Single-Cell RNA Sequencing Reveals Sexually Dimorphic Transcriptome and Type 2 Diabetes Genes in Mouse Islet β Cells

Abstract

Type 2 diabetes (T2D) is characterized by the malfunction of pancreatic β cells. Susceptibility and pathogenesis of T2D can be affected by multiple factors, including sex differences. However, the mechanisms underlying sex differences in T2D susceptibility and pathogenesis remain unclear. Using single-cell RNA sequencing (scRNA-seq), we demonstrate the presence of sexually dimorphic transcriptomes in mouse β cells. Using a high-fat diet-induced T2D mouse model, we identified sex-dependent T2D altered genes, suggesting sex-based differences in the pathological mechanisms of T2D. Furthermore, based on islet transplantation experiments, we found that compared to mice with sex-matched islet transplants, sex-mismatched islet transplants in healthy mice showed down-regulation of genes involved in the longevity regulating pathway of β cells. Moreover, the diabetic mice with sex-mismatched islet transplants showed impaired glucose tolerance. These data suggest sexual dimorphism in T2D pathogenicity, indicating that sex should be considered when treating T2D. We hope that our findings could provide new insights for the development of precision medicine in T2D.

Sex Differences in Response to Treatment with Glucagon-like Peptide 1 Receptor Agonists: Opportunities for a Tailored Approach to Diabetes and Obesity Care

“…These data therefore support the notion that sex plays a pivotal role in the pathophysiology of T2DM and thus may be an important factor to consider when opting for personalized T2DM management. However, the two sexes share some aspects of the disease pathogenesis since sex-independent DEGs involving several disease-specific processes were also demonstrated [ 84 ].…”

Sex differences in islet stress responses support female beta cell resilience

“…Because many of these genes may have been missed if the scRNAseq data was not analyzed by sex, our findings advance our understanding of β cell changes in T2D by identifying additional genes that are differentially regulated in this context. This knowledge adds to a growing number of studies that identify sex differences in β cell gene expression during aging in humans ( 40 ), and in mice fed either a normal ( 32, 33 ) or a high fat diet ( 32 ). Further, given that our RNAseq on islets from male and female mice with equivalent insulin sensitivity identifies genes and biological pathways that align with previous studies on sex differences in murine β cell gene expression ( 32, 33 ), our data suggests that sex differences in islet and β cell gene expression cannot be explained solely by a male-female difference in peripheral insulin resistance.…”

“…This knowledge adds to a growing number of studies that identify sex differences in β cell gene expression during aging in humans ( 40 ), and in mice fed either a normal ( 32, 33 ) or a high fat diet ( 32 ). Further, given that our RNAseq on islets from male and female mice with equivalent insulin sensitivity identifies genes and biological pathways that align with previous studies on sex differences in murine β cell gene expression ( 32, 33 ), our data suggests that sex differences in islet and β cell gene expression cannot be explained solely by a male-female difference in peripheral insulin resistance. Instead, there is likely a basal sex difference in the β cell gene expression landscape that forms the foundation for sex-specific transcriptional responses to ER stress, and T2D.…”

“…Insight into potential sex differences in β cells has emerged from multiple studies. For example, large-scale surveys of gene expression in mice and humans illustrate that differences exist between the sexes in the pancreas ( 29–31 ), and also in β cells ( 32, 33 ). While these data suggest differential β cell gene expression between the sexes, insulin sensitivity was not monitored in these studies.…”

Advanced Single-Cell Omics Technologies and Informatics Tools for Genomics, Proteomics, and Bioinformatics Analysis

“…Also as an application-oriented work, Hu et al demonstrated that miRNAs are important posttranscriptional regulators for reducing gene expression noise and conferring robustness to biological processes through the integrated analysis of single-cell RNA and miRNA expression profiles [18] . Moreover, Liu et al elucidated sexual dimorphism in type 2 diabetes (T2D) pathogenicity and provided novel insights towards the development of precision medicine in T2D [19] . Li et al provided a valuable resource for understanding embryonic osteogenesis and angiogenesis underlying vertebrate thoracolumbar vertebra (TLV) and rib primordium (RP) development at the cell type-specific resolution, which offers a comprehensive view on the transcriptional profile of animal embryonic development [20] .…”