Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Allagnat, Florent; Christulia, Foteini; Ortis, Fernanda; Pirot, Pierre; Lortz, Stephan; Lenzen, Sigurd; Eizirik, Décio L.; Cardozo, Alessandra K

doi:10.1007/s00125-010-1699-7

Cited by 109 publications

(83 citation statements)

References 51 publications

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“…Surprisingly, prolonged XBP1 overproduction in rat islet cells impaired glucose-stimulated insulin secretion, BAX (BCL2-associated X protein) translocation, cytochrome c release and activation of caspase 3 and beta cell apoptosis [141]. However, sustained production of XBP1 inhibits beta cell function and eventually triggers the mitochondrial pathway of apoptosis, probably secondary to inhibition of PDX1 and musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) expression [141]. In summary, ER stress and its related proteins seem to affect beta cell mass by inducing apoptotic death, while alpha cell mass remains relatively normal.…”

Section: Old Agementioning

confidence: 96%

“…Mice with alpha cell-specific disruption of XBP1 expression (alpha-XBP1KO) [140] exhibit altered glucagon secretion as a result of increased ER stress that is not directly associated with alpha cell mass or growth. Surprisingly, prolonged XBP1 overproduction in rat islet cells impaired glucose-stimulated insulin secretion, BAX (BCL2-associated X protein) translocation, cytochrome c release and activation of caspase 3 and beta cell apoptosis [141]. However, sustained production of XBP1 inhibits beta cell function and eventually triggers the mitochondrial pathway of apoptosis, probably secondary to inhibition of PDX1 and musculoaponeurotic fibrosarcoma oncogene homologue A (MAFA) expression [141].…”

Section: Old Agementioning

confidence: 99%

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The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

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Regeneration of mature cells that produce functional insulin represents a major focus and a challenge of current diabetes research aimed at restoring beta cell mass in patients with most forms of diabetes, as well as in ageing. The capacity to adapt to diverse physiological states during life and the consequent ability to cope with increased metabolic demands in the normal regulation of glucose homeostasis is a distinctive feature of the endocrine pancreas in mammals. Both beta and alpha cells, and presumably other islet cells, are dynamically regulated via nutrient, neural and/or hormonal activation of growth factor signalling and the post-transcriptional modification of a variety of genes or via the microbiome to continually maintain a balance between regeneration (e.g. proliferation, neogenesis) and apoptosis. Here we review key regulators that determine islet cell mass at different ages in mammals. Understanding the chronobiology and the dynamics and agedependent processes that regulate the relationship between the different cell types in the overall maintenance of an optimally functional islet cell mass could provide important insights into planning therapeutic approaches to counter and/or prevent the development of diabetes.

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Section: Old Agementioning

confidence: 96%

Section: Old Agementioning

confidence: 99%

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Mezza

Kulkarni

2014

Diabetologia

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“…Adenoviral infections were conducted as previously described. 16,22,52 ROS and/or RNS and superoxide measurements. The ROS-RNS and superoxide production were measured using the total ROS and Superoxide Detection Kit (Enzo Life Sciences AG, Lausen, Switzerland) as previously described.…”

