A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt?

Herbert, Terence P.; Laybutt, D. Ross

doi:10.2337/db15-1633

Cited by 64 publications

(52 citation statements)

References 86 publications

(120 reference statements)

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“…This was consistent with our finding of reduced ER stress capacity in prediabetic rats (Fig. 2) (Bellmann et al 1997, Herbert & Laybutt 2016. Downregulation of Plin2 is associated with decreased ER stress and prevention of β-cell apoptosis (Chen et al 2017), and it was increased in 60-day BBdp rats.…”

Section: Journal Of Endocrinologysupporting

confidence: 91%

“…High insulin production in response to fluctuating glucose makes pancreatic islets particularly susceptible to ER stress due to protein misfolding. Unresolved or sustained ER stress can invoke programmed cell death (Pirot et al 2007, Pino et al 2009, Brozzi & Eizirik 2016, Herbert & Laybutt 2016, Szabat et al 2016. Increased ER stress response-related genes in neonatal pancreas were associated with a corresponding increase in proapoptotic genes but decreased levels of caspase-1 and cleaved caspase-3 compared with control animals.…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

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Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Crookshank

Serrano

Wang

et al. 2018

Journal of Endocrinology

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It is unknown whether there is a gene signature in pancreas which is associated with type 1 diabetes (T1D). We performed partial pancreatectomies on 30 day preinsulitic, diabetes-prone BioBreeding (BBdp) rats to prospectively identify factors involved in early prediabetes. Microarrays of the biopsies revealed downregulation of ER stress, metabolism and apoptosis. Based on these results, additional investigations compared gene expression in control (BBc) and BBdp rats age ~8, 30 and 60 days using RT-qPCR. Neonates had increased ER stress gene expression in pancreas. This was associated with decreased insulin, cleaved caspase-3 and Ins1 whereas Gcg and Pcsk2 were increased. The increase in ER stress was not sustained at 30 days and decreased by 60 days. In parallel, the liver gene profile showed a similar signature in neonates but with an early decrease of the unfolded protein response (UPR) at 30 days. This suggested that changes in the liver precede those in the pancreas. Tnf and Il1b expression was increased in BBdp pancreas in association with increased caspase-1, cleaved caspase-3 and decreased proinsulin area. Glucagon area was increased in both 30 day and 60 day BBdp rats. Increased co-localization of BIP and proinsulin was observed at 60 days in the pancreas, suggesting insulin-related ER dysfunction. We propose that dysregulated metabolism leads to ER stress in neonatal rats long before insulitis, creating a microenvironment in both pancreas and liver that promotes autoimmunity.

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Section: Journal Of Endocrinologysupporting

confidence: 91%

Section: Journal Of Endocrinologymentioning

confidence: 99%

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Crookshank

Serrano

Wang

et al. 2018

Journal of Endocrinology

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“…The fine-tuning of this adaptive response is vital for the preservation of the β-cell differentiated phenotype. Indeed, our and others recent evidence indicated that the failure of adaptive UPR is associated with the progression to diabetes and altered β-cell differentiation (Herbert & Laybutt 2016) (see 'The loss of β-cell differentiation in diabetes: causes and mechanisms' section).…”

Section: Figurementioning

confidence: 94%

“…This led to the hypothesis that β-cell dysfunction in T2D may result from a failure of the UPR to adequately adapt rather than from a maladaptive UPR (Herbert & Laybutt 2016). By comparing timedependent gene expression changes in islets of diabetesprone (db/db mice on C57BL/KsJ genetic background) and diabetes-resistant (ob/ob mice on C57BL/6J genetic background) mouse models of obesity, we observed in ob/ob mice a progressive upregulation of adaptive UPR genes, including Hspa5, Fkbp11 and Dnajc3, in parallel with the maintenance of increased spliced/total Xbp1 (Xbp1s/t) mRNA ratio.…”

