Sex Differences in β-cells Endoplasmic Reticulum Stress Response

Abstract

Biological sex affects the risk of developing type 2 diabetes (T2D): ∼40% more men develop T2D than pre-menopausal women. To gain insight into mechanisms underlying this male-biased risk, we analyzed islet scRNAseq to monitor diabetes-associated changes in human β-cells. While both sexes showed a significant upregulation of genes associated with unfolded protein response (UPR) function/regulation in T2D, we observed sex differences in the magnitude of gene expression changes in which UPR-associated genes were altered. In support of a sex difference in UPR regulation, unbiased pathway analysis of islet RNAseq data from 20-week-old male and female mice showed significant enrichment of UPR pathway genes. Specifically, our results suggest that females show higher expression of genes involved in protein synthesis and folding compared with males. Because dysfunction of protein folding machinery triggers endoplasmic reticulum (ER) stress, we hypothesized sex differences may exist in the cellular ER stress response. Indeed, when we treated mouse islets with ER stress-inducing thapsigargin (Tg), we found that Tg-treated islets from females, but not males, were able to restore protein synthesis following acute ER stress induction. Further, kinetic cell death assays showed significant Tg-induced cell death in males at 0.1μM and 1μM Tg concentrations, with no effect in females until a higher 10μM dose. These results indicate that female islets maintain increased protein synthesis and lower cell death in an ER stress context. Given that ER stress has been implicated in the pathogenesis of T2D, these findings provide insight into potential mechanisms underlying the male prevalence in T2D.