Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation

in Journal of Molecular Endocrinology

Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

Abstract

Insulin-secreting pancreatic β-cells are extremely dependent on their endoplasmic reticulum (ER) to cope with the oscillatory requirement of secreted insulin to maintain normoglycemia. Insulin translation and folding rely greatly on the unfolded protein response (UPR), an array of three main signaling pathways designed to maintain ER homeostasis and limit ER stress. However, prolonged or excessive UPR activation triggers alternative molecular pathways that can lead to β-cell dysfunction and apoptosis. An increasing number of studies suggest a role of these pro-apoptotic UPR pathways in the downfall of β-cells observed in diabetic patients. Particularly, the past few years highlighted a cross talk between the UPR and inflammation in the context of both type 1 (T1D) and type 2 diabetes (T2D). In this article, we describe the recent advances in research regarding the interplay between ER stress, the UPR, and inflammation in the context of β-cell apoptosis leading to diabetes.

Introduction

The endoplasmic reticulum (ER) is an intracellular organelle responsible for several crucial features of cellular homeostasis, such as protein maturation and transport and Ca2+homeostasis (Ellgaard & Helenius 2003, Walter & Ron 2011). Therefore, maintaining the ER homeostasis is crucial for proper cellular function and cells have developed an adaptive response to the disruption of this homeostasis named the unfolded protein response (UPR). The UPR encompasses an array of signaling pathways mediated by the action of three signaling proteins named inositol-requiring protein 1α (IRE1α), protein kinase RNA (PKR)-like ER kinase (PERK), and activating transcription factor 6 (ATF6) (Walter & Ron 2011).

Upon ER stress, IRE1α autophosphorylates leading to alternate splicing and translation of the active form of the transcription factor XBP1 (XBP1s), which stimulates the expression of chaperones and components of the ER-associated protein degradation (ERAD) pathway (Pincus et al. 2010, Walter & Ron 2011). Moreover, IRE1α selectively degrades mRNAs (RIDD, regulated IRE1-dependent decay), thereby decreasing the ER protein load (Maurel et al. 2014). PERK also undergoes autophosphorylation and activation upon ER stress, leading to phosphorylation of the eukaryotic initiation factor 2α (eIF2α) and decreased general translational activity, reducing ER protein overload (Walter & Ron 2011). However, PERK-mediated eIF2α phosphorylation also triggers selective induction of ATF4 (Lu et al. 2004). Moreover, PERK directly phosphorylates and activates the nuclear erythroid 2 p45-related factor 2 (NRF2) by disrupting the NRF2–KEAP1 (Kelch-like ECH-associated protein 1) complex (Cullinan & Diehl 2006). Both NRF2 and ATF4 induce the expression of antioxidant genes, which counteracts the increase in reactive oxygen species (ROS) due to the boosted oxidation/reduction reactions during UPR-stimulated protein folding (Harding et al. 2003, Malhotra & Kaufman 2007, Hybertson et al. 2011). However, PERK/ATF4 can initiate pro-apoptotic responses via upregulation of the C/EBP homologous protein (CHOP) (McCullough et al. 2001, Oyadomari et al. 2002a, b, Oyadomari & Mori 2004). Activation of the third UPR branch, the transcription factor ATF6, is mediated via cleavage by site-1 and site-2 proteases (SP1 and SP2) in the Golgi. Cleaved ATF6 regulates the expression of several genes encoding chaperones, ERAD components, and XBP1 (Hetz 2012). Notably, the three UPR branches may be independently and differentially activated depending on the type and duration of ER stress and the cell type (Cardozo et al. 2005, Gomez et al. 2008, Engin et al. 2013). However, it remains unclear how this differential activation is coordinated.

The UPR can be divided into two distinct phases: the initial or the adaptive phase and the second or the maladaptive phase. While the first phase is characterized by cell survival and restoration of ER homeostasis by the mechanisms described above, the second phase is initiated under conditions of irreversible ER stress and results in the activation of pro-inflammatory responses and cell death (for more details of cell death pathways activated during ER stress, please see reviews of Tabas & Ron 2011, Gorman et al. 2012, Cao & Kaufman 2014).

Glucose homeostasis depends on a tightly regulated secretion of insulin by the pancreatic β-cells. The ever-changing demand for insulin production and secretion in response to nutrient stimulation relies greatly on the ER, to ensure synthesis and proper folding of pro-insulin (Back et al. 2009, Hassler et al. 2015). As a result, β-cells are exquisitely sensitive to additional ER pressure and accumulating evidence indicate a major role of the UPR in the context of β-cell demise leading to diabetes (Brozzi & Eizirik 2016, Hasnain et al. 2016).

This article focuses on (1) the signal transduction pathways involved in the UPR and their connections to inflammation, (2) the specific role of the UPR in pancreatic β-cell survival in the context of diabetes, (3) the interplay between UPR signaling and inflammation in pancreatic β-cells, and (4) the potential ER stress-targeting therapies to treat diabetes.

UPR and inflammation

The pro-inflammatory signaling pathways initiated downstream of the UPR are mainly coordinated via activation of the nuclear factor κB (NF-κB) and activating protein (AP)-1 transcription factors (Hotamisligil 2010, Garg et al. 2012). NF-κB is a major modulator of inflammatory responses controlled by the IκB kinase (IKK) complex formed by IKKβ, IKKα, and IKKγ (Shih et al. 2011). When stimulated, the IKK complex leads to phosphorylation and degradation of the inhibitory κB (IκB) protein, allowing NF-κB dimers to migrate to the nucleus and induce the expression of several cytokines and chemokines (Shih et al. 2011). During ER stress, NF-κB can be induced due to PERK-mediated attenuation of protein translation, leading to decreased levels of IκB proteins and consequent increase of NF-κB (Fig. 1) (Deng et al. 2004). IRE1α may also trigger NF-κB activation by binding to the tumor necrosis factor (TNF)-receptor associated factor 2 (TRAF2), which activates the IKK complex (Kaneko et al. 2003, Hu et al. 2006) (Fig. 1). Loss of either IRE1α or PERK reduces NF-κB during ER stress, indicating a synergistic effect of these kinases on NF-κB activity (Tam et al. 2012). In addition, two studies have shown that ATF6 stimulates NF-κB activity downstream of AKT phosphorylation (Yamazaki et al. 2009, Rao et al. 2014).

Figure 1
Figure 1

Schematic representation of the possible cross talks between UPR and pro-inflammatory pathways in pancreatic β-cells under ER stress. Pro-inflammatory cytokines (IL1β, TNF, IFN, IL23, and IL24), lipids (free fatty acids), IAPP aggregates, and Serca2 blockers induce ER stress by diverse mechanisms such as NO formation, ROS production, and ER calcium depletion leading to UPR activation in pancreatic β-cells. UPR-mediated activation of IRE1α (by its dimerization and phosphorylation) may lead to the recruitment of the adaptor protein tumor necrosis factor receptor-associated factor 2 (TRAF2) leading to activation of NF-κB (via IκBα degradation) and JNK. JNK activation in turn increases AP1 activity and both AP1 and NF-κB migrate to the nucleus to induce expression of pro-inflammatory genes. Under pro-inflammatory stimulation, JNK (via AP1) upregulates CHOP expression, consequently increasing IκBα degradation, NF-κB activation and elevated NO production further potentiating ER stress responses. Furthermore, IRE1α induces the alternative splicing of XBP1s, which may increase NF-κB activation via its inhibitory effect on FOX01. Finally, IRE1α increases degradation of miRNA that targets Txnip, leading to increased activation of the NLRP3 inflammasome and IL1β production, under certain conditions. Activation of the PERK arm in ER-stressed β-cells might activate NF-κB via ATF4-mediated increase in the expression of CHOP. Moreover, PERK inhibits general protein translation (via phosphorylation and activation of eIF2α), which may also increase NF-κB activation, due to inhibition of de novo IκBα expression. Finally, PERK was also shown to contribute to the activation of the NLRP3 inflammasome and IL1β release. Furthermore, cytokine-induced ER stress stimulates translocation of citrullinated BiP to the plasma membrane where it may activate the immune system, thereby contributing to the inflammatory response in the islets. This ER stress-mediated inflammatory state contributes to the maintenance of ER stress and probably leads to β-cell demise. Additional information and supporting references are provided in the text.

Citation: Journal of Molecular Endocrinology 57, 1; 10.1530/JME-15-0306

AP1 is a dimer composed of transcription factors from different families of proteins such as JUN, FOS, ATF, and MAF (Davis 2000). The diversity of AP1 dimers implicates this transcription factor in different cellular responses. Thus, AP1 modulates inflammation by upregulating the expression of cytokines, chemokines, and other pro-inflammatory molecules (Angel et al. 2001, Shaulian & Karin 2001, Eferl & Wagner 2003). Several pro-inflammatory genes have binding sites for both AP1 and NF-κB (Angel et al. 2001). During ER stress, AP1 activation can be initiated downstream of IRE1α, via TRAF2-mediated JNK phosphorylation (Fig. 1) (Urano et al. 2000). Moreover, both NF-κB and AP1 signaling may be activated by ROS generated during ER stress (Garg et al. 2012).

Besides NF-κB and AP1, the UPR may trigger pro-inflammatory responses via XBP1s and ATF4, since these transcription factors were shown to stimulate the expression of pro-inflammatory cytokines and chemokines, such as TNF, IL6, IL8, C-X-C motif ligand 2 (CXCL2), and C-X-C motif ligand 3 (CXCL3) in endothelial cells during UPR (Gargalovic et al. 2006). ATF4 was also shown to contribute to LPS-induced C–C motif ligand 2 (CCL2) production in endothelial cells and retina and IL6 in macrophages (Iwasaki et al. 2014, Huang et al. 2015). Furthermore, XBP1s is implicated in synergistic production of type 1 interferons (IFNs), for example, IFN-β or IFN-α, in response to combination of ER stress and Toll-like receptor (TLR) signaling in macrophages (Martinon et al. 2010, Zeng et al. 2010).

Both the UPR and inflammation are important protective cellular/tissue responses that when deregulated can lead to cellular damage. In line with this, UPR dysfunction is involved in many autoimmune and inflammatory disorders, such as diabetes (Hotamisligil 2010, Kaser & Blumberg 2010, Oslowski & Urano 2011a, Chaudhari et al. 2014).

Pancreatic β-cell susceptibility to ER stress

The two main forms of diabetes are T1D and T2D. T1D is primarily caused by an autoimmune attack leading to β-cell destruction and insulin deficiency (Seino et al. 2010). T2D is triggered by the combination of insulin resistance and impaired β-cell function and survival, mostly secondary to metabolic factors through a process referred to as glucolipotoxicity (Seino et al. 2010). Both pathologies are characterized by decreased β-cell mass secondary to apoptosis; however, β-cell loss is more marked in T1D and is a relative late event in T2D, probably contributing to secondary failure of oral therapies (Christoffersson et al. 2016, Hara et al. 2016). In T1D, pro-inflammatory cytokines are early mediators of β-cell apoptosis, while in T2D a combination of high glucose, cholesterol, and free fatty acid (FFA) levels contribute to β-cell death. Cytokines, high glucose, and FFAs induce ER stress in β-cells (Eizirik et al. 2008, Cnop et al. 2010, Brozzi & Eizirik 2016). CHOP and BiP levels are increased in islets from individuals with T1D as compared with nondiabetic individuals (Marhfour et al. 2012). In islets from T2D patients, an increased ER density together with augmented levels of CHOP and the ER chaperones BiP and DNAJC3 (also known as p58IPK) was observed as compared with nondiabetic controls (Huang et al. 2007, Laybutt et al. 2007, Marchetti et al. 2007). These studies suggest an involvement of the ER stress pathways in the development of both T1D and T2D.

β-cells are unique due to their capacity to sense blood glucose and to respond to changeable demands in insulin secretion. An increase in insulin production, up to 20-fold induced by glucose, is a common physiological response of β-cells that results in an intense trafficking of proteins through the ER (Eizirik et al. 2008). Therefore, β-cells express high levels of the UPR transducers IRE1α and PERK, which are necessary for strict quality control of pro-insulin synthesis and to limit oxidative stress induced during the insulin folding, a process that could lead to β-cell failure (Lipson et al. 2006, Eizirik et al. 2008, Back et al. 2009, Oslowski & Urano 2011a, Hassler et al. 2015). Thus, β-cell exposure to intermittent physiological levels of high glucose increases pro-insulin production with a controlled and regulated UPR activation, which contributes to proper β-cell function and survival (Oslowski & Urano 2011a). However, chronic exposure to hyperglycemia induces prolonged activation of the IRE1α pathway leading to β-cell apoptosis (Lipson et al. 2006, 2008, Elouil et al. 2007, Pirot et al. 2007a, Hou et al. 2008, Han et al. 2009, Jonas et al. 2009). Sustained activation of ATF6 also contributes to β-cell dysfunction via inhibition of the insulin promoter activity and induction of β-cell death (Seo et al. 2008). Similarly, persistent XBP1s production hampers β-cell function, eventually leading to apoptosis (Allagnat et al. 2010). Sustained PERK activation/eIF2α phosphorylation contributes to β-cell apoptosis via inhibition of protein translation leading to decreased levels of the anti-apoptotic protein MCL1 and by inducing the pro-apoptotic protein CHOP (Oyadomari et al. 2002b, Scheuner et al. 2005, Cnop et al. 2007, Song et al. 2008, Allagnat et al. 2011, 2012).

