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Sex differences in islet stress responses support female beta cell resilience

View ORCID ProfileGeorge P. Brownrigg, View ORCID ProfileYi Han Xia, Chieh Min Jamie Chu, View ORCID ProfileSu Wang, Charlotte Chao, View ORCID ProfileJiashuo Aaron Zhang, View ORCID ProfileSøs Skovsø, View ORCID ProfileEvgeniy Panzhinskiy, Xiaoke Hu, View ORCID ProfileJames D. Johnson, View ORCID ProfileElizabeth J. Rideout
doi: https://doi.org/10.1101/2022.05.10.491428
George P. Brownrigg
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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  • ORCID record for George P. Brownrigg
Yi Han Xia
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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Chieh Min Jamie Chu
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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Su Wang
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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Charlotte Chao
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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Jiashuo Aaron Zhang
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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Søs Skovsø
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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Evgeniy Panzhinskiy
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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Xiaoke Hu
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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James D. Johnson
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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  • For correspondence: elizabeth.rideout@ubc.ca james.d.johnson@ubc.ca
Elizabeth J. Rideout
1Department of Cellular and Physiological Sciences, Life Sciences Institute, The University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada
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  • For correspondence: elizabeth.rideout@ubc.ca james.d.johnson@ubc.ca
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ABSTRACT

Type 2 diabetes risk is ∼40% higher in men than in pre-menopausal women. Despite evidence that sex differences in pancreatic β cells play a role in this differential diabetes risk, few studies have examined diabetes-associated changes to β cell function in each sex. Our single-cell analysis of human β cells revealed profound sex-specific changes to gene expression and function in type 2 diabetes. To gain deeper insight into sex differences in β cells, we generated a well-powered islet RNAseq dataset from 20-week-old male and female mice with equivalent insulin sensitivity. This unbiased analysis revealed differential enrichment of unfolded protein response pathway-associated genes, where female islets showed higher expression of genes linked with protein synthesis, folding, and processing. This differential expression was biologically significant, as female islets were more resilient to endoplasmic reticulum (ER) stress induction with thapsigargin. Specifically, female islets maintained better insulin secretion and showed a distinct transcriptional response under ER stress compared with males. Given the known links between ER stress and T2D pathogenesis, our findings suggest sex differences in β cells contribute to the differential T2D risk between men and women.

Competing Interest Statement

The authors have declared no competing interest.

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  • https://hpap.pmacs.upenn.edu/

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted May 11, 2022.
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Sex differences in islet stress responses support female beta cell resilience
George P. Brownrigg, Yi Han Xia, Chieh Min Jamie Chu, Su Wang, Charlotte Chao, Jiashuo Aaron Zhang, Søs Skovsø, Evgeniy Panzhinskiy, Xiaoke Hu, James D. Johnson, Elizabeth J. Rideout
bioRxiv 2022.05.10.491428; doi: https://doi.org/10.1101/2022.05.10.491428
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Sex differences in islet stress responses support female beta cell resilience
George P. Brownrigg, Yi Han Xia, Chieh Min Jamie Chu, Su Wang, Charlotte Chao, Jiashuo Aaron Zhang, Søs Skovsø, Evgeniy Panzhinskiy, Xiaoke Hu, James D. Johnson, Elizabeth J. Rideout
bioRxiv 2022.05.10.491428; doi: https://doi.org/10.1101/2022.05.10.491428

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