2055-LB: Temporal Resolution of Single-Cell Transcriptomics and Epigenomics of Murine Pancreatic Islet in Diet-Induced Obesity

Introduction: The escalating global prevalence of obesity has contributed significantly to the burgeoning incidence of type 2 diabetes (T2D). Despite major advancements in modern medicine, more effective therapies for treating obesity and T2D are needed. Pancreatic islets are the most dynamic endocrine organ with remarkable abilities to adapt to the dietary status. However, the transcriptional, epigenetic, metabolic, and cellular events that occur in pancreatic islets during the progression from a healthy state to insulin resistance and T2D are poorly characterized.

Objective: To address this issue, we took the advantage of single-cell omics and challenged mice with either regular and/or high-fat diet for different time intervals, to decipher the different molecular events associated with the progression of insulin resistance and diabetes. Method: To assess changes in gene expression in murine pancreatic islet cells, we used single-cell RNA and ATAC seq techniques during different degrees of obesity and insulin resistance.

Result: We identified subpopulations of alpha, beta, delta, gamma, endothelial, and immune cells and demonstrated commonalities and differences across murine and human species and dietary conditions. We found that different stages of obesity are associated with the trans-differentiation of endocrine cell types. Obesity led to dysregulated gene expression networks, including several metabolic and inflammatory pathways in a cell subtype-specific manner. Our findings also highlight the underappreciated role of endothelial islet cell in obesity across human and mouse population.

Conclusion: Our study provides a powerful resource for identification of heterogeneity across islet endocrine and non-endocrine populations during different states of obesity.