Several studies in animal models demonstrated a prominent role for the different UPR pathways on β-cell survival and function (Eizirik et al. 2008, Volchuk & Ron 2010). Moreover, mutations in diverse genes leading to β-cell ER stress contribute to the development of diabetes in humans (Inoue et al. 1998, Delepine et al. 2000, Stoy et al. 2007, Colombo et al. 2008, Polak et al. 2008, Liu et al. 2015, Sun et al. 2015). These results suggest that tight control of ER homeostasis is crucial to maintain β-cell function and survival.

Inflammation induces ER stress in pancreatic β-cells

Type 1 diabetes

The most evident role of inflammation-induced ER stress in pancreatic β-cells is in the context of T1D (Brozzi & Eizirik 2016). At early stages of the disease, T-cells, macrophages, dendritic cells, and natural killer cells surround the islets in a process called insulitis (Eizirik et al. 2009). During insulitis, β-cells are exposed to pro-inflammatory cytokines and free radicals, such as interleukin-1β (IL1β), TNF, IFN-γ, interleukin-17 (IL17), and NO secreted by these infiltrating immune cells, inducing a first wave of β-cell apoptosis (Eizirik et al. 2009). Cytokine-mediated β-cell death is a complex phenomenon involving NO production, activation of the diverse transcription factors (e.g., NF-κB and STAT1), MAP kinases (e.g., JNK), and ER stress that culminate in the induction of the intrinsic pro-apoptotic pathway (Eizirik et al. 2009, Gurzov & Eizirik 2011). In addition, pro-inflammatory cytokines stimulate the expression and secretion of cytokines and chemokines by the β-cells themselves, initiating a pro-inflammatory dialog between β-cells and the immune system (Eizirik et al. 2009, Grieco et al. 2011). This contributes to massive T-cell infiltration within the islets and final β-cell destruction (Eizirik et al. 2009, Grieco et al. 2011). Recent evidences suggest that ER stress is also involved in the pro-inflammatory responses induced by cytokines in β-cells (see below, ER stress-induced inflammation in pancreatic β-cells).

Increased expression of ER stress markers is observed in insulitis-positive and cell-containing islets of T1D patients (Marhfour et al. 2012). In line with these results, virus-inducible autoimmune diabetes in the diabetes-resistant BB (BBDR) rat is accompanied by an activation of the IRE1α/XBP1 pathway preceding insulitis and a later increase in CHOP expression and caspase 3 activation coinciding with diabetes development (Yang et al. 2013). Moreover, expression of ER stress markers and β-cell dysfunction appear before the development of hyperglycemia in nonobese diabetic (NOD) mice, in which a clear increase in the expression of NF-κB target genes is observed (Tersey et al. 2012). These results indicate, in vivo, a cross talk between inflammatory signaling and ER stress induction that probably contributes to diabetes onset.

Exposure of rat primary β-cells to IL1β+IFN-γ in vitro decreases the expression of Serca2b, the main Ca2+ pump driving Ca2+ influx into the ER, leading to ER Ca2+ depletion and activation of the UPR in rat pancreatic β-cells (Cardozo et al. 2005). Cytokine-induced ER stress in rat primary β-cells is a consequence of NF-κB-mediated NO production, since inhibition of NO prevents Serca2b downregulation, splicing of XBP1 and CHOP upregulation (Fig. 1) (Cardozo et al. 2005). By contrast, in mouse β-cells/islets, cytokine-mediated Serca2b downregulation and UPR activation are independent of NO production (Chan et al. 2011). However, in these β-cells, the free radical contributes to the activation of pro-apoptotic responses by upregulating CHOP and decreasing the expression of ER chaperones (Chan et al. 2011). In human β-cells, pro-inflammatory cytokines also induce ER stress responses (Allagnat et al. 2012, Brozzi et al. 2015) and, similar to mouse β-cells, this effect is independent of NO production (Brozzi et al. 2015). The factors inducing ER stress in cytokine-treated human β-cells remain to be determined.

Cytokine-induced UPR in β-cells is characterized by a strong activation of the PERK-ATF4-CHOP pathway and a defective induction of ER chaperones, probably due to the lack of ATF6 activation and a modest increase in XBP1 splicing (Rasschaert et al. 2003, Cardozo et al. 2005, Ortis et al. 2010). Moreover, IFN-γ potentiates IL1β-induced death of a rat insulinoma cell line (INS-1E cells) by decreasing the expression of spliced Xbp1 mRNA and several ER chaperones (Fig. 1) (Pirot et al. 2006). Cytokine-mediated NO production was shown to inhibit the expression of the ER chaperones, foldases, and degradation enhancers, decreasing the capacity of a mouse insulinoma cell line (MIN6) cells and primary mouse β-cells to alleviate ER stress (Chan et al. 2011). In line with these in vitro results, the levels of XBP1s and ATF6 are diminished in islets from T1D patients and two mouse models of T1D (NOD and RIP-LCMV-GP (rat insulin promoter–lymphocytic choriomeningitis virus–glycoprotein)) (Engin et al. 2013). Interestingly, administration of the chemical chaperone TUDCA increases ATF6 expression and decreases β-cell death, islet inflammation, and development of diabetes in these mouse models (Engin et al. 2013). These results indicate that a defective expression of ER chaperones may contribute to β-cell susceptibility to ER stress and cell death in T1D.

Type 2 diabetes

Obesity, a major risk factor for T2D, is characterized by systemic low-grade chronic inflammation in the form of increased circulating levels of pro-inflammatory cytokines such as TNF, IL1β, and IL6 and lower levels of anti-inflammatory adipokines such as adiponectin and omentin (Pereira & Alvarez-Leite 2014). In line with this, elevated circulating levels of pro-inflammatory cytokines characterize the early (or pre-clinical) stages of T2D and exhibit a graded increase with the disease progression (Duncan et al. 2003, Grossmann et al. 2015). Interestingly, recent studies also suggest links between inflammation and ER stress in T2D patients at the level of the immune system. Thus, peripheral blood mononuclear cells (PBMCs) of T2D patients express higher levels of BiP, CHOP, and thioredoxin-interacting protein (TXNIP), and lower levels of IκBα and NRF2 (Lenin et al. 2015, Mozzini et al. 2015), suggesting chronic ER stress in PBMCs and increased pro-inflammatory signals in those patients. Whether these relatively low levels of circulating cytokines affect β-cell survival in vivo remains unclear, although they seem to affect the secretory function of INS1E cells in vitro (Eizirik 1991, Zhang & Kim 1995, Kiely et al. 2007). FFAs may also activate TLR2 and TLR4 in mouse islets, leading to the expression of pro-inflammatory factors via NF-κB (Eguchi et al. 2012, Pal et al. 2012, Yin et al. 2014). This local inflammation probably contributes to increased recruitment of immune cells, particularly macrophages, in the vicinity of islets in T2D patients, promoting a pro-inflammatory environment and UPR activation (Eguchi & Manabe 2013, Cucak et al. 2014). Islets from T2D patients produce amyloid polypeptide (hIAPP), which aggregates to form amyloid fibrils. Interestingly, extracellular hIAPP aggregation provokes ER stress and impairs the ubiquitin–proteasome pathway in INS-1 cells (Haataja et al. 2008). Thus, while lipids, via Ca2+ modulation and ROS generation, are probably the major cause of ER stress, β-cell dysfunction, and apoptosis in T2D (reviewed in (Cnop et al. 2010)), lipid-induced inflammation together with adipose-tissue-mediated low-grade inflammation likely contribute to ER stress and to the progression of the disease (Fig. 1).

Recently, Hasnain et al. (2014) provided a direct evidence for the role of inflammation in ER stress induction in T2D. Thus, they showed that IL23 and IL24 are increased in islets of T2D patients, and that blocking these cytokines partially reduced oxidative and ER stress in the islets and improved glucose tolerance in obese mice (Fig. 1) (Hasnain et al. 2014). The authors further demonstrated that administration of IL22, a cytokine that decreases ROS formation, was able suppress ER stress and improve islet function, leading to the restoration of glucose homeostasis in these animals (Hasnain et al. 2014). Overall, there is a growing amount of evidence suggesting that inflammation contributes to UPR induction and β-cell fate in both T1D and T2D.

ER stress-induced inflammation in pancreatic β-cells

ER stress, NF-κB, and JNK signaling

Although this research area is not yet well developed, different lines of evidence support a role for the UPR in inducing and/or amplifying inflammatory responses in pancreatic β-cells. They are mainly focused on the transcription factor NF-κB, a key regulator of pro-inflammatory responses in these cells (Cardozo et al. 2005, Ortis et al. 2010, 2012). Microarray analysis of INS-1E cells exposed to the Serca2 blocker and ER stress inducer cyclopiazonic acid (CPA) demonstrated modulation of pro-inflammatory genes, some of them which are NF-κB dependent (Pirot et al. 2007a). Thus, CPA-treated INS-1E cells express increased levels of the chemokines, CXCL1 and CXCL2; the cytokines IL1β, TNF, TNF ligand superfamily member 1 (TNFSF1, previously known as TNF-β), and IFN-γ receptor; and decreased levels of IL6, IL15, and CCL5 (Pirot et al. 2007a). Later studies showed that CPA and another Serca2 blocker, namely thapsigargin, induce NF-κB activation in INS-1E cells and human islets (Tonnesen et al. 2009, Igoillo-Esteve et al. 2010). Notably, NF-κB activation and expression of its downstream genes induced by the Serca2 inhibitors are of a much lower magnitude than that observed in β-cells treated with pro-inflammatory cytokines (Pirot et al. 2007a, Tonnesen et al. 2009, Igoillo-Esteve et al. 2010). While TNF and IL1β induce a strong NF-κB activation due to binding to their respective receptors (Shih et al. 2011), the mechanisms linking Serca2 inhibition with NF-κB activation in β-cells were not fully investigated. Translational attenuation does not seem to be the main mechanism since salubrinal, a selective inhibitor of eIF2α dephosphorylation, did not modify CPA-mediated NF-κB activation in human islet cells (Igoillo-Esteve et al. 2010). However, thapsigargin was shown to potentiate cytokine-mediated NF-κB activation and pro-inflammatory gene expression by increasing IκBα protein degradation in MIN6 cells (Chan et al. 2012). ER calcium depletion is probably an important trigger of NF-κB activation in β-cells, since tunicamycin, an agent inducing ER stress via inhibition of protein glycosylation (Oslowski & Urano 2011b) does not induce or potentiate NF-κB activation in MIN6 and rat primary β-cells (our own unpublished data) (Chan et al. 2011). A subsequent study by Miani et al. (2012) showed that INS-1E cells or primary rat β-cells exposed to a low concentration of CPA are sensitized to IL1β-mediated pro-inflammatory responses. Thus, expression of NF-κB downstream genes such as FAS, CCL2, CXCL1, and iNOS, as well as NO production were higher in β-cells pre-exposed to CPA, as compared with cells treated with IL1β alone. This effect was due to a XBP1-mediated degradation of the NF-κB-inhibitor fork head boxO1 (FoxO1) protein (Fig. 1), suggesting pro-inflammatory properties of XBP1 (Miani et al. 2012). However a recent article showed that IRE1α/XBP1 ablation in adult mouse islets leads to increased levels of IL1β, iNOS, and CXCL2 after exposure to high glucose (Hassler et al. 2015). The authors suggest that this increase in pro-inflammatory gene expression occurs downstream of elevated ROS formation in Ire1α islets and is not a direct effect of XBP1 on these genes (Hassler et al. 2015). Therefore, the outcome of the pro- or anti-inflammatory effects of XBP1 in β-cells seems to be context dependent and defined by the balance between its anti-apoptotic/anti-oxidative responses versus its direct pro-inflammatory signaling. This is in agreement with data obtained in other tissues showing that while XBP1 deficiency may stimulate inflammation (Kaser et al. 2008), XBP-1 signaling may also directly induce pro-inflammatory responses (Smith et al. 2008, Martinon et al. 2010, Zeng et al. 2010, Hu et al. 2011, Ziogas et al. 2015).

