Journal
CELLS
Volume 10, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/cells10123585
Keywords
human pancreatic islets; beta-cells; ER stress; islet integrity; single-cell RNAseq; type 2 diabetes
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Funding
- JDRF
- Dutch Diabetes Research Foundation
- DON Foundation
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The study revealed that altering pancreatic islet structure triggers an unfolded protein response, leading to downregulation of mature genes in beta cells and affecting their function. This highlights the close relationship between endoplasmic reticulum homeostasis and beta-cell phenotype, suggesting that altered beta-cell identity may be a mechanism underlying the loss of functional beta-cell mass.
The maintenance of pancreatic islet architecture is crucial for proper beta-cell function. We previously reported that disruption of human islet integrity could result in altered beta-cell identity. Here we combine beta-cell lineage tracing and single-cell transcriptomics to investigate the mechanisms underlying this process in primary human islet cells. Using drug-induced ER stress and cytoskeleton modification models, we demonstrate that altering the islet structure triggers an unfolding protein response that causes the downregulation of beta-cell maturity genes. Collectively, our findings illustrate the close relationship between endoplasmic reticulum homeostasis and beta-cell phenotype, and strengthen the concept of altered beta-cell identity as a mechanism underlying the loss of functional beta-cell mass.
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