Endoplasmic Reticulum Stress Induced Proliferation Remains Intact in Aging Mouse β-Cells

Abstract

Aging is associated with loss of proliferation of the insulin-secreting β-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 β-cell proliferation response. Specifically, the ATF6α arm of the tripartite Unfolded Protein Response (UPR) promotes β-cell replication in glucose excess conditions. We hypothesized that β-cells from older mice have reduced proliferation due to aberrant UPR signaling or an impaired proliferative response to ER stress or ATF6α activation. To investigate, young and old mouse islet cells were exposed to high glucose with low-dose thapsigargin or activation of overexpressed ATF6α, and β-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 β-cells had reduced proliferation in high glucose compared to young β-cells, UPR activation and induction of proliferation in response to low-dose thapsigargin or ATF6α 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 β-cells, and raise the exciting possibility that future therapies that engage adaptive UPR could increase β-cell number through proliferation even in older individuals.

Permanent neonatal diabetes-causing insulin mutations have dominant negative effects on beta cell identity

“…Other genetic forms of neonatal diabetes due to explicit ER stress, including Wolfram and Wolcott–Rallison syndromes [ 61 ] may also be associated with beta cell de-differentiation. ER stress – perhaps depending on intensity and duration – can have various outcomes, including beneficial ones, such as cell proliferation [ 58 , 59 ]. In the case of insulin folding mutation, which appear to cause relatively modest ER stress levels, but over long-time frames, a prevalent consequence is de-differentiation.…”

Permanent Neonatal diabetes-causing Insulin mutations have dominant negative effects on beta cell identity

“…Other genetic forms of neonatal diabetes due to explicit ER stress, including Wolfram and Wolcott-Rallison syndromes (Stone et al, 2021) may also be associated with beta cell de-differentiation. That ER stress (perhaps depending on the duration and intensity) can have various outcomes, including beneficial ones, such as cell proliferation (Sharma et al, 2015; Snyder et al, 2021). In the case of insulin folding mutation, lasting stress has the consequence of de-differentiation.…”

LncRNAs and CircRNAs in Endoplasmic Reticulum Stress: A Promising Target for Cardiovascular Disease?

“…Early activation of UPR—named adaptive UPR—exerts a protective role against several injuries promoting cell survival and improving cellular function. Furthermore, UPR is required for different cellular processes such as differentiation and proliferation, pinpointing an important role in appropriate development and cellular physiology [ 45 , 46 , 47 , 48 ]. For example, activation of three branches of UPR- IRE1, PERK and ATF6- is necessary for the expression of several myogenic genes such as Mef2c or MyoD , the correct formation of myotubes and therefore proper embryonic myogenesis [ 49 , 50 , 51 , 52 ].…”