The transcription factor CHOP is induced upon ER stress downstream of the PERK pathway (Fig. 1) (Oyadomari & Mori 2004). CHOP contributes to rodent and human β-cell apoptosis and its expression is upregulated in islets from both T1D and T2D patients (Laybutt et al. 2007, Cunha et al. 2008, Allagnat et al. 2012). Besides its pro-apoptotic role, recent studies revealed a pro-inflammatory role for CHOP in different disease models, including myocardial inflammation (Miyazaki et al. 2011), lung damage induced by LPS (Endo et al. 2005), chemical hepatocarcinogenesis (DeZwaan-McCabe et al. 2013), and high fat diet-induced diabetes (Maris et al. 2012). Other studies have also shown that CHOP positively regulates the expression of pro-inflammatory cytokines such as IL1β and IL8 and chemokines such as CCL2 in different tissues (Kodama et al. 2005, Endo et al. 2006, Cucinotta et al. 2008, Suyama et al. 2008, Namba et al. 2009). In INS-1E cells and rat primary β-cells CHOP contributes to NF-κB activation by promoting IκBα degradation and subsequent p65 translocation to the nucleus (Fig. 1) (Allagnat et al. 2012). This leads to an increased expression of key NF-κB target genes involved in apoptosis and inflammation, including iNOS, FAS, IRF7, IL15, CCL5, and CXCL10 (Allagnat et al. 2012). The mechanisms by which CHOP regulates NF-κB activation are not yet clear. Moreover, the impact of CHOP knockdown in in vivo models of T1D is controversial. Thus, backcrossing NOD mice with Chop–/– mice did not prevent or delayed diabetes incidence (Satoh et al. 2011). However, Chop–/– mice are protected against multiple low-dose streptozotocin (MLDSZT)-induced diabetes (Ariyama et al. 2008). The observed protection against MLDSZT, however, suggests that Chop deletion may favor β-cell survival in a model where inflammation plays a key role, as suggested by the previously described protection afforded by inhibiting NF-κB expression in β-cells from MLDSZT-treated mice (Eldor et al. 2006).

In summary, when activated by pro-inflammatory cytokines, the transcription factor NF-κB regulates UPR responses of β-cells. However, the UPR positively regulates NF-κB activity and pro-inflammatory responses, increasing apoptotic signaling and expression of pro-inflammatory cytokines and chemokines that may contribute to β-cell demise (Fig. 1).

As mentioned above, JNK is another player linking ER stress to inflammation in other cell types. In β-cells, IL1β IFN-γ-mediated JNK activation is partially mediated by IRE1α (Fig. 1) (Brozzi et al. 2014). Although the pro-apoptotic role for JNK in β-cells is well established (Bonny et al. 2001, Nikulina et al. 2003), few studies have evaluated and demonstrated a pro-inflammatory role for JNK in these cells (Hou et al. 2011, Tan et al. 2013, Lawrence et al. 2015). One of the mechanisms by which JNK contributes to ER stress-mediated inflammation in β-cells is by upregulating CHOP expression (Fig. 1) (Pirot et al. 2007b, Allagnat et al. 2012). Further studies are necessary to evaluate the role of JNK in β-cell mediated-pro-inflammatory responses.

ER stress, IL1β, and the inflammasome

Although controversial, it has been proposed that exposure of mouse or human islets to high glucose concentrations induces production of IL1β contributing to β-cell apoptosis and constitutes a common mechanism for β-cell death in both T1D and T2D (Cnop et al. 2005, Mandrup-Poulsen et al. 2010). IL1β production is mediated via the NLR family pyrin domain containing 3 (NLRP3) inflammasome, which in turn can be activated via increased expression of TXNIP (Yoshihara et al. 2014). The chemical ER stressor, thapsigargin, was shown to upregulate Txnip mRNA in INS-1E cells, mouse, and human primary islets leading to activation of the NLRP3 inflammasome and release of IL1β, contributing to β-cell death (Lerner et al. 2012, Oslowski et al. 2012). While Txnip induction is directly modulated by PERK (Oslowski et al. 2012), IRE1α exhibits an indirect effect on Txnip via IRE1α-mediated degradation of a repressive microRNA (Fig. 1) (Lerner et al. 2012). However, a subsequent study failed to observe protection of mouse NLRP3–/– or caspase-1–/– islets against ER stress, glucose, or glucolipotoxicity-mediated cell death (Wali et al. 2014). Moreover, genetic activation of NLRP3 specifically in mouse β-cells did not induce IL1β expression/production or increased cell death in response to glucolipotoxicity stimuli (Wali et al. 2014). The latter results contradict a role for IL1β or NLRP3 inflammasome in high-glucose- and/or ER stress-mediated β-cell death and are consistent with other studies that failed to show a role for IL1β under these conditions (Kharroubi et al. 2004, Cnop et al. 2005, McKenzie et al. 2010). Notably, IL1β alone does not induce apoptosis in primary β-cells (Eizirik & Mandrup-Poulsen 2001, Cardozo et al. 2005). Therefore, further studies are necessary to clarify the role of ER stress in IL1β production and its involvement in β-cell death in diabetes.

ER stress and antigen presentation

In T1D, initiation and progression of the disease is related to the presence of β-cell-specific autoantibodies (van Belle et al. 2011). Notably, the majority of β-cell autoantigens recognize proteins produced in the ER (van Belle et al. 2011). Pro-inflammatory cytokines induce both ER stress and assembly of the MHC complex in the organelle (Rasschaert et al. 2003, Cardozo et al. 2005). Therefore, it is plausible that cytokine-mediated UPR could influence post-translational modification of proteins, leading to production and presentation of potential autoantigens. It was previously shown that ER calcium depletion drives the translocation of ER-resident proteins BiP, GRP94, and calreticulin in the plasma membrane (Peters & Raghavan 2011), which may have pro- or anti-inflammatory outcomes depending on the protein and cellular context (Panayi & Corrigall 2006, Peters & Raghavan 2011, Raghavan et al. 2013, Pockley et al. 2014). A recent publication showed that cytokines and ER stressors induce translocation of BiP to the plasma membrane in INS-1E, MIN6 cells, and mouse islets (Rondas et al. 2015). Interestingly, pro-inflammatory cytokines, but not ER stressors, induced BiP citrullination in INS-1E cells (Rondas et al. 2015). Citrullinated BiP induced production of autoantibodies that stimulated effector T-cells in pre-diabetic NOD mice (Fig. 1) (Rondas et al. 2015). The presence of citrullinated proteins correlates with activation of the immune system in autoimmune diseases (Blass et al. 2001, Shoda et al. 2011) and increased response to citrullinated GAD65 peptides is observed in T1D patients (McGinty et al. 2014). Another evidence that ER stress response may influence β-cell antigen presentation is delayed appearance of autoantibodies observed in NOD mice knockout for Chop (Satoh et al. 2011). However, the mechanism leading to this delayed antibody response was not investigated in this study (Satoh et al. 2011). A recent elegant publication showed that β-cells transfer antigenic epitopes to antigen presenting cells via a direct membrane contact (Vomund et al. 2015). This is a novel mechanism, however, not specific for ‘diabetic’ β-cells, since it was observed in both diabetic and nondiabetic mice and in nondiabetic humans. Interestingly, high glucose increased the transfer of epitopes (Vomund et al. 2015). The mechanism for this increase has not been yet investigated, but it would be interesting to verify whether it is not due to high glucose-induced ER stress. Further work is necessary to clarify the role for ER stress in the process of autoantibody production in patients with T1D and its consequences on β-cell autoimmunity (Marre et al. 2015).

ER stress-targeting therapies

As described above, several studies support an important role for ER stress in the pathogenesis of T1D and T2D. Therefore, the development of strategies to prevent or alleviate ER stress in β-cells may prove useful for prevention and/or treatment of these diseases. Approaches targeting the UPR for therapeutic purposes remain largely in their infancy, but several strategies aimed at improving ER function in pancreatic β-cells are emerging (Fig. 2).

Figure 2
Figure 2

ER stress-targeting therapies. Several strategies to improve ER function in pancreatic β-cells are emerging. (1) The use of the chemical chaperones 4-phenyl butyric acid (4-PBA) and taurine-conjugated ursodeoxycholic acid (TUDCA) show promising results regarding diabetes therapy, although their mode of action remains largely unknown. (2) Several compounds such as valproic acid (VPA) or BiP inducer X (BiX) may promote the expression of endogenous chaperones, thereby reducing ER stress and apoptosis. (3) Two novel compounds, namely telithromycin and RH01687, were shown to inhibit CHOP and promote β-cell function and survival during ER stress. (4) Strategies aimed at blocking pro-apoptotic UPR pathway such as ASK1 or JNK activity downstream of IRE1α have been shown to protect against ER stress-mediated cell death. Notably, the anti-apoptotic properties of GLP1 are partly mediated by reduced ER stress through actions on ASK1 and the transcription factor JunB downstream JNK (5). GLP1 may also stimulate BiP expression. (6) Finally, other anti-diabetic therapies such as pioglitazone, metformin, or resveratrol have been shown to reduce ER stress in β-cells through unknown mechanisms.

Citation: Journal of Molecular Endocrinology 57, 1; 10.1530/JME-15-0306

Targeting the chaperone capacity of the cells

One strategy to alleviate ER stress in β-cells relies on the use of chemical chaperones. Two compounds, in particular 4-phenyl butyric acid (4-PBA) and taurine-conjugated ursodeoxycholic acid (TUDCA), show promising results regarding diabetes therapy. As mentioned above, TUDCA administration at the pre-diabetic stage reduces diabetes incidence in the NOD and RIP-LCMV-GP mouse models of T1D and this reduction is accompanied by improved survival and preserved insulin secretion (Engin et al. 2013). In vitro, TUDCA inhibits eIF2α phosphorylation and restores thapsigargin-induced β-cell dysfunction in porcine islets (Fig. 2) (Lee et al. 2010), while 4-PBA ameliorates palmitate-induced GSIS inhibition in primary rat islet cells (Choi et al. 2008). Besides β-cell dysfunction, ER stress also contributes to insulin resistance in T2D (Salvado et al. 2015). Both PBA and TUDCA alleviate ER stress in obese mice, restoring insulin sensitivity and normoglycemia (Ozcan et al. 2006). Importantly, these compounds also improved insulin sensitivity in obese subjects (Kars et al. 2010, Xiao et al. 2011). However, no evidence of improved β-cell function was provided in these studies and despite these encouraging results, additional research is required to better clarify by which mechanism these compounds are acting, verify their specificity, and explore their long-term benefit and safety.

Another potential strategy is to increase the folding capacity of the ER by enhancing endogenous chaperone expression in β-cells. Valproic acid (VPA), a drug widely used for the treatment of epilepsy and mood disorders (Chen et al. 2014), has been shown to increase the expression of BiP, reduce expression of CHOP, and protect from ER stress-induced neuronal cell death in various rat models (Fig. 2) (Wang et al. 1999, Bown et al. 2002, Penas et al. 2011, Zhang et al. 2011, Lee et al. 2014). Interestingly, Huang et al. recently demonstrated that VPA protects rat INS-1 cells from palmitate-induced ER stress and apoptosis via GSK-3β inhibition, independent of ATF4/CHOP pathway (Huang et al. 2014). Notably, GSKβ3 inhibition also protects β-cells against both chemical ER stress- and cytokine-mediated β-cell apoptosis (Srinivasan et al. 2005, Fukaya et al. 2016). One of the possible mechanisms could be stabilization of the anti-apoptotic protein MCL1, since inhibition of GSK3β hampers cytokine-mediated MCL1 degradation and protects INS-1E and human β-cells against apoptosis (Meyerovich K, Ortis F, Allagnat F and Cardozo AK unpublished observations). Further studies are required to extend these findings in animal models and explore the potential efficacy of VPA and/or GSK3β inhibition on β-cell death in vivo.

Studies carried out in neuronal cells suggest that the BiP inducer X (BIX) compound protects against ER stress-induced neuronal cell death in mice (Fig. 2) (Kudo et al. 2008, Inokuchi et al. 2009). Whether or not this compound might be of interest for the treatment of diabetes, in general, and the survival of pancreatic β-cells, in particular, remains to be assessed.

Targeting the UPR

The PERK-eIF2α pathway plays a central role in the UPR pro-apoptotic signaling (Laybutt et al. 2007, Song et al. 2008, Allagnat et al. 2012). Thus, salubrinal, a compound preventing eIF2α dephosphorylation and driving CHOP expression, increases the sensitivity of rat and human pancreatic β-cells to fatty-acid-induced ER stress and apoptosis (Cnop et al. 2007, Ladriere et al. 2010). Moreover, upregulation of CHOP and downregulation of the anti-apoptotic protein MCL1 contributes to ER stress-mediated β-cell apoptosis downstream of PERK (Laybutt et al. 2007, Allagnat et al. 2012). Therefore, compounds that prevent eIF2α phosphorylation and subsequently CHOP expression might prove useful for the treatment of diabetes. However, salubrinal protects neuronal cells from ER stress-induced cell death (Boyce et al. 2005, Fullwood et al. 2012), suggesting the need for cell-specific therapies when targeting UPR pathways. Recently, the screening of a bank of compounds identify telithromycin and RH01687 as potential anti-apoptotic molecules targeting CHOP and reducing tunicamycin-induced apoptosis and restoring the insulin secretion in vitro in βTC6 and MIN6 (Fig. 2) (Tran et al. 2014). Further studies are necessary to extend those findings in primary cells and in vivo and test whether such molecules do not have adverse effects on other organs.

Another possibility to block CHOP expression is to act on another upstream regulator, that is, JNK (Allagnat et al. 2012, Gurzov et al. 2012). As mentioned above, the kinase JNK plays a central role in ER stress and pancreatic β-cell dysfunction (Bonny et al. 2001, Nikulina et al. 2003). Besides CHOP, JNK may activate other pro-apoptotic proteins such as BID, BIM, and death protein 5 (DP5), while inhibiting anti-apoptotic proteins such as BCL2 and MCL1 (Dhanasekaran & Reddy 2008, Gurzov et al. 2009, Allagnat et al. 2011, Santin et al. 2011). Moreover, JNK activation resulting from ER stress contributes to insulin resistance in insulin-stimulated cells and organs, such as liver and adipose tissue (Kaneto et al. 2006). Therefore, compounds targeting JNK activation may have a positive impact on multiple organs in the context of T2D. The cell-permeable peptide inhibitor of JNK (Fig. 2) (1) prevents islet apoptosis after isolation (Noguchi et al. 2005), (2) improves islet grafts survival (Noguchi et al. 2008), and (3) prevents ER stress-induced CHOP expression in rat INS-1E cells (Allagnat et al. 2012, Gurzov et al. 2012). Further studies are required to test the potential of this JNK inhibitor in vivo.

