Relationships between type 2 diabetes, cell dysfunction, and redox signaling: A meta‐analysis of single‐cell gene expression of human pancreatic α‐ and β‐cells

摘要

Abstract Background Type 2 diabetes mellitus (T2DM) 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 T2DM. 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 T2DM may modify the transcriptomes of α‐ and β‐cells. Methods Annotated sc‐RNA‐Seq data from six studies of human pancreatic islets from metabolically healthy and donors with T2DM 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 were then evaluated to further understand the role that redox signaling may play in T2DM‐induced β‐cell dysfunction. Results α‐ and β‐cells from T2DM donors modified genes involved in energy metabolism, immune response, autophagy, and cellular stress. α‐ and β‐cells also had an increased nuclear factor erythroid 2‐related factor 2 (NFE2L2)‐mediated antioxidant response in T2DM donors. The proportion of immature and senescent β‐cells increased in T2DM 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 T2DM therapeutics.