2021
DOI: 10.1101/2021.05.24.445193
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Adaptation to chronic ER stress enforces pancreatic β-cell plasticity

Abstract: Pancreatic β-cells undergo high levels of endoplasmic reticulum (ER) stress due to their role in insulin secretion. Hence, they require sustainable and efficient adaptive stress responses to cope with the stress. Whether duration and episodes of chronic ER stress directly compromises β-cell identity is largely unknown. We show that under reversible, chronic ER stress, β-cells undergo a distinct transcriptional and translational reprogramming. During reprogramming, expression of master regulators of β-cell func… Show more

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Cited by 3 publications
(5 citation statements)
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“…Furthermore, decreasing proinsulin synthesis via the deletion of one or both of the insulin genes in mice ( INS1 and INS2 ; human insulin is encoded by a single gene, INS ) was shown to greatly attenuate markers of the ER stress response in models of nutrient overload [ 120 ]. Thus, the balance between client protein (proinsulin) load and ER folding capacity is a critical feature of the β-cell’s secretory program to adjust insulin production with the demands for insulin release; however, repeated and/or long-term stress may eventually overcome the β-cells adaptive capacity leading to irreversible damage and β-cell demise [ 121 ].…”
Section: Nutrient Sensing Of Client Protein Load In the Ermentioning
confidence: 99%
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“…Furthermore, decreasing proinsulin synthesis via the deletion of one or both of the insulin genes in mice ( INS1 and INS2 ; human insulin is encoded by a single gene, INS ) was shown to greatly attenuate markers of the ER stress response in models of nutrient overload [ 120 ]. Thus, the balance between client protein (proinsulin) load and ER folding capacity is a critical feature of the β-cell’s secretory program to adjust insulin production with the demands for insulin release; however, repeated and/or long-term stress may eventually overcome the β-cells adaptive capacity leading to irreversible damage and β-cell demise [ 121 ].…”
Section: Nutrient Sensing Of Client Protein Load In the Ermentioning
confidence: 99%
“…As discussed earlier, increased nutrient-stimulated proinsulin biosynthesis can overcome the ER’s capacity to efficiently fold proinsulin and lead to the activation of an ER stress response program [ 16 , 28 , 97 , 99 , 121 , 122 ]. Oscillations between proinsulin biosynthesis and ER stress were documented in human β-cells and are likely to be a natural adaptation to changes in nutrient status [ 28 ].…”
Section: Nutrient Regulation Of Golgi Functionmentioning
confidence: 99%
“…In contrast, some gene groups were conversely expressed in NOD and db/db+mSTZ analyses. For example, NOD group T1-down3, containing some genes involved in adaptive stress response ( Txnip , Herpud1 ) 44, 130 , was, in addition to healthy cells, also highly expressed in db/db and mSTZ model cells.…”
Section: Resultsmentioning
confidence: 99%
“…Implication of single-cell RNA sequencing (scRNA-seq) has greatly enhanced our understanding of β-cell maturation, heterogeneity and function in health and disease 2,12,40,[42][43][44][45][46][47][48] . Nevertheless, there is no consensus on which β-cell populations exist 14,16,49 and which pathways lead to β-cell dysfunction in different conditions.…”
Section: Introductionmentioning
confidence: 99%
“…ISR 'exhaustion' has also been recently appreciated where translational-demanding cell types (in this study, pancreatic β cells) are susceptible to ATF4-mediated transcriptome decay when faced with frequent ER stress insults (Chen et al, 2022).…”
Section: Discussionmentioning
confidence: 96%