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.

中文翻译：

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内质网应激诱导的增殖在衰老的小鼠 β 细胞中保持完整。


衰老与分泌胰岛素的 β 细胞增殖能力丧失有关，这可能是老年人 2 型糖尿病患病率增加的一个因素。我们的小组之前发现，葡萄糖暴露期间发生的中度内质网（ER）应激会增加适应性β细胞增殖反应。具体来说，三方未折​​叠蛋白反应 (UPR) 的 ATF6α 臂在葡萄糖过量条件下促进 β 细胞复制。我们假设老年小鼠的 β 细胞由于 UPR 信号异常或对 ER 应激或 ATF6α 激​​活的增殖反应受损而减少了增殖。为了进行研究，将年轻和年老的小鼠胰岛细胞暴露于含有低剂量毒胡萝卜素的高葡萄糖或激活过表达的 ATF6α，并通过 BrdU 掺入来量化 β 细胞增殖。通过靶基因的 qPCR 和半定量 Xbp1 剪接测定来比较 UPR 通路激活。有趣的是，尽管与年轻 β 细胞相比，老年 β 细胞在高葡萄糖条件下增殖减少，但在高葡萄糖条件下响应低剂量毒胡萝卜素或 ATF6α 激​​活的 UPR 激活和增殖诱导在年轻人和老年人之间基本相似。这些结果表明，UPR主导的适应性增殖的丧失并不能解释老年β细胞进入细胞周期的减少，并且提出了令人兴奋的可能性，即未来利用适应性UPR的疗法甚至可以通过增殖来增加老年个体中的β细胞数量。