Cytokine-induced JNK activation is at least partially mediated via the IRE1α pathway. However, targeting IRE1α is not ideal since this protein is also responsible for activation of Xbp1- and Ire1α-knockout mice are not viable (Zhang et al. 2005). The best alternative is to interfere with IRE1α downstream signaling leading to JNK activation. It was recently shown that N-MYC interactor (NMI) protein negatively modulates IRE1α-dependent activation of JNK and apoptosis in rodent and human pancreatic β-cells (Brozzi et al. 2014), thus NMI could be pointed as a potential target. IRE1-mediated JNK activation is also downstream of the apoptosis signal-regulated kinase 1 protein (ASK1). Interestingly, ASK1 is activated by ER stress in MIN6 cells in vitro and ASK1 deficiency in vivo decreases β-cell apoptosis and delays the onset of diabetes in Akita mice (Yamaguchi et al. 2013). Therefore, chemical inhibitors of ASK1 might provide cytoprotection in the context of ER stress.

Existing treatments of T2D that reduce ER stress

One of the most promising avenues for the treatment of diabetes relies on GLP1 receptor agonists such as liraglutide and exenatide (reviewed in (Madsbad 2016)) and inhibitors of the dipeptidyl peptidase-4 (DPP4) peptidase responsible for rapid degradation of GLP1 (reviewed in Li et al. 2015, Deacon & Lebovitz 2016, Nauck 2016). The anti-apoptotic properties of GLP1 in β-cells are well known and they are at least partially mediated by reduced ER stress through actions on several targets including BiP, ASK1, SIRT1, and the transcription factors C/EBPs and JunB (Fig. 2) (Yusta et al. 2006, Tsunekawa et al. 2007, Cunha et al. 2009, Kwon et al. 2009, Widenmaier et al. 2009, Oh et al. 2013, Kim et al. 2015).

Other existing treatments of T2D such as the insulin sensitizers Metformin and Pioglitazone are known to improve insulin sensitivity partly by reducing ER stress in the liver and peripheral tissues (Fig. 2) (Singh et al. 2015). Pioglitazone was recently shown to reduce ER stress in Wfs1-deficient mice (Yamada et al. 2006), a genetic model for ER stress-mediated β-cell loss and diabetes, thus almost preventing the onset of diabetes in those mice (Akiyama et al. 2009). Pioglitazone also protects rat insulin-secreting cells from thapsigargin-induced cell death (Hara et al. 2014). Similarly, Metformin partially protects INS-1 cells from palmitate-induced ER stress and cell death (Simon-Szabo et al. 2014). The fact that current T2D therapies act, at least partly, through modulation of UPR pathways underscores the central role of ER stress in β-cell dysfunction and death.

An array of additional molecules with anti-oxidant properties improve several circulating markers of T2D such as fasting blood glucose, HbA1c, insulin, and lipid (LDL and triglycerides) levels (Azadmehr et al. 2014, Szkudelski & Szkudelska 2015). Among them resveratrol was shown to protect against ER stress-driven cell dysfunc­tion in the context of obesity-related disorders and diabetes (Andrade et al. 2014, Guo et al. 2015). However, further studies are required to better characterize the molecular mechanisms regulating the effects of resveratrol in β-cells.

Conclusions

Research on the UPR is a relatively new field and although its role on β-cell function, dysfunction, and survival is well studied, the role of the UPR in β-cell pro-inflammatory responses is just beginning to be elucidated. Thus, ‘sterile’ (non-inflammatory/chemically induced) UPR activation is able to induce pro-inflammatory responses in β-cells. However, β-cell exposure to pro-inflammatory cytokines released in and from the islets in both T1D and T2D induces UPR responses that in turn may potentiate inflammation and contribute to β-cell death. The mechanisms by which the UPR modulates inflammation are not completely clarified, but the available data indicates that it is context-dependent. Recent studies showing that manipulating UPR responses may decrease inflammatory responses and reduced diabetes developments in animal models of both T1D and T2D indicate that these pathways are of relevance and can be used as new targets for interventional therapies to prevent these diseases.

As discussed in this article, ER stress and disrupted UPR are likely to play a central role in the pathophysiology of diabetes, not only at the β-cell level, but also in the liver, muscle, adipose tissue, and immune system. Therefore, approaches aimed at reducing ER stress might have beneficial effects on multiple organs. However, one should keep in mind that certain strategies to protect β-cells might have detrimental effects in other tissues. The studies indicating that current therapies for treating T2D alleviate ER stress and the fact that existing molecules already used to treat other pathologies may also reduce ER stress in β-cells provide exciting opportunities to advance the treatment of diabetes.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.

Funding

A.K.C. group’s work was supported by the Juvenile Diabetes Research Foundation (JDRF-New York-USA; 1-2011-589), Actions de Recherché Concertées de la Communauté Française (ARC – Belgium; 20063), and National Funds from Scientific Research (FNRS, Belgium; F.4521.11). Research of F.O. is financed by Fundação de Auxilio a Pesquisa do Estado de São Paulo (FAPESP; 2010/05587-1). F.A. is supported by the Swiss National Fund (SNF 31003A-155897).

References

  • AkiyamaMHatanakaMOhtaYUedaKYanaiAUeharaYTanabeKTsuruMMiyazakiMSaekiS2009Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice. Diabetologia52653663. (doi:10.1007/s00125-009-1270-6)

    • Search Google Scholar
    • Export Citation
  • AllagnatFChristuliaFOrtisFPirotPLortzSLenzenSEizirikDLCardozoAK2010Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis. Diabetologia5311201130. (doi:10.1007/s00125-010-1699-7)

    • Search Google Scholar
    • Export Citation
  • AllagnatFCunhaDMooreFVanderwindenJMEizirikDLCardozoAK2011Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to beta-cell apoptosis. Cell Death and Differentiation18328337. (doi:10.1038/cdd.2010.105)

    • Search Google Scholar
    • Export Citation
  • AllagnatFFukayaMNogueiraTCDelarocheDWelshNMarselliLMarchettiPHaefligerJAEizirikDLCardozoAK2012C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in beta-cells. Cell Death and Differentiation1918361846. (doi:10.1038/cdd.2012.67)

    • Search Google Scholar
    • Export Citation
  • AndradeJMParaisoAFde OliveiraMVMartinsAMNetoJFGuimaraesALde PaulaAMQureshiMSantosSH2014Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition30915919. (doi:10.1016/j.nut.2013.11.016)

    • Search Google Scholar
    • Export Citation
  • AngelPSzabowskiASchorpp-KistnerM2001Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene2024132423. (doi:10.1038/sj.onc.1204380)

    • Search Google Scholar
    • Export Citation
  • AriyamaYTanakaYShimizuHShimomuraKOkadaSSaitoTYamadaEOyadomariSMoriM2008The role of CHOP messenger RNA expression in the link between oxidative stress and apoptosis. Metabolism5716251635. (doi:10.1016/j.metabol.2008.06.019)

    • Search Google Scholar
    • Export Citation
  • AzadmehrAZiaeeAGhaneiLFallah HuseiniHHajiaghaeeRTavakoli-FarBKordafshariG2014A randomized clinical trial study: anti-oxidant, anti-hyperglycemic and anti-hyperlipidemic effects of olibanum gum in type 2 diabetic patients. Iranian Journal of Pharmaceutical Research1310031009.

    • Search Google Scholar
    • Export Citation
  • BackSHScheunerDHanJSongBRibickMWangJGildersleeveRDPennathurSKaufmanRJ2009Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metabolism101326. (doi:10.1016/j.cmet.2009.06.002)

    • Search Google Scholar
    • Export Citation
  • BlassSUnionARaymackersJSchumannFUngethumUMuller-SteinbachSDe KeyserFEngelJMBurmesterGR2001The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis and Rheumatism44761771.

    • Search Google Scholar
    • Export Citation
  • BonnyCObersonANegriSSauserCSchorderetDF2001Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death. Diabetes507782. (doi:10.2337/diabetes.50.1.77)

    • Search Google Scholar
    • Export Citation
  • BownCDWangJFChenBYoungLT2002Regulation of ER stress proteins by valproate: therapeutic implications. Bipolar Disorders4145151. (doi:10.1034/j.1399-5618.2002.bib1-1-40201.x)

    • Search Google Scholar
    • Export Citation
  • BoyceMBryantKFJousseCLongKHardingHPScheunerDKaufmanRJMaDCoenDMRonD2005A selective inhibitor of eIF2alpha dephosphorylation protects cells from ER stress. Science307935939. (doi:10.1126/science.1101902)

    • Search Google Scholar
    • Export Citation
  • BrozziFEizirikDL2016ER stress and the decline and fall of pancreatic beta cells in type 1 diabetes. Upsala Journal of Medical Sciences17. (doi:10.3109/03009734.2015.1135217)

    • Search Google Scholar
    • Export Citation
  • BrozziFGerloSGriecoFANardelliTRLievensSGysemansCMarselliLMarchettiPMathieuCTavernierJ2014A combined ‘omics’ approach identifies N-Myc interactor as a novel cytokine-induced regulator of IRE1 protein and c-Jun N-terminal kinase in pancreatic beta cells. Journal of Biological Chemistry2892067720693. (doi:10.1074/jbc.M114.568808)

    • Search Google Scholar
    • Export Citation
  • BrozziFNardelliTRLopesMMillardIBarthsonJIgoillo-EsteveMGriecoFAVillateOOliveiraJMCasimirM2015Cytokines induce endoplasmic reticulum stress in human, rat and mouse beta cells via different mechanisms. Diabetologia5823072316. (doi:10.1007/s00125-015-3669-6)

    • Search Google Scholar
    • Export Citation
  • CaoSSKaufmanRJ2014Endoplasmic reticulum stress and oxidative stress in cell fate decision and human disease. Antioxidants & Redox Signaling21396413. (doi:10.1089/ars.2014.5851)

    • Search Google Scholar
    • Export Citation
  • CardozoAKOrtisFStorlingJFengYMRasschaertJTonnesenMVan EylenFMandrup-PoulsenTHerchuelzAEizirikDL2005Cytokines downregulate the sarcoendoplasmic reticulum pump Ca2+ ATPase 2b and deplete endoplasmic reticulum Ca2+, leading to induction of endoplasmic reticulum stress in pancreatic beta-cells. Diabetes54452461. (doi:10.2337/diabetes.54.2.452)

    • Search Google Scholar
    • Export Citation
  • ChanJYCooneyGJBidenTJLaybuttDR2011Differential regulation of adaptive and apoptotic unfolded protein response signalling by cytokine-induced nitric oxide production in mouse pancreatic beta cells. Diabetologia5417661776. (doi:10.1007/s00125-011-2139-z)

    • Search Google Scholar
    • Export Citation
  • ChanJYBidenTJLaybuttDR2012Cross-talk between the unfolded protein response and nuclear factor-kappaB signalling pathways regulates cytokine-mediated beta cell death in MIN6 cells and isolated mouse islets. Diabetologia5529993009. (doi:10.1007/s00125-012-2657-3)

    • Search Google Scholar
    • Export Citation
  • ChaudhariNTalwarPParimisettyALefebvred’Hellencourt CRavananP2014A molecular web: endoplasmic reticulum stress, inflammation, and oxidative stress.Frontiers in Cellular Neuroscience8213. (doi:10.3389/fncel.2014.00213)

    • Search Google Scholar
    • Export Citation
  • ChenSWuHKlebeDHongYZhangJ2014Valproic acid: a new candidate of therapeutic application for the acute central nervous system injuries. Neurochemical Research3916211633. (doi:10.1007/s11064-014-1241-2)

    • Search Google Scholar
    • Export Citation
  • ChoiSELeeYJJangHJLeeKWKimYSJunHSKangSSChunJKangY2008A chemical chaperone 4-PBA ameliorates palmitate-induced inhibition of glucose-stimulated insulin secretion (GSIS). Archives of Biochemistry and Biophysics475109114. (doi:10.1016/j.abb.2008.04.015)

    • Search Google Scholar
    • Export Citation
  • ChristofferssonGRodriguez-CalvoTvon HerrathM2016Recent advances in understanding type 1 diabetes. F1000Research5pii: F1000. (doi:10.12688/f1000research.7356.1)

    • Search Google Scholar
    • Export Citation
  • CnopMWelshNJonasJCJornsALenzenSEizirikDL2005Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes54 (Supplement 2) S97S107.

