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UBC Theses and Dissertations

Sex differences in islet stress responses support female beta cell resilience Brownrigg, George


The risk of developing type 2 diabetes (T2D) is ~40% higher in men than in pre-menopausal women. While lifestyle and cultural factors play a role in this male-biased risk of T2D, studies across animal species suggest biological sex contributes significantly to the sex difference in developing T2D. Large-scale gene expression studies suggest sex differences in pancreatic β cells play a role in the differential T2D risk between men and women. Yet, we lack a comprehensive understanding of β cell dysfunction between the sexes in both normal and pathological contexts. Here, we examined scRNA-seq data of human insulin-producing pancreatic β cells from non-diabetic (ND) and T2D men and women, revealing profound sex-specific changes to β cell gene expression in T2D. To gain deeper insight into sex-specific β cell responses in T2D, we sought a detailed understanding of β cell gene expression in normal physiological conditions. Unbiased pathway analysis of our well-powered islet RNAseq dataset from 20-week-old male and female mice with equivalent insulin sensitivity revealed a sex difference in the enrichment of UPR pathway-associated genes under basal conditions. Because female islets had higher expression of genes involved in protein synthesis, folding, and processing compared with males, we hypothesized female islets would be more resilient to acute ER stress induction with thapsigargin. Indeed, we found female islets resolved ER stress-induced protein synthesis repression faster than males and showed less cell death. These differences were significant for β cell function, as female islets maintained better insulin secretion than males in an ER stress context. Given the profound differences that we observed between the sexes in the transcriptional response to thapsigargin and the known links between ER stress and T2D pathogenesis, these findings provide additional insight into potential mechanisms underlying the differential risk of T2D between men and women.

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