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.
Highlights
Type 2 diabetes is an age-associated chronic disease, with a peak incidence of 25% in the US population aged ≥65 [1]
Dispersed cells were plated in 500 μL islet complete media (ICM; RPMI containing 10% FBS (Atlanta Biologics), penicillin/streptomycin, and 5 mM glucose) on uncoated glass coverslips for immunostaining [50 islet equivalents (IEQ)] or directly onto Nunc-treated polystyrene 24-well plates (ThermoFisher) for RNA extraction (100 IEQ). 16-24 hours later the media was replaced with ICM containing 15mM glucose simultaneously with the addition of experimental treatments
Proliferation was measured by BrdU incorporation, which is a reliable marker for b-cell S-phase entry in young and old islet cells in our hands [19]
Summary
Type 2 diabetes is an age-associated chronic disease, with a peak incidence of 25% in the US population aged ≥65 [1]. Lifestyle interventions targeting people with prediabetes delay onset and reduce incidence of disease [2], but most people pass through the prediabetes phase without being diagnosed, and multiple barriers limit implementation of successful lifestyle changes. Treatments targeting aging as a risk factor for diabetes are lacking. Stress-Induced Proliferation in Aging b-Cells population aging in the coming decades, the incidence of diabetes is expected to increase around the world [3]. Complications of diabetes including cardiovascular disease, renal disease, blindness and neuropathy are more frequent and severe in the elderly [4], underscoring the need for better prevention and treatment of diabetes in this growing population
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