    • Search Google Scholar
    • Export Citation
  • CnopMLadriereLHekermanPOrtisFCardozoAKDogusanZFlamezDBoyceMYuanJEizirikDL2007Selective inhibition of eukaryotic translation initiation factor 2 alpha dephosphorylation potentiates fatty acid-induced endoplasmic reticulum stress and causes pancreatic beta-cell dysfunction and apoptosis. Journal of Biological Chemistry28239893997. (doi:10.1074/jbc.M607627200)

    • Search Google Scholar
    • Export Citation
  • CnopMLadriereLIgoillo-EsteveMMouraRFCunhaDA2010Causes and cures for endoplasmic reticulum stress in lipotoxic beta-cell dysfunction. Diabetes Obesity and Metabolism12 (Supplement 2) 7682. (doi:10.1111/j.1463-1326.2010.01279.x)

    • Search Google Scholar
    • Export Citation
  • ColomboCPorzioOLiuMMassaOVastaMSalardiSBeccariaLMonciottiCToniSPedersenO2008Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. Journal of Clinical Investigation11821482156. (doi:10.1172/JCI33777)

    • Search Google Scholar
    • Export Citation
  • CucakHMayerCTonnesenMThomsenLHGrunnetLGRosendahlA2014Macrophage contact dependent and independent TLR4 mechanisms induce beta-cell dysfunction and apoptosis in a mouse model of type 2 diabetes. PLoS ONE9e90685. (doi:10.1371/journal.pone.0090685)

    • Search Google Scholar
    • Export Citation
  • CucinottaMVisalliMAguennouzMValentiALoddoSAltucciLTetiD2008Regulation of interleukin-8 gene at a distinct site of its promoter by CCAAT enhancer-binding protein homologous protein in prostaglandin E2-treated human T cells. Journal of Biological Chemistry2832976029769. (doi:10.1074/jbc.M803145200)

    • Search Google Scholar
    • Export Citation
  • CullinanSBDiehlJA2006Coordination of ER and oxidative stress signaling: the PERK/Nrf2 signaling pathway. International Journal of Biochemistry and Cell Biology38317332. (doi:10.1016/j.biocel.2005.09.018)

    • Search Google Scholar
    • Export Citation
  • CunhaDAHekermanPLadriereLBazarra-CastroAOrtisFWakehamMCMooreFRasschaertJCardozoAKBellomoE2008Initiation and execution of lipotoxic ER stress in pancreatic beta-cells. Journal of Cell Science12123082318. (doi:10.1242/jcs.026062)

    • Search Google Scholar
    • Export Citation
  • CunhaDALadriereLOrtisFIgoillo-EsteveMGurzovENLupiRMarchettiPEizirikDLCnopM2009Glucagon-like peptide-1 agonists protect pancreatic beta-cells from lipotoxic endoplasmic reticulum stress through upregulation of BiP and JunB. Diabetes5828512862. (doi:10.2337/db09-0685)

    • Search Google Scholar
    • Export Citation
  • DavisRJ2000Signal transduction by the JNK group of MAP kinases. Cell103239252. (doi:10.1016/S0092-8674(00)00116-1)

  • DeaconCFLebovitzHE2016Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obesity and Metabolism18333347. (doi:10.1111/dom.12610)

    • Search Google Scholar
    • Export Citation
  • DelepineMNicolinoMBarrettTGolamaullyMLathropGMJulierC2000EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott-Rallison syndrome. Nature Genetics25406409. (doi:10.1038/78085)

    • Search Google Scholar
    • Export Citation
  • DengJLuPDZhangYScheunerDKaufmanRJSonenbergNHardingHPRonD2004Translational repression mediates activation of nuclear factor kappa B by phosphorylated translation initiation factor 2. Molecular and Cellular Biology241016110168. (doi:10.1128/MCB.24.23.10161-10168.2004)

    • Search Google Scholar
    • Export Citation
  • DeZwaan-McCabeDRiordanJDArensdorfAMIcardiMSDupuyAJRutkowskiDT2013The stress-regulated transcription factor CHOP promotes hepatic inflammatory gene expression, fibrosis, and oncogenesis. PLoS Genetics9e1003937. (doi:10.1371/journal.pgen.1003937)

    • Search Google Scholar
    • Export Citation
  • DhanasekaranDNReddyEP2008JNK signaling in apoptosis. Oncogene2762456251. (doi:10.1038/onc.2008.301)

  • DuncanBBSchmidtMIPankowJSBallantyneCMCouperDVigoAHoogeveenRFolsomARHeissGAtherosclerosis Risk in Communities Study 2003 Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study. Diabetes5217991805. (doi:10.2337/diabetes.52.7.1799)

    • Search Google Scholar
    • Export Citation
  • EferlRWagnerEF2003AP-1: a double-edged sword in tumorigenesis. Nature Reviews Cancer3859868. (doi:10.1038/nrc1209)

  • EguchiKManabeI2013Macrophages and islet inflammation in type 2 diabetes. Diabetes Obesity and Metabolism15 (Supplement 3) 152158. (doi:10.1111/dom.12168)

    • Search Google Scholar
    • Export Citation
  • EguchiKManabeIOishi-TanakaYOhsugiMKonoNOgataFYagiNOhtoUKimotoMMiyakeK2012Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell Metabolism15518533. (doi:10.1016/j.cmet.2012.01.023)

    • Search Google Scholar
    • Export Citation
  • EizirikDL1991Interleukin-1 beta induces an early decrease in insulin release, (pro)insulin biosynthesis and insulin mRNA in mouse pancreatic islets by a mechanism dependent on gene transcription and protein synthesis. Autoimmunity10107113. (doi:10.3109/08916939109004814)

    • Search Google Scholar
    • Export Citation
  • EizirikDLMandrup-PoulsenT2001A choice of death – the signal-transduction of immune-mediated beta-cell apoptosis. Diabetologia4421152133. (doi:10.1007/s001250100021)

    • Search Google Scholar
    • Export Citation
  • EizirikDLCardozoAKCnopM2008The role for endoplasmic reticulum stress in diabetes mellitus. Endocrine Reviews294261. (doi:10.1210/er.2007-0015)

    • Search Google Scholar
    • Export Citation
  • EizirikDLColliMLOrtisF2009The role of inflammation in insulitis and beta-cell loss in type 1 diabetes.Nature Reviews Endocrinology5219226. (doi:10.1038/nrendo.2009.21)

    • Search Google Scholar
    • Export Citation
  • EldorRYeffetABaumKDovinerVAmarDBen-NeriahYChristoforiGPeledACarelJCBoitardC2006Conditional and specific NF-kappaB blockade protects pancreatic beta cells from diabetogenic agents. PNAS10350725077. (doi:10.1073/pnas.0508166103)

    • Search Google Scholar
    • Export Citation
  • EllgaardLHeleniusA2003Quality control in the endoplasmic reticulum. Nature Reviews in Molecular Cell Biology4181191. (doi:10.1038/nrm1052)

    • Search Google Scholar
    • Export Citation
  • ElouilHBensellamMGuiotYVander MierdeDPascalSMSchuitFCJonasJC2007Acute nutrient regulation of the unfolded protein response and integrated stress response in cultured rat pancreatic islets. Diabetologia5014421452. (doi:10.1007/s00125-007-0674-4)

    • Search Google Scholar
    • Export Citation
  • EndoMOyadomariSSugaMMoriMGotohT2005The ER stress pathway involving CHOP is activated in the lungs of LPS-treated mice. Journal of Biochemistry138501507. (doi:10.1093/jb/mvi143)

    • Search Google Scholar
    • Export Citation
  • EndoMMoriMAkiraSGotohT2006C/EBP homologous protein (CHOP) is crucial for the induction of caspase-11 and the pathogenesis of lipopolysaccharide-induced inflammation. Journal of Immunology17662456253. (doi:10.4049/jimmunol.176.10.6245)

    • Search Google Scholar
    • Export Citation
  • EnginFYermalovichANgyuenTHummastiSFuWEizirikDLMathisDHotamisligilGS2013Restoration of the unfolded protein response in pancreatic beta cells protects mice against type 1 diabetes. Science Translational Medicine5211ra156. (doi:10.1126/scitranslmed.3006534)

    • Search Google Scholar
    • Export Citation
  • FukayaMBrorssonCAMeyerovichKCatrysseLDelarocheDVanzelaECOrtisFBeyaertRNielsenLBAndersenML2016A20 Inhibits beta-cell apoptosis by multiple mechanisms and predicts residual beta-cell function in type 1 diabetes. Molecular Endocrinology304861. (doi:10.1210/me.2015-1176)

    • Search Google Scholar
    • Export Citation
  • FullwoodMJZhouWShenolikarS2012Targeting phosphorylation of eukaryotic initiation factor-2alpha to treat human disease. Progress in Molecular Biology and Translational Science10675106. (doi:10.1016/B978-0-12-396456-4.00005-5)

    • Search Google Scholar
    • Export Citation
  • GargADKaczmarekAKryskoOVandenabeelePKryskoDVAgostinisP2012ER stress-induced inflammation: does it aid or impede disease progression?Trends in Molecular Medicine18589598. (doi:10.1016/j.molmed.2012.06.010)

    • Search Google Scholar
    • Export Citation
  • GargalovicPSGharaviNMClarkMJPagnonJYangWPHeATruongABaruch-OrenTBerlinerJAKirchgessnerTG2006The unfolded protein response is an important regulator of inflammatory genes in endothelial cells. Arteriosclerosis Thrombosis and Vascular Biology2624902496. (doi:10.1161/01.ATV.0000242903.41158.a1)

    • Search Google Scholar
    • Export Citation
  • GomezEPowellMLBevingtonAHerbertTP2008A decrease in cellular energy status stimulates PERK-dependent eIF2alpha phosphorylation and regulates protein synthesis in pancreatic beta-cells. Biochemical Journal410485493. (doi:10.1042/BJ20071367)

    • Search Google Scholar
    • Export Citation
  • GormanAMHealySJJagerRSamaliA2012Stress management at the ER: regulators of ER stress-induced apoptosis. Pharmacology & Therapeutics134306316. (doi:10.1016/j.pharmthera.2012.02.003)

    • Search Google Scholar
    • Export Citation
  • GriecoFAVendrameFSpagnuoloIDottaF2011Innate immunity and the pathogenesis of type 1 diabetes. Seminars in Immunopathology335766. (doi:10.1007/s00281-010-0206-z)

    • Search Google Scholar
    • Export Citation
  • GrossmannVSchmittVHZellerTPanova-NoevaMSchulzALaubert-RehDJuengerCSchnabelRBAbtTGLaskowskiR2015Profile of the immune and inflammatory response in individuals with prediabetes and type 2 diabetes. Diabetes Care3813561364. (doi:10.2337/dc14-3008)

    • Search Google Scholar
    • Export Citation
  • GuoRLiuWLiuBZhangBLiWXuY2015SIRT1 suppresses cardiomyocyte apoptosis in diabetic cardiomyopathy: an insight into endoplasmic reticulum stress response mechanism. International Journal of Cardiology1913645. (doi:10.1016/j.ijcard.2015.04.245)

    • Search Google Scholar
    • Export Citation
  • GurzovENEizirikDL2011Bcl-2 proteins in diabetes: mitochondrial pathways of beta-cell death and dysfunction. Trends in Cell Biology21424431. (doi:10.1016/j.tcb.2011.03.001)

    • Search Google Scholar
    • Export Citation
  • GurzovENOrtisFCunhaDAGossetGLiMCardozoAKEizirikDL2009Signaling by IL-1beta+IFN-gamma and ER stress converge on DP5/Hrk activation: a novel mechanism for pancreatic beta-cell apoptosis. Cell Death and Differentiation1615391550. (doi:10.1038/cdd.2009.99)

    • Search Google Scholar
    • Export Citation
  • GurzovENBarthsonJMarhfourIOrtisFNaamaneNIgoillo-EsteveMGysemansCMathieuCKitajimaSMarchettiP2012Pancreatic beta-cells activate a JunB/ATF3-dependent survival pathway during inflammation. Oncogene3117231732. (doi:10.1038/onc.2011.353)

    • Search Google Scholar
    • Export Citation
  • HaatajaLGurloTHuangCJButlerPC2008Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. Endocrine Reviews29303316. (doi:10.1210/er.2007-0037)

    • Search Google Scholar
    • Export Citation
  • HanDLernerAGVande WalleLUptonJPXuWHagenABackesBJOakesSAPapaFR2009IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Cell138562575. (doi:10.1016/j.cell.2009.07.017)

    • Search Google Scholar
    • Export Citation
  • HaraTMahadevanJKanekuraKHaraMLuSUranoF2014Calcium efflux from the endoplasmic reticulum leads to beta-cell death. Endocrinology155758768. (doi:10.1210/en.2013-1519)

    • Search Google Scholar
    • Export Citation
  • HaraMFowlerJLBellGIPhilipsonLH2016Resting beta-cells – a functional reserve?Diabetes & Metabolism[in press]. (doi:10.1016/j.diabet.2016.01.001)

    • Search Google Scholar
    • Export Citation
  • HardingHPZhangYZengHNovoaILuPDCalfonMSadriNYunCPopkoBPaulesR2003An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Molecular Cell11619633. (doi:10.1016/S1097-2765(03)00105-9)

    • Search Google Scholar
    • Export Citation
  • HasnainSZBorgDJHarcourtBETongHShengYHNgCPDasIWangRChenACLoudovarisT2014Glycemic control in diabetes is restored by therapeutic manipulation of cytokines that regulate beta cell stress. Nature Medicine2014171426. (doi:10.1038/nm.3705)

