Single cell regulatory architecture of human pancreatic islets suggests sex differences in β cell function and the pathogenesis of type 2 diabetes

TL;DR

This study explores sex differences in human pancreatic islets and finds that type 2 diabetes affects β cell function differently in males and females.

Contribution

The study reveals sex-specific molecular changes in β cells during type 2 diabetes, linking them to mitochondrial and insulin secretion differences.

Findings

Sex differences in gene accessibility and expression in ND islets mainly involve sex chromosomes.

T2D islets show sex differences in both sex chromosomes and autosomal genes.

Female β cells in T2D show suppressed mitochondrial respiration, while male β cells show suppressed insulin secretion.

Abstract

Type 2 and type 1 diabetes (T2D, T1D) exhibit sex 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-seq (scRNA-seq), single nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq), hormone secretion, and bioenergetics. In nondiabetic (ND) donors, sex differences in islet cells gene accessibility and expression predominantly involved sex chromosomes. Islets from T2D donors exhibited similar sex differences in sex chromosomes differentially expressed genes (DEGs), but also exhibited sex differences in autosomal genes. Comparing β cells from T2D vs. ND donors, gene enrichment of female β cells showed suppression in mitochondrial respiration, while male β cells exhibited suppressed insulin secretion. Thus, although sex differences in gene accessibility and expression of ND β cells predominantly affect sex chromosomes, the transition to T2D reveals sex differences in autosomes highlighting mitochondrial failure in females.

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