Endoplasmic Reticulum Stress Induced Proliferation Remains Intact in Aging Mouse beta-Cells
Snyder, Jarin T. ; Darko, Christine ; Sharma, Rohit B. ; Alonso, Laura C.
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aging/aging beta cells
endoplasm Reticulum Stress
pancreatic beta cells
proliferation
thapsigargin
unfolded protein response
Cellular and Molecular Physiology
Endocrine System Diseases
Endocrinology
Endocrinology, Diabetes, and Metabolism
Nutritional and Metabolic Diseases
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Abstract
Aging is associated with loss of proliferation of the insulin-secreting beta-cell, a possible contributing factor to the increased prevalence of type 2 diabetes in the elderly. Our group previously discovered that moderate endoplasmic reticulum (ER) stress occurring during glucose exposure increases the adaptive beta-cell proliferation response. Specifically, the ATF6alpha arm of the tripartite Unfolded Protein Response (UPR) promotes beta-cell replication in glucose excess conditions. We hypothesized that beta-cells from older mice have reduced proliferation due to aberrant UPR signaling or an impaired proliferative response to ER stress or ATF6alpha activation. To investigate, young and old mouse islet cells were exposed to high glucose with low-dose thapsigargin or activation of overexpressed ATF6alpha, and beta-cell proliferation was quantified by BrdU incorporation. UPR pathway activation was compared by qPCR of target genes and semi-quantitative Xbp1 splicing assay. Intriguingly, although old beta-cells had reduced proliferation in high glucose compared to young beta-cells, UPR activation and induction of proliferation in response to low-dose thapsigargin or ATF6alpha activation in high glucose were largely similar between young and old. These results suggest that loss of UPR-led adaptive proliferation does not explain the reduced cell cycle entry in old beta-cells, and raise the exciting possibility that future therapies that engage adaptive UPR could increase beta-cell number through proliferation even in older individuals.
Source
Snyder JT, Darko C, Sharma RB, Alonso LC. Endoplasmic Reticulum Stress Induced Proliferation Remains Intact in Aging Mouse β-Cells. Front Endocrinol (Lausanne). 2021 Aug 31;12:734079. doi: 10.3389/fendo.2021.734079. PMID: 34531828; PMCID: PMC8438540. Link to article on publisher's site