    • Search Google Scholar
    • Export Citation
  • HasnainSZPrinsJBMcGuckinMA2016Oxidative and endoplasmic reticulum stress in beta-cell dysfunction in diabetes. Journal of Molecular Endocrinology56R33R54. (doi:10.1530/JME-15-0232)

    • Search Google Scholar
    • Export Citation
  • HasslerJRScheunerDLWangSHanJKodaliVKLiPNguyenJGeorgeJSDavisCWuSP2015The IRE1alpha/XBP1s pathway is essential for the glucose response and protection of beta cells. PLoS Biology13e1002277. (doi:10.1371/journal.pbio.1002277)

    • Search Google Scholar
    • Export Citation
  • HetzC2012The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nature Reviews in Molecular Cell Biology1389102. (doi:10.1038/nrm3270)

    • Search Google Scholar
    • Export Citation
  • HotamisligilGS2010Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell140900917. (doi:10.1016/j.cell.2010.02.034)

    • Search Google Scholar
    • Export Citation
  • HouZQLiHLGaoLPanLZhaoJJLiGW2008Involvement of chronic stresses in rat islet and INS-1 cell glucotoxicity induced by intermittent high glucose. Molecular and Cellular Endocrinology2917178. (doi:10.1016/j.mce.2008.03.004)

    • Search Google Scholar
    • Export Citation
  • HouXWangOLiZMouHChenJDengBQianLLiuXLeY2011Upregulation of pancreatic derived factor (FAM3B) expression in pancreatic beta-cells by MCP-1 (CCL2). Molecular and Cellular Endocrinology3431824. (doi:10.1016/j.mce.2011.05.039)

    • Search Google Scholar
    • Export Citation
  • HuPHanZCouvillonADKaufmanRJExtonJH2006Autocrine tumor necrosis factor alpha links endoplasmic reticulum stress to the membrane death receptor pathway through IRE1alpha-mediated NF-kappaB activation and down-regulation of TRAF2 expression. Molecular and Cellular Biology2630713084. (doi:10.1128/MCB.26.8.3071-3084.2006)

    • Search Google Scholar
    • Export Citation
  • HuFYuXWangHZuoDGuoCYiHTiroshBSubjeckJRQiuXWangXY2011ER stress and its regulator X-box-binding protein-1 enhance polyIC-induced innate immune response in dendritic cells. European Journal of Immunology4110861097. (doi:10.1002/eji.201040831)

    • Search Google Scholar
    • Export Citation
  • HuangCJLinCYHaatajaLGurloTButlerAERizzaRAButlerPC2007High expression rates of human islet amyloid polypeptide induce endoplasmic reticulum stress mediated beta-cell apoptosis, a characteristic of humans with type 2 but not type 1 diabetes. Diabetes5620162027. (doi:10.2337/db07-0197)

    • Search Google Scholar
    • Export Citation
  • HuangSZhuMWuWRashidALiangYHouLNingQLuoX2014Valproate pretreatment protects pancreatic beta-cells from palmitate-induced ER stress and apoptosis by inhibiting glycogen synthase kinase-3beta. Journal of Biomedical Science2138. (doi:10.1186/1423-0127-21-38)

    • Search Google Scholar
    • Export Citation
  • HuangHJingGWangJJSheibaniNZhangSX2015ATF4 is a novel regulator of MCP-1 in microvascular endothelial cells. Journal of Inflammation1231. (doi:10.1186/s12950-015-0076-1)

    • Search Google Scholar
    • Export Citation
  • HybertsonBMGaoBBoseSKMcCordJM2011Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Molecular Aspects of Medicine32234246. (doi:10.1016/j.mam.2011.10.006)

    • Search Google Scholar
    • Export Citation
  • Igoillo-EsteveMMarselliLCunhaDALadriereLOrtisFGriecoFADottaFWeirGCMarchettiPEizirikDL2010Palmitate induces a pro-inflammatory response in human pancreatic islets that mimics CCL2 expression by beta cells in type 2 diabetes. Diabetologia5313951405. (doi:10.1007/s00125-010-1707-y)

    • Search Google Scholar
    • Export Citation
  • InokuchiYNakajimaYShimazawaMKuritaTKuboMSaitoASajikiHKudoTAiharaMImaizumiK2009Effect of an inducer of BiP, a molecular chaperone, on endoplasmic reticulum (ER) stress-induced retinal cell death. Investigative Ophthalmology & Visual Science50334344. (doi:10.1167/iovs.08-2123)

    • Search Google Scholar
    • Export Citation
  • InoueHTanizawaYWassonJBehnPKalidasKBernal-MizrachiEMuecklerMMarshallHDonis-KellerHCrockP1998A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nature Genetics20143148. (doi:10.1038/2441)

    • Search Google Scholar
    • Export Citation
  • IwasakiYSuganamiTHachiyaRShirakawaIKim-SaijoMTanakaMHamaguchiMTakai-IgarashiTNakaiMMiyamotoY2014Activating transcription factor 4 links metabolic stress to interleukin-6 expression in macrophages. Diabetes63152161. (doi:10.2337/db13-0757)

    • Search Google Scholar
    • Export Citation
  • JonasJCBensellamMDuprezJElouilHGuiotYPascalSM2009Glucose regulation of islet stress responses and beta-cell failure in type 2 diabetes. Diabetes Obesity and Metabolism11 (Supplement 4) 6581. (doi:10.1111/j.1463-1326.2009.01112.x)

    • Search Google Scholar
    • Export Citation
  • KanekoMNiinumaYNomuraY2003Activation signal of nuclear factor-kappaB in response to endoplasmic reticulum stress is transduced via IRE1 and tumor necrosis factor receptor-associated factor 2. Biological and Pharmaceutical Bulletin26931935. (doi:10.1248/bpb.26.931)

    • Search Google Scholar
    • Export Citation
  • KanetoHNakataniYKawamoriDMiyatsukaTMatsuokaTAMatsuhisaMYamasakiY2006Role of oxidative stress, endoplasmic reticulum stress, and c-Jun N-terminal kinase in pancreatic beta-cell dysfunction and insulin resistance. International Journal of Biochemistry and Cell Biology38782793. (doi:10.1016/j.biocel.2006.01.004)

    • Search Google Scholar
    • Export Citation
  • KarsMYangLGregorMFMohammedBSPietkaTAFinckBNPattersonBWHortonJDMittendorferBHotamisligilGS2010Tauroursodeoxycholic acid may improve liver and muscle but not adipose tissue insulin sensitivity in obese men and women. Diabetes5918991905. (doi:10.2337/db10-0308)

    • Search Google Scholar
    • Export Citation
  • KaserABlumbergRS2010Endoplasmic reticulum stress and intestinal inflammation. Mucosal Immunology31116. (doi:10.1038/mi.2009.122)

  • KaserALeeAHFrankeAGlickmanJNZeissigSTilgHNieuwenhuisEEHigginsDESchreiberSGlimcherLH2008XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell134743756. (doi:10.1016/j.cell.2008.07.021)

    • Search Google Scholar
    • Export Citation
  • KharroubiILadriereLCardozoAKDogusanZCnopMEizirikDL2004Free fatty acids and cytokines induce pancreatic beta-cell apoptosis by different mechanisms: role of nuclear factor-kappaB and endoplasmic reticulum stress. Endocrinology14550875096. (doi:10.1210/en.2004-0478)

    • Search Google Scholar
    • Export Citation
  • KielyAMcClenaghanNHFlattPRNewsholmeP2007Pro-inflammatory cytokines increase glucose, alanine and triacylglycerol utilization but inhibit insulin secretion in a clonal pancreatic beta-cell line. Journal of Endocrinology195113123. (doi:10.1677/JOE-07-0306)

    • Search Google Scholar
    • Export Citation
  • KimMKChoJHLeeJJSonMHLeeKJ2015Proteomic analysis of INS-1 rat insulinoma cells: ER stress effects and the protective role of exenatide, a GLP-1 receptor agonist. PLoS ONE10e0120536. (doi:10.1371/journal.pone.0120536)

    • Search Google Scholar
    • Export Citation
  • KodamaKNishioYSekineOSatoYEgawaKMaegawaHKashiwagiA2005Bidirectional regulation of monocyte chemoattractant protein-1 gene at distinct sites of its promoter by nitric oxide in vascular smooth muscle cells. American Journal of Physiology: Cell Physiology289C582C590. (doi:10.1152/ajpcell.00558.2004)

    • Search Google Scholar
    • Export Citation
  • KudoTKanemotoSHaraHMorimotoNMoriharaTKimuraRTabiraTImaizumiKTakedaM2008A molecular chaperone inducer protects neurons from ER stress. Cell Death and Differentiation15364375. (doi:10.1038/sj.cdd.4402276)

    • Search Google Scholar
    • Export Citation
  • KwonDYKimYSAhnISKimda SKangSHongSMParkS2009Exendin-4 potentiates insulinotropic action partly via increasing beta-cell proliferation and neogenesis and decreasing apoptosis in association with the attenuation of endoplasmic reticulum stress in islets of diabetic rats. Journal of Pharmacology Science111361371. (doi:10.1254/jphs.09178FP)

    • Search Google Scholar
    • Export Citation
  • LadriereLIgoillo-EsteveMCunhaDABrionJPBuglianiMMarchettiPEizirikDLCnopM2010Enhanced signaling downstream of ribonucleic acid-activated protein kinase-like endoplasmic reticulum kinase potentiates lipotoxic endoplasmic reticulum stress in human islets. Journal of Clinical Endocrinology and Metabolism9514421449. (doi:10.1210/jc.2009-2322)

    • Search Google Scholar
    • Export Citation
  • LawrenceMCBorenstein-AuerbachNMcGlynnKKunnathodiFShahbazovRSyedIKanakMTakitaMLevyMFNaziruddinB2015NFAT targets signaling molecules to gene promoters in pancreatic beta-cells. Molecular Endocrinology29274288. (doi:10.1210/me.2014-1066)

    • Search Google Scholar
    • Export Citation
  • LaybuttDRPrestonAMAkerfeldtMCKenchJGBuschAKBiankinAVBidenTJ2007Endoplasmic reticulum stress contributes to beta cell apoptosis in type 2 diabetes. Diabetologia50752763. (doi:10.1007/s00125-006-0590-z)

    • Search Google Scholar
    • Export Citation
  • LeeYYHongSHLeeYJChungSSJungHSParkSGParkKS2010Tauroursodeoxycholate (TUDCA), chemical chaperone, enhances function of islets by reducing ER stress. Biochemical and Biophysical Research Communications397735739. (doi:10.1016/j.bbrc.2010.06.022)

    • Search Google Scholar
    • Export Citation
  • LeeJYMaengSKangSRChoiHYOhTHJuBGYuneTY2014Valproic acid protects motor neuron death by inhibiting oxidative stress and endoplasmic reticulum stress-mediated cytochrome C release after spinal cord injury. Journal of Neurotrauma31582594. (doi:10.1089/neu.2013.3146)

    • Search Google Scholar
    • Export Citation
  • LeninRSankaramoorthyAMohanVBalasubramanyamM2015Altered immunometabolism at the interface of increased endoplasmic reticulum (ER) stress in patients with type 2 diabetes. Journal of Leukocyte Biology98615622. (doi:10.1189/jlb.3A1214-609R)

    • Search Google Scholar
    • Export Citation
  • LernerAGUptonJPPraveenPVGhoshRNakagawaYIgbariaAShenSNguyenVBackesBJHeimanM2012IRE1alpha induces thioredoxin-interacting protein to activate the NLRP3 inflammasome and promote programmed cell death under irremediable ER stress. Cell Metabolism16250264. (doi:10.1016/j.cmet.2012.07.007)

    • Search Google Scholar
    • Export Citation
  • LiRWangRLiHSunSZouMChengG2015Short-term and long-term effects of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with renal impairment: a meta-analysis of randomized controlled trials.Diabetes Metabolism Research and Reviews[in press]. (doi:10.1002/dmrr.2731)

    • Search Google Scholar
    • Export Citation
  • LipsonKLFonsecaSGIshigakiSNguyenLXFossEBortellRRossiniAAUranoF2006Regulation of insulin biosynthesis in pancreatic beta cells by an endoplasmic reticulum-resident protein kinase IRE1. Cell Metabolism4245254. (doi:10.1016/j.cmet.2006.07.007)

    • Search Google Scholar
    • Export Citation
  • LipsonKLGhoshRUranoF2008 The role of IRE1alpha in the degradation of insulin mRNA in pancreatic beta-cells. PLoS ONE3e1648. (doi:10.1371/journal.pone.0001648)

    • Search Google Scholar
    • Export Citation
  • LiuMSunJCuiJChenWGuoHBarbettiFArvanP2015INS-gene mutations: from genetics and beta cell biology to clinical disease. Molecular Aspects of Medicine42318. (doi:10.1016/j.mam.2014.12.001)

    • Search Google Scholar
    • Export Citation
  • LuPDHardingHPRonD2004Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. Journal of Cell Biology1672733. (doi:10.1083/jcb.200408003)

