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

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.