August 11, 2025

Multi-omics islet profiling in type 2 diabetes reveals differential transcriptomics and chromatin accessibility by ancestry

Key Points

AA individuals with T2D show differences in islet cell composition compared to EA individuals, leading to implications for treatment strategies and understanding disease mechanisms.
In a study analyzing 85,112 pancreatic islet cells, AA donors had fewer beta and alpha cells, indicating potential ancestry-related differences in T2D progression.
Utilizing scRNA-Seq and snATAC-Seq approaches, significant variations were identified in gene expression and chromatin accessibility across cell types in AA and EA individuals.
These findings highlight the role of ancestry in the molecular mechanisms of T2D, calling for tailored therapeutic approaches based on genetic backgrounds.

Abstract

Abstract Type 2 diabetes (T2D) disproportionally affects African Americans (AA) compared to European Americans (EA) in the United States. To investigate how the molecular pathophysiology T2D may vary by ancestry, we analyzed scRNA-Seq and snATAC-Seq data from 85,112 pancreatic islet cells from AA and EA individuals with T2D. AA donors had proportionally fewer beta and alpha cells but more exocrine cells (FDR ≤ 1.5x10− 3) compared to EA. AA donors beta cells displayed upregulated exocrine genes (e.g., PNLIP, PRSS1) and mildly downregulated INS compared to EA. However, AA donor alpha cells expressed more INS, and higher HNF4A and HNF4G transcription factor binding accessibility. In contrast, EA exocrine cells expressed higher INS, GCG, SST, and PPY, with a corresponding increase of HNF4A and HNF4G binding site accessibility. These data demonstrate key differences in both islet cell composition and insulin signaling between AA and EA individuals with T2D.

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