Section: Rna Interference and Adenoviral Cell Infection Rat Cx36mentioning

confidence: 99%

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

et al. 2013

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Cell-to-cell communication mediated by gap junctions made of Connexin36 (Cx36) contributes to pancreatic b-cell function. We have recently demonstrated that Cx36 also supports b-cell survival by a still unclear mechanism. Using specific Cx36 siRNAs or adenoviral vectors, we now show that Cx36 downregulation promotes apoptosis in INS-1E cells exposed to the pro-inflammatory cytokines (IL-1b, TNF-a and IFN-c) involved at the onset of type 1 diabetes, whereas Cx36 overexpression protects against this effect. Cx36 overexpression also protects INS-1E cells against endoplasmic reticulum (ER) stress-mediated apoptosis, and alleviates the cytokine-induced production of reactive oxygen species, the depletion of the ER Ca 2 þ stores, the CHOP overexpression and the degradation of the anti-apoptotic protein Bcl-2 and Mcl-1. We further show that cytokines activate the AMP-dependent protein kinase (AMPK) in a NO-dependent and ER-stress-dependent manner and that AMPK inhibits Cx36 expression. Altogether, the data suggest that Cx36 is involved in Ca 2 þ homeostasis within the ER and that Cx36 expression is downregulated following ER stress and subsequent AMPK activation. As a result, cytokine-induced Cx36 downregulation elicits a positive feedback loop that amplifies ER stress and AMPK activation, leading to further Cx36 downregulation. The data reveal that Cx36 plays a central role in the oxidative stress and ER stress induced by cytokines and the subsequent regulation of AMPK activity, which in turn controls Cx36 expression and mitochondria-dependent apoptosis of insulin-producing cells.

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“…However, coordination with the other branches of ER stress signalling, including XBP1-independent IRE1α activity, is crucial for the UPR irrespective of the stimulus. In line with this, experimental manipulation of XBP1 activation alone has profound effects on the UPR as well as on the optimisation of beta cell gene expression, insulin secretion and apoptosis [20,34]. ER stressindependent factors, including JNK [24,35], DP5 [16], JunB [19], Mcl-1 [17] and PPARγ [21], may also influence cytokine activation of the UPR in beta cells.…”

Section: Discussionmentioning

confidence: 84%

“…Since ER stress is capable of inducing apoptosis in beta cells [10,11], its potential involvement in cytokinemediated beta cell death in type 1 diabetes has been widely investigated [8,10,[12][13][14][15][16][17][18][19][20][21][22][23][24][25]. Cytokine-stimulated beta cells are characterised by suppression of the adaptive UPR, which may contribute to a lowering of defence mechanisms and activation of the proapoptotic UPR [24,26].…”

Section: Introductionmentioning

confidence: 99%

Cross-talk between the unfolded protein response and nuclear factor-κB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets

2012

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Aims/hypothesis Pancreatic beta cell destruction in type 1 diabetes may be mediated by cytokines such as IL-1β, IFN-γ and TNF-α. Endoplasmic reticulum (ER) stress and nuclear factor-κB (NFκB) signalling are activated by cytokines, but their significance in beta cells remains unclear. Here, we investigated the role of cytokine-induced ER stress and NFκB signalling in beta cell destruction. Methods Isolated mouse islets and MIN6 beta cells were incubated with IL-1β, IFN-γ and TNF-α. The chemical chaperone 4-phenylbutyric acid (PBA) was used to inhibit ER stress. Protein production and gene expression were assessed by western blot and real-time RT-PCR. Results We found in beta cells that inhibition of cytokineinduced ER stress with PBA unexpectedly potentiated cell death and NFκB-regulated gene expression. These responses were dependent on NFκB activation and were associated with a prolonged decrease in the inhibitor of κB-α (IκBα) protein, resulting from increased IκBα protein degradation. Cytokine-mediated NFκB-regulated gene expression was also potentiated after pre-induction of ER stress with thapsigargin, but not tunicamycin. Both PBA and thapsigargin treatments led to preferential upregulation of ER degradation genes over ER-resident chaperones as part of the adaptive unfolded protein response (UPR). In contrast, tunicamycin activated a balanced adaptive UPR in association with the maintenance of Xbp1 splicing. Conclusions/interpretation These data suggest a novel mechanism by which cytokine-mediated ER stress interacts with NFκB signalling in beta cells, by regulating IκBα degradation. The cross-talk between the UPR and NFκB signalling pathways may be important in the regulation of cytokine-mediated beta cell death.

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Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis

Cited by 109 publications

References 51 publications

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

The regulation of pre- and post-maturational plasticity of mammalian islet cell mass

Connexin36 contributes to INS-1E cells survival through modulation of cytokine-induced oxidative stress, ER stress and AMPK activity

Cross-talk between the unfolded protein response and nuclear factor-κB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets

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