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Sex-specific regulatory architecture of pancreatic islets from subjects with and without type 2 diabetes.
The EMBO Journal ( IF 9.4 ) Pub Date : 2024-11-20 , DOI: 10.1038/s44318-024-00313-z Mirza Muhammad Fahd Qadir,Ruth M Elgamal,Kejing Song,Parul Kudtarkar,Siva S V P Sakamuri,Prasad V Katakam,Samir S El-Dahr,Jay K Kolls,Kyle J Gaulton,Franck Mauvais-Jarvis
The EMBO Journal ( IF 9.4 ) Pub Date : 2024-11-20 , DOI: 10.1038/s44318-024-00313-z Mirza Muhammad Fahd Qadir,Ruth M Elgamal,Kejing Song,Parul Kudtarkar,Siva S V P Sakamuri,Prasad V Katakam,Samir S El-Dahr,Jay K Kolls,Kyle J Gaulton,Franck Mauvais-Jarvis
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:
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。
更新日期:2024-11-20
中文翻译:

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。