Sex-specific regulatory architecture of pancreatic islets from subjects with and without type 2 diabetes

• Published in: The EMBO journal Vol. 43; no. 24; pp. 6364 - 6382
• Main Authors: Qadir, Mirza Muhammad Fahd, Elgamal, Ruth M, Song, Kejing, Kudtarkar, Parul, Sakamuri, Siva S V P, Katakam, Prasad V, El-Dahr, Samir S, Kolls, Jay K, Gaulton, Kyle J, Mauvais-Jarvis, Franck
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.12.2024
• Subjects: Adult; Biomedical and Life Sciences; Chromatin - genetics; Chromatin - metabolism; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; EMBO09; EMBO21; EMBO24; Female; Gene Expression Regulation; Genome-Wide Association Study; Humans; Insulin - metabolism; Insulin Secretion; Insulin-Secreting Cells - metabolism; Islets of Langerhans - metabolism; Life Sciences; Male; Middle Aged; Mitochondria - genetics; Mitochondria - metabolism; Sex Characteristics; Sex Factors; Sex Differences; Diabetes; Islet; OMICS; Precision Medicine
• ISSN: 1460-2075; 0261-4189; 1460-2075
• DOI: 10.1038/s44318-024-00313-z

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. Synopsis Diabetic patients show sex-specific differences in insulin secretion; however, the underlying mechanisms remain unclear. This study analyses the single-cell regulatory architecture of human pancreatic islets and establishes biological sex as a genetic modifier of β cell function and the pathogenesis of type 2 diabetes (T2D). Islet cells from non-diabetic (ND) donors exhibit sex differences in chromatin accessibility and gene expression, predominantly affecting sex chromosomes. Islets from T2D donors not only exhibit similar differences in sex chromosomes as ND donors, but also show sex-specific differences in autosomal gene regulation. Comparing β cells from T2D and ND donors, gene enrichment suggests a role for mitochondrial failure in the pathogenesis of T2D in females. A GWAS restricted to differentially accessible chromatin regions across T2D traits identified regions that overlap with T2D-associated variants in a sex- and cell type-specific manner. Single cell-level analyses of human islet cell transcriptome and chromatin accessibility reveal sex-specific differences in β cell gene regulation in donors without and with type 2 diabetes.