1769-P: Single-Nucleus Multiomics Reveals Unique Molecular Signatures of ß-Cell Heterogeneity and Compensation in Human Obesity

Abstract

The increasing prevalence of obesity and type 2 diabetes (T2D) continues to be a major economic burden worldwide. Healthy humans adapt to metabolic stress by increasing their functional β-cell mass. Failure of this process, called de-compensation, potentially triggers the development of T2D. However, molecular mechanism(s) underlying the ability of heterogenous human β-cells to compensate remain elusive. To interrogate the heterogeneity of gene expression regulation during successful β-cell compensation, we performed single-nucleus multiome (RNA/ATAC) sequencing in human islet cells. In this study, we analyzed a total of 160,954 islet nuclei isolated from nondiabetic lean (LN-ND, n=7), overweight (OW-ND, n=5), obese (OB-ND, n=7), or T2D (n=10) cadaveric donors. Following total cell integration and subclustering, we identified 16 islet/pancreatic cell types including 6 human β-cell subtypes (β1-6). Single-nucleus multiomics revealed unique molecular signatures of the β-cell subtypes that compensate for obesity. We identified unique sets of genes and biological pathways for each β-cell subtype that correlated with the body mass index among the ND individuals. We also identified β-cell subtype-specific transcription factor motifs and intra-islet interactions that are enriched during compensation. Finally, the intersection of publicly available human islet/β-cell-specific chromatin looping data with our datasets revealed compensatory β-cell subtype-specific cis-regulatory elements that overlap with T2D genomic variants. In summary, we report the discovery of unique signatures of chromatin landscape and gene expression regulation in heterogenous β-cells secondary to potential cell-cell interactions during islet compensation in human obesity. These results provide novel insights into the epigenetic regulation in human islet cells that can be harnessed to develop new therapeutic approaches in precision medicine to counter T2D. Disclosure H. Kim: None. Y. Li: None. H. Zhu: None. Z. Ren: None. K. El Jellas: None. N. Shukla: None. M. Chen: None. R. Kulkarni: Advisory Panel; Novo Nordisk, Inversago. Research Support; Inversago. Advisory Panel; Biomea Fusion, Inc., REDD Pharma. Funding National Institutes of Health (R01067536)