Section: Journal Of Endocrinologymentioning

confidence: 99%

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Bensellam

Jonas

Laybutt

2018

Journal of Endocrinology

203

171

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Like all the cells of an organism, pancreatic β-cells originate from embryonic stem cells through a complex cellular process termed differentiation. Differentiation involves the coordinated and tightly controlled activation/repression of specific effectors and gene clusters in a time-dependent fashion thereby giving rise to particular morphological and functional cellular features. Interestingly, cellular differentiation is not a unidirectional process. Indeed, growing evidence suggests that under certain conditions, mature β-cells can lose, to various degrees, their differentiated phenotype and cellular identity and regress to a less differentiated or a precursor-like state. This concept is termed dedifferentiation and has been proposed, besides cell death, as a contributing factor to the loss of functional β-cell mass in diabetes. β-cell dedifferentiation involves: (1) the downregulation of β-cell-enriched genes, including key transcription factors, insulin, glucose metabolism genes, protein processing and secretory pathway genes; (2) the concomitant upregulation of genes suppressed or expressed at very low levels in normal β-cells, the β-cell forbidden genes; and (3) the likely upregulation of progenitor cell genes. These alterations lead to phenotypic reconfiguration of β-cells and ultimately defective insulin secretion. While the major role of glucotoxicity in β-cell dedifferentiation is well established, the precise mechanisms involved are still under investigation. This review highlights the identified molecular mechanisms implicated in β-cell dedifferentiation including oxidative stress, endoplasmic reticulum (ER) stress, inflammation and hypoxia. It discusses the role of Foxo1, Myc and inhibitor of differentiation proteins and underscores the emerging role of non-coding RNAs. Finally, it proposes a novel hypothesis of β-cell dedifferentiation as a potential adaptive mechanism to escape cell death under stress conditions.

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“…Despite the strong association between ER stress and diabetes, the mechanism by which PERK regulates diabetes-related genes and the role of ER stress in the development of the disease are still largely unknown. Nevertheless, the failure of the UPR to restore homeostasis can become harmful to pancreatic β cells by eventually initiating apoptosis, thereby reducing insulin secretion, and contributing to T2D pathogenesis 22 .…”

Section: Introductionmentioning

confidence: 99%

Glucose increases the lifespan of post-reproductiveC. elegansindependently of FOXO

Wang

Beaudoin‐Chabot

Thibault

2018

Preprint

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Aging is one of the most critical risk factors for the development of metabolic syndromes 1 . Prominent metabolic diseases, namely type 2 diabetes and insulin resistance, have a strong association with endoplasmic reticulum (ER) stress 2 . Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage by adapting to stress conditions and restoring ER homeostasis 3,4 . However, adaptive genes upregulated from the UPR tend to decrease with age 5 . Although stress resistance correlates with increased longevity in a variety of model organisms, the links between the UPR, ER stress resistance, and longevity remain poorly understood. Here, we show that supplementing bacteria diet with 2% glucose (high glucose diet, HGD) in post-reproductive 7-day-old (7DO) C. elegans significantly extend their lifespan in contrast to shortening the lifespan of reproductive 3-day-old (3DO) animals. The insulin-IGF receptor DAF-2 and its immediate downstream target, phosphoinositide 3-kinase (PI3K) AGE-1, were found to be critical factors in extending the lifespan of 7DO worms on HGD. The downstream transcription factor forkhead box O (FOXO) DAF-16 did not extend the lifespan of 7DO worms on HGD in contrast of its previously reported role in modulating lifespan of 3DO worms 6. Furthermore, we identified that UPR activation through the highly conserved ATF-6 and PEK-1 sensors significantly extended the longevity of 7DO worms on HGD but not through the IRE-1 sensor. Our results demonstrate that HGD extends lifespan of postreproductive worms in a UPR-dependent manner but independently of FOXO. Based on these observations, we hypothesise that HGD activates the otherwise quiescent UPR in aged worms to overcome age-related stress and to restore ER homeostasis. In contrast, young adult animals subjected to HGD leads to unresolved ER stress, conversely leading to a deleterious stress response.3

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A Reevaluation of the Role of the Unfolded Protein Response in Islet Dysfunction: Maladaptation or a Failure to Adapt?

Cited by 64 publications

References 86 publications

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Changes in insulin, glucagon and ER stress precede immune activation in type 1 diabetes

Mechanisms of β-cell dedifferentiation in diabetes: recent findings and future research directions

Glucose increases the lifespan of post-reproductiveC. elegansindependently of FOXO

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