    • Search Google Scholar
    • Export Citation
  • MadsbadS2016Review of head-to-head comparisons of glucagon-like peptide-1 receptor agonists. Diabetes Obesity and Metabolism18317332. (doi:10.1111/dom.12596)

    • Search Google Scholar
    • Export Citation
  • MalhotraJDKaufmanRJ2007Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?Antioxidants & Redox Signaling922772293. (doi:10.1089/ars.2007.1782)

    • Search Google Scholar
    • Export Citation
  • Mandrup-PoulsenTPickersgillLDonathMY2010Blockade of interleukin 1 in type 1 diabetes mellitus. Nature Reviews Endocrinology6158166. (doi:10.1038/nrendo.2009.271)

    • Search Google Scholar
    • Export Citation
  • MarchettiPBuglianiMLupiRMarselliLMasiniMBoggiUFilipponiFWeirGCEizirikDLCnopM2007The endoplasmic reticulum in pancreatic beta cells of type 2 diabetes patients. Diabetologia5024862494. (doi:10.1007/s00125-007-0816-8)

    • Search Google Scholar
    • Export Citation
  • MarhfourILopezXMLefkaditisDSalmonIAllagnatFRichardsonSJMorganNGEizirikDL2012Expression of endoplasmic reticulum stress markers in the islets of patients with type 1 diabetes. Diabetologia5524172420. (doi:10.1007/s00125-012-2604-3)

    • Search Google Scholar
    • Export Citation
  • MarisMOverberghLGysemansCWagetACardozoAKVerdrenghECunhaJPGotohTCnopMEizirikDL2012Deletion of C/EBP homologous protein (Chop) in C57Bl/6 mice dissociates obesity from insulin resistance. Diabetologia5511671178. (doi:10.1007/s00125-011-2427-7)

    • Search Google Scholar
    • Export Citation
  • MarreMLJamesEAPiganelliJD2015beta cell ER stress and the implications for immunogenicity in type 1 diabetes. Frontiers in Cell and Developmental Biology3 67. (doi:10.3389/fcell.2015.00067)

    • Search Google Scholar
    • Export Citation
  • MartinonFChenXLeeAHGlimcherLH2010TLR activation of the transcription factor XBP1 regulates innate immune responses in macrophages. Nature Immunology11411418. (doi:10.1038/ni.1857)

    • Search Google Scholar
    • Export Citation
  • MaurelMChevetETavernierJGerloS2014Getting RIDD of RNA: IRE1 in cell fate regulation. Trends in Biochemical Sciences39245254. (doi:10.1016/j.tibs.2014.02.008)

    • Search Google Scholar
    • Export Citation
  • McCulloughKDMartindaleJLKlotzLOAwTYHolbrookNJ2001Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Molecular Cell Biology2112491259. (doi:10.1128/MCB.21.4.1249-1259.2001)

    • Search Google Scholar
    • Export Citation
  • McGintyJWChowITGreenbaumCOdegardJKwokWWJamesEA2014Recognition of posttranslationally modified GAD65 epitopes in subjects with type 1 diabetes. Diabetes6330333040. (doi:10.2337/db13-1952)

    • Search Google Scholar
    • Export Citation
  • McKenzieMDJamiesonEJansenESScottCLHuangDCBouilletPAllisonJKayTWStrasserAThomasHE2010Glucose induces pancreatic islet cell apoptosis that requires the BH3-only proteins Bim and Puma and multi-BH domain protein Bax. Diabetes59644652. (doi:10.2337/db09-1151)

    • Search Google Scholar
    • Export Citation
  • MianiMColliMLLadriereLCnopMEizirikDL2012Mild endoplasmic reticulum stress augments the proinflammatory effect of IL-1beta in pancreatic rat beta-cells via the IRE1alpha/XBP1s pathway. Endocrinology15330173028. (doi:10.1210/en.2011-2090)

    • Search Google Scholar
    • Export Citation
  • MiyazakiYKaikitaKEndoMHorioEMiuraMTsujitaKHokimotoSYamamuroMIwawakiTGotohT2011C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation. Arteriosclerosis Thrombosis and Vascular Biology3111241132. (doi:10.1161/ATVBAHA.111.224519)

    • Search Google Scholar
    • Export Citation
  • MozziniCGarbinUStranieriCPasiniASolaniETinelliIACominaciniLFratta PasiniAM2015Endoplasmic reticulum stress and Nrf2 repression in circulating cells of type 2 diabetic patients without the recommended glycemic goals. Free Radical Research49244252. (doi:10.3109/10715762.2014.997229)

    • Search Google Scholar
    • Export Citation
  • NambaTTanakaKItoYIshiharaTHoshinoTGotohTEndoMSatoKMizushimaT2009Positive role of CCAAT/enhancer-binding protein homologous protein, a transcription factor involved in the endoplasmic reticulum stress response in the development of colitis. American Journal of Pathology17417861798. (doi:10.2353/ajpath.2009.080864)

    • Search Google Scholar
    • Export Citation
  • NauckM2016Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obesity and Metabolism18203216. (doi:10.1111/dom.12591)

    • Search Google Scholar
    • Export Citation
  • NikulinaMASandhuNShamimZAndersenNAObersonADuprazPThorensBKarlsenAEBonnyCMandrup-PoulsenT2003The JNK binding domain of islet-brain 1 inhibits IL-1 induced JNK activity and apoptosis but not the transcription of key proapoptotic or protective genes in insulin-secreting cell lines. Cytokine241324. (doi:10.1016/S1043-4666(03)00242-4)

    • Search Google Scholar
    • Export Citation
  • NoguchiHNakaiYMatsumotoSKawaguchiMUedaMOkitsuTIwanagaYYonekawaYNagataHMinamiK2005Cell permeable peptide of JNK inhibitor prevents islet apoptosis immediately after isolation and improves islet graft function. American Journal of Transplantation518481855. (doi:10.1111/j.1600-6143.2005.00985.x)

    • Search Google Scholar
    • Export Citation
  • NoguchiHMatsumotoSKobayashiNHayashiSIwanagaYNagataHJacksonANaziruddinBOkitsuTLevyMF2008Effect of JNK inhibitor during islet isolation and transplantation. Transplantation Proceedings40379381. (doi:10.1016/j.transproceed.2008.01.055)

    • Search Google Scholar
    • Export Citation
  • OhYSLeeYJKangYHanJLimOKJunHS2013Exendin-4 inhibits glucolipotoxic ER stress in pancreatic beta cells via regulation of SREBP1c and C/EBPbeta transcription factors. Journal of Endocrinology216343352. (doi:10.1530/JOE-12-0311)

    • Search Google Scholar
    • Export Citation
  • OrtisFNaamaneNFlamezDLadriereLMooreFCunhaDAColliMLThykjaerTThorsenKOrntoftTF2010Cytokines interleukin-1beta and tumor necrosis factor-alpha regulate different transcriptional and alternative splicing networks in primary beta-cells. Diabetes59358374. (doi:10.2337/db09-1159)

    • Search Google Scholar
    • Export Citation
  • OrtisFMianiMColliMLCunhaDAGurzovENAllagnatFChariotAEizirikDL2012Differential usage of NF-kappaB activating signals by IL-1beta and TNF-alpha in pancreatic beta cells. FEBS Letters586984989. (doi:10.1016/j.febslet.2012.02.021)

    • Search Google Scholar
    • Export Citation
  • OslowskiCMUranoF2011aThe binary switch that controls the life and death decisions of ER stressed beta cells.Current Opinion in Cell Biology23207215. (doi:10.1016/j.ceb.2010.11.005)

    • Search Google Scholar
    • Export Citation
  • OslowskiCMUranoF2011bMeasuring ER stress and the unfolded protein response using mammalian tissue culture system.Methods in Enzymology4907192. (doi:10.1016/B978-0-12-385114-7.00004-0)

    • Search Google Scholar
    • Export Citation
  • OslowskiCMHaraTO’Sullivan-MurphyBKanekuraKLuSHaraMIshigakiSZhuLJHayashiEHuiST2012Thioredoxin-interacting protein mediates ER stress-induced beta cell death through initiation of the inflammasome. Cell Metabolism16265273. (doi:10.1016/j.cmet.2012.07.005)

    • Search Google Scholar
    • Export Citation
  • OyadomariSMoriM2004Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death and Differentiation11381389. (doi:10.1038/sj.cdd.4401373)

    • Search Google Scholar
    • Export Citation
  • OyadomariSArakiEMoriM2002aEndoplasmic reticulum stress-mediated apoptosis in pancreatic beta-cells.Apoptosis7335345. (doi:10.1023/A:1016175429877)

    • Search Google Scholar
    • Export Citation
  • OyadomariSKoizumiATakedaKGotohTAkiraSArakiEMoriM2002bTargeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes.Journal of Clinical Investigation109525532. (doi:10.1172/JCI14550)

    • Search Google Scholar
    • Export Citation
  • OzcanUYilmazEOzcanLFuruhashiMVaillancourtESmithROGorgunCZHotamisligilGS2006Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science31311371140. (doi:10.1126/science.1128294)

    • Search Google Scholar
    • Export Citation
  • PalDDasguptaSKunduRMaitraSDasGMukhopadhyaySRaySMajumdarSSBhattacharyaS2012Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nature Medicine1812791285. (doi:10.1038/nm.2851)

    • Search Google Scholar
    • Export Citation
  • PanayiGSCorrigallVM2006BiP regulates autoimmune inflammation and tissue damage. Autoimmunity Reviews5140142. (doi:10.1016/j.autrev.2005.08.006)

    • Search Google Scholar
    • Export Citation
  • PenasCVerduEAsensio-PinillaEGuzman-LenisMSHerrando-GrabulosaMNavarroXCasasC2011Valproate reduces CHOP levels and preserves oligodendrocytes and axons after spinal cord injury. Neuroscience1783344. (doi:10.1016/j.neuroscience.2011.01.012)

    • Search Google Scholar
    • Export Citation
  • PereiraSSAlvarez-LeiteJI2014Low-grade inflammation, obesity, and diabetes. Current Obesisty Reports3422431. (doi:10.1007/s13679-014-0124-9)

    • Search Google Scholar
    • Export Citation
  • PetersLRRaghavanM2011Endoplasmic reticulum calcium depletion impacts chaperone secretion, innate immunity, and phagocytic uptake of cells. Journal of Immunology187919931. (doi:10.4049/jimmunol.1100690)

    • Search Google Scholar
    • Export Citation
  • PincusDChevalierMWAragonTvan AnkenEVidalSEEl-SamadHWalterP2010BiP binding to the ER-stress sensor Ire1 tunes the homeostatic behavior of the unfolded protein response. PLoS Biology8e1000415. (doi:10.1371/journal.pbio.1000415)

    • Search Google Scholar
    • Export Citation
  • PirotPEizirikDLCardozoAK2006Interferon-gamma potentiates endoplasmic reticulum stress-induced death by reducing pancreatic beta cell defence mechanisms. Diabetologia4912291236. (doi:10.1007/s00125-006-0214-7)

    • Search Google Scholar
    • Export Citation
  • PirotPNaamaneNLibertFMagnussonNEOrntoftTFCardozoAKEizirikDL2007aGlobal profiling of genes modified by endoplasmic reticulum stress in pancreatic beta cells reveals the early degradation of insulin mRNAs.Diabetologia5010061014. (doi:10.1007/s00125-007-0609-0)

    • Search Google Scholar
    • Export Citation
  • PirotPOrtisFCnopMMaYHendershotLMEizirikDLCardozoAK2007bTranscriptional regulation of the endoplasmic reticulum (ER) stress gene Chop in pancreatic insulin producing cells.Diabetes5610691077. (doi:10.2337/db06-1253)

    • Search Google Scholar
    • Export Citation
  • PockleyAGHendersonBMulthoffG2014Extracellular cell stress proteins as biomarkers of human disease. Biochemical Society Transactions4217441751. (doi:10.1042/BST20140205)

    • Search Google Scholar
    • Export Citation
  • PolakMDechaumeACaveHNimriRCrosnierHSulmontVde KerdanetMScharfmannRLebenthalYFroguelP2008Heterozygous missense mutations in the insulin gene are linked to permanent diabetes appearing in the neonatal period or in early infancy: a report from the French ND (Neonatal Diabetes) Study Group. Diabetes5711151119. (doi:10.2337/db07-1358)

    • Search Google Scholar
    • Export Citation
  • RaghavanMWijeyesakereSJPetersLRDel CidN2013Calreticulin in the immune system: ins and outs. Trends in Immunology341321. (doi:10.1016/j.it.2012.08.002)

    • Search Google Scholar
    • Export Citation
  • RaoJYueSFuYZhuJWangXBusuttilRWKupiec-WeglinskiJWLuLZhaiY2014ATF6 mediates a pro-inflammatory synergy between ER stress and TLR activation in the pathogenesis of liver ischemia-reperfusion injury. American Journal of Transplantation1415521561. (doi:10.1111/ajt.12711)

    • Search Google Scholar
    • Export Citation
  • RasschaertJLiuDKutluBCardozoAKKruhofferMOrntoftTFEizirikDL2003Global profiling of double stranded RNA- and IFN-gamma-induced genes in rat pancreatic beta cells. Diabetologia4616411657. (doi:10.1007/s00125-003-1245-y)

