based on expression levels of key marker genes. Each dataset was analyzed individually, before combining using weighted comparisons. Pathways of significant genes and individual redox-related gene expression was then evaluated to further understand the role that redox signaling may play in T2D-induced β-cell dysfunction.

Results

α- and β-cells from T2D donors modified genes involved in energy metabolism, immune response, autophagy, and cellular stress. α- and β-cells also had an increased nuclear factor-erythroid factor 2-related factor 2 (NFE2L2)-mediated antioxidant response in T2D donors. The proportion of immature and senescent β-cells increased in T2D donors, and in immature and senescent β-cells, genes regulated by NFE2L2 were further upregulated.

Conclusions

These findings suggest that NFE2L2 plays a role in β-cell maturation and dysfunction. Redox singling maybe a key pathway for β-cell restoration and T2D therapeutics.

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