Patients with type 2 and type 1 diabetes (T2D and T1D) exhibit sex-specific differences in insulin secretion, the mechanisms of which are unknown. We examined sex differences in human pancreatic islets from 52 donors with and without T2D combining single cell RNA-sequencing (scRNA-seq) and single nucleus ATAC-sequencing (snATAC-seq) with assays probing hormone secretion and bioenergetics. In non-diabetic (ND) donors, sex differences in islet cell chromatin accessibility and gene expression predominantly involved sex chromosomes. In contrast, islets from T2D donors exhibited similar sex differences in sex chromosome-encoded differentially expressed genes (DEGs) as ND donors, but also exhibited sex differences in autosomal genes. Comparing β cells from T2D and ND donors, gene enrichment of female β cells showed suppression in mitochondrial respiration, while male β cells exhibited suppressed insulin secretion, suggesting a role for mitochondrial failure in females in the transition to T2D. We finally performed cell type-specific, sex stratified, GWAS restricted to differentially accessible chromatin peaks across T2D, fasting glucose, and fasting insulin traits. We identified that differentially accessible regions overlap with T2D-associated variants in a sex- and cell type-specific manner.

中文翻译：

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来自患有和不患有 2 型糖尿病的受试者的胰岛的性别特异性调节结构。


2 型和 1 型糖尿病 （T2D 和 T1D） 患者在胰岛素分泌方面表现出性别特异性差异，其机制尚不清楚。我们检查了 52 名有和没有 T2D 的供体的人胰岛的性别差异，结合单细胞 RNA 测序 （scRNA-seq） 和单核 ATAC 测序 （snATAC-seq），检测激素分泌和生物能量学。在非糖尿病 （ND） 供体中，胰岛细胞染色质可及性和基因表达的性别差异主要涉及性染色体。相比之下，来自 T2D 供体的胰岛在性染色体编码的差异表达基因 （DEG） 方面表现出与 ND 供体相似的性别差异，但在常染色体基因中也表现出性别差异。比较来自 T2D 和 ND 供体的 β 细胞，雌性 β 细胞的基因富集显示线粒体呼吸受到抑制，而雄性 β 细胞表现出胰岛素分泌受到抑制，表明女性线粒体衰竭在向 T2D 过渡中的作用。我们最终进行了细胞类型特异性、性别分层、GWAS 仅限于跨 T2D 的差异可及染色质峰、空腹血糖和空腹胰岛素性状。我们发现差异可及区域以性别和细胞类型特异性方式与 T2D 相关变异重叠。