UMMS Affiliation

Graduate School of Biomedical Sciences

Publication Date

2021-08-31

Document Type

Article

Disciplines

Cellular and Molecular Physiology | Endocrine System Diseases | Endocrinology | Endocrinology, Diabetes, and Metabolism | Nutritional and Metabolic Diseases

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.

Keywords

ATF6 (activating transcription factor 6), aging/aging beta cells, endoplasm Reticulum Stress, pancreatic beta cells, proliferation, thapsigargin, unfolded protein response

Rights and Permissions

Copyright © 2021 Snyder, Darko, Sharma and Alonso. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

DOI of Published Version

10.3389/fendo.2021.734079

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

Journal/Book/Conference Title

Frontiers in endocrinology

Related Resources

Link to Article in PubMed

PubMed ID

34531828

Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.

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