80 - Sex Differences in β-Cell Protein Folding Machinery

Abstract

Type 2 diabetes (T2D) is characterized by progressive dysfunction and destruction of β-cells. Biological sex affects the risk of developing T2D: ∼40% more men develop T2D than premenopausal women. To gain insight into mechanisms underlying the male-biased risk of T2D, we used RNAseq to examine gene expression in 20-week male and female mice islets. Unbiased pathway analysis of islet RNAseq data revealed higher expression of genes that encode components of the cellular protein folding machinery in females compared with males. Importantly, a comparison of islet and β-cell RNAseq datasets confirmed this sex difference was also present in β-cells. Given that the dysfunction of the cellular protein folding machinery triggers endoplasmic reticulum (ER) stress, we hypothesized that there may be a sex difference in the induction of ER stress. To test this, we treated mouse islets with ER stress-inducing thapsigargin (Tg), and measured markers of protein folding dysfunction. While no sex difference in ER stress responses were observed in 20-week mice, there was a male-specific induction of ER stress in 60-week mice. When we performed kinetic cell death assays on Tg-treated islets, we found a trend towards increased cell death in males. Together, this data suggests that male mice islets are more susceptible to dysfunction of the protein folding machinery leading to greater induction of ER stress and increased ER stress-induced apoptosis in males than females. 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.