    • Search Google Scholar
    • Export Citation
  • RondasDCrevecoeurID’HertogWFerreiraGBStaesAGargADEizirikDLAgostinisPGevaertKOverberghL2015Citrullinated glucose-regulated protein 78 is an autoantigen in type 1 diabetes. Diabetes64573586. (doi:10.2337/db14-0621)

    • Search Google Scholar
    • Export Citation
  • SalvadoLPalomerXBarrosoEVazquez-CarreraM2015Targeting endoplasmic reticulum stress in insulin resistance. Trends in Endocrinology and Metabolism26438448. (doi:10.1016/j.tem.2015.05.007)

    • Search Google Scholar
    • Export Citation
  • SantinIMooreFColliMLGurzovENMarselliLMarchettiPEizirikDL2011PTPN2, a candidate gene for type 1 diabetes, modulates pancreatic beta-cell apoptosis via regulation of the BH3-only protein Bim. Diabetes6032793288. (doi:10.2337/db11-0758)

    • Search Google Scholar
    • Export Citation
  • SatohTAbiruNKobayashiMZhouHNakamuraKKuriyaGNakamuraHNagayamaYKawasakiEYamasakiH2011CHOP deletion does not impact the development of diabetes but suppresses the early production of insulin autoantibody in the NOD mouse. Apoptosis16438448. (doi:10.1007/s10495-011-0576-2)

    • Search Google Scholar
    • Export Citation
  • ScheunerDMierdeDVSongBFlamezDCreemersJWTsukamotoKRibickMSchuitFCKaufmanRJ2005Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. Nature Medicine11757764. (doi:10.1038/nm1259)

    • Search Google Scholar
    • Export Citation
  • SeinoYNanjoKTajimaNKadowakiTKashiwagiAArakiEItoCInagakiNIwamotoY & Committee of the Japan Diabetes Society on the Diagnostic Criteria of Diabetes Mellitus 2010 Report of the committee on the classification and diagnostic criteria of diabetes mellitus.Journal of Diabetes Investigation1212228. (doi:10.1111/j.2040-1124.2010.00074.x)

    • Search Google Scholar
    • Export Citation
  • SeoHYKimYDLeeKMMinAKKimMKKimHSWonKCParkJYLeeKUChoiHS2008Endoplasmic reticulum stress-induced activation of activating transcription factor 6 decreases insulin gene expression via up-regulation of orphan nuclear receptor small heterodimer partner. Endocrinology14938323841. (doi:10.1210/en.2008-0015)

    • Search Google Scholar
    • Export Citation
  • ShaulianEKarinM2001AP-1 in cell proliferation and survival. Oncogene2023902400. (doi:10.1038/sj.onc.1204383)

  • ShihVFTsuiRCaldwellAHoffmannA2011A single NFkappaB system for both canonical and non-canonical signaling. Cell Research2186102. (doi:10.1038/cr.2010.161)

    • Search Google Scholar
    • Export Citation
  • ShodaHFujioKShibuyaMOkamuraTSumitomoSOkamotoASawadaTYamamotoK2011Detection of autoantibodies to citrullinated BiP in rheumatoid arthritis patients and pro-inflammatory role of citrullinated BiP in collagen-induced arthritis. Arthritis Research and Therapy13R191.

    • Search Google Scholar
    • Export Citation
  • Simon-SzaboLKokasMMandlJKeriGCsalaM2014Metformin attenuates palmitate-induced endoplasmic reticulum stress, serine phosphorylation of IRS-1 and apoptosis in rat insulinoma cells. PLoS ONE9e97868. (doi:10.1371/journal.pone.0097868)

    • Search Google Scholar
    • Export Citation
  • SinghRKGuptaBTripathiKSinghSK2015Anti oxidant potential of metformin and pioglitazone in type 2 diabetes mellitus: beyond their anti glycemic effect.Diabetes and Metabolic Syndrome10102104. (doi:10.1016/j.dsx.2015.08.016)

    • Search Google Scholar
    • Export Citation
  • SmithJATurnerMJDeLayMLKlenkEISowdersDPColbertRA2008Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN-beta induction via X-box binding protein 1. European Journal of Immunology3811941203. (doi:10.1002/eji.200737882)

    • Search Google Scholar
    • Export Citation
  • SongBScheunerDRonDPennathurSKaufmanRJ2008Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. Journal of Clinical Investigation11833783389. (doi:10.1172/JCI34587)

    • Search Google Scholar
    • Export Citation
  • SrinivasanSOhsugiMLiuZFatraiSBernal-MizrachiEPermuttMA2005Endoplasmic reticulum stress-induced apoptosis is partly mediated by reduced insulin signaling through phosphatidylinositol 3-kinase/Akt and increased glycogen synthase kinase-3beta in mouse insulinoma cells. Diabetes54968975. (doi:10.2337/diabetes.54.4.968)

    • Search Google Scholar
    • Export Citation
  • StoyJEdghillELFlanaganSEYeHPazVPPluzhnikovABelowJEHayesMGCoxNJLipkindGM2007Insulin gene mutations as a cause of permanent neonatal diabetes. PNAS1041504015044. (doi:10.1073/pnas.0707291104)

    • Search Google Scholar
    • Export Citation
  • SunJCuiJHeQChenZArvanPLiuM2015Proinsulin misfolding and endoplasmic reticulum stress during the development and progression of diabetes. Molecular Aspects of Medicine42105118. (doi:10.1016/j.mam.2015.01.001)

    • Search Google Scholar
    • Export Citation
  • SuyamaKOhmurayaMHirotaMOzakiNIdaSEndoMArakiKGotohTBabaHYamamuraK2008C/EBP homologous protein is crucial for the acceleration of experimental pancreatitis. Biochemical and Biophysical Research Communications367176182. (doi:10.1016/j.bbrc.2007.12.132)

    • Search Google Scholar
    • Export Citation
  • SzkudelskiTSzkudelskaK2015Resveratrol and diabetes: from animal to human studies. Biochimica et Biophysica Acta185211451154. (doi:10.1016/j.bbadis.2014.10.013)

    • Search Google Scholar
    • Export Citation
  • TabasIRonD2011Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nature Cell Biology13184190. (doi:10.1038/ncb0311-184)

    • Search Google Scholar
    • Export Citation
  • TamABMercadoELHoffmannANiwaM2012ER stress activates NF-kappaB by integrating functions of basal IKK activity, IRE1 and PERK. PLoS ONE7e45078. (doi:10.1371/journal.pone.0045078)

    • Search Google Scholar
    • Export Citation
  • TanBMZammitNWYamAOSlatteryRWaltersSNMalleEGreyST2013Baculoviral inhibitors of apoptosis repeat containing (BIRC) proteins fine-tune TNF-induced nuclear factor kappaB and c-Jun N-terminal kinase signalling in mouse pancreatic beta cells. Diabetologia56520532. (doi:10.1007/s00125-012-2784-x)

    • Search Google Scholar
    • Export Citation
  • TerseySANishikiYTemplinATCabreraSMStullNDColvinSCEvans-MolinaCRickusJLMaierBMirmiraRG2012Islet beta-cell endoplasmic reticulum stress precedes the onset of type 1 diabetes in the nonobese diabetic mouse model. Diabetes61818827. (doi:10.2337/db11-1293)

    • Search Google Scholar
    • Export Citation
  • TonnesenMFGrunnetLGFribergJCardozoAKBillestrupNEizirikDLStorlingJMandrup-PoulsenT2009Inhibition of nuclear factor-kappaB or Bax prevents endoplasmic reticulum stress- but not nitric oxide-mediated apoptosis in INS-1E cells. Endocrinology15040944103. (doi:10.1210/en.2009-0029)

    • Search Google Scholar
    • Export Citation
  • TranKLiYDuanHAroraDLimHYWangW2014Identification of small molecules that protect pancreatic beta cells against endoplasmic reticulum stress-induced cell death. ACS Chemical Biology927962806. (doi:10.1021/cb500740d)

    • Search Google Scholar
    • Export Citation
  • TsunekawaSYamamotoNTsukamotoKItohYKanekoYKimuraTAriyoshiYMiuraYOisoYNikiI2007Protection of pancreatic beta-cells by exendin-4 may involve the reduction of endoplasmic reticulum stress: in vivo and in vitro studies. Journal of Endocrinology1936574. (doi:10.1677/JOE-06-0148)

    • Search Google Scholar
    • Export Citation
  • UranoFWangXBertolottiAZhangYChungPHardingHPRonD2000Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science287664666. (doi:10.1126/science.287.5453.664)

    • Search Google Scholar
    • Export Citation
  • van BelleTLCoppietersKTvon HerrathMG2011Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiological Reviews9179118. (doi:10.1152/physrev.00003.2010)

    • Search Google Scholar
    • Export Citation
  • VolchukARonD2010The endoplasmic reticulum stress response in the pancreatic beta-cell. Diabetes Obesity and Metabolism12 (Supplement 2) 4857. (doi:10.1111/j.1463-1326.2010.01271.x)

    • Search Google Scholar
    • Export Citation
  • VomundANZinselmeyerBHHughesJCalderonBValderramaCFerrisSTWanXKanekuraKCarreroJAUranoF2015Beta cells transfer vesicles containing insulin to phagocytes for presentation to T cells. PNAS112E5496E5502. (doi:10.1073/pnas.1515954112)

    • Search Google Scholar
    • Export Citation
  • WaliJAGurzovENFynchSElkerboutLKayTWMastersSLThomasHE2014Activation of the NLRP3 inflammasome complex is not required for stress-induced death of pancreatic islets. PLoS ONE9e113128. (doi:10.1371/journal.pone.0113128)

    • Search Google Scholar
    • Export Citation
  • WalterPRonD2011The unfolded protein response: from stress pathway to homeostatic regulation. Science33410811086. (doi:10.1126/science.1209038)

    • Search Google Scholar
    • Export Citation
  • WangJFBownCYoungLT1999Differential display PCR reveals novel targets for the mood-stabilizing drug valproate including the molecular chaperone GRP78. Molecular Pharmacology55521527.

    • Search Google Scholar
    • Export Citation
  • WidenmaierSBAoZKimSJWarnockGMcIntoshCH2009Suppression of p38 MAPK and JNK via Akt-mediated inhibition of apoptosis signal-regulating kinase 1 constitutes a core component of the beta-cell pro-survival effects of glucose-dependent insulinotropic polypeptide. Journal of Biological Chemistry2843037230382. (doi:10.1074/jbc.M109.060178)

    • Search Google Scholar
    • Export Citation
  • XiaoCGiaccaALewisGF2011Sodium phenylbutyrate, a drug with known capacity to reduce endoplasmic reticulum stress, partially alleviates lipid-induced insulin resistance and beta-cell dysfunction in humans. Diabetes60918924. (doi:10.2337/db10-1433)

    • Search Google Scholar
    • Export Citation
  • YamadaTIshiharaHTamuraATakahashiRYamaguchiSTakeiDTokitaASatakeCTashiroFKatagiriH2006WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Human Molecular Genetics1516001609. (doi:10.1093/hmg/ddl081)

    • Search Google Scholar
    • Export Citation
  • YamaguchiKTakedaKKadowakiHUedaINambaYOuchiYNishitohHIchijoH2013Involvement of ASK1-p38 pathway in the pathogenesis of diabetes triggered by pancreatic ss cell exhaustion. Biochimica et Biophysica Acta183036563663. (doi:10.1016/j.bbagen.2013.01.029)

    • Search Google Scholar
    • Export Citation
  • YamazakiHHiramatsuNHayakawaKTagawaYOkamuraMOgataRHuangTNakajimaSYaoJPatonAW2009Activation of the Akt-NF-kappaB pathway by subtilase cytotoxin through the ATF6 branch of the unfolded protein response. Journal of Immunology18314801487. (doi:10.4049/jimmunol.0900017)

    • Search Google Scholar
    • Export Citation
  • YangCDiiorioPJurczykAO'Sullivan-MurphyBUranoFBortellR2013Pathological endoplasmic reticulum stress mediated by the IRE1 pathway contributes to pre-insulitic beta cell apoptosis in a virus-induced rat model of type 1 diabetes. Diabetologia5626382646. (doi:10.1007/s00125-013-3044-4)

    • Search Google Scholar
    • Export Citation
  • YinJPengYWuJWangYYaoL2014Toll-like receptor 2/4 links to free fatty acid-induced inflammation and beta-cell dysfunction. Journal of Leukocyte Biology954752. (doi:10.1189/jlb.0313143)

    • Search Google Scholar
    • Export Citation
  • YoshiharaEMasakiSMatsuoYChenZTianHYodoiJ2014Thioredoxin/Txnip: redoxisome, as a redox switch for the pathogenesis of diseases. Frontiers in Immunology4 514. (doi:10.3389/fimmu.2013.00514)

    • Search Google Scholar
    • Export Citation
  • YustaBBaggioLLEstallJLKoehlerJAHollandDPLiHPipeleersDLingZDruckerDJ2006GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress. Cell Metabolism4391406. (doi:10.1016/j.cmet.2006.10.001)

    • Search Google Scholar
    • Export Citation
  • ZengLLiuYPShaHChenHQiLSmithJA2010XBP-1 couples endoplasmic reticulum stress to augmented IFN-beta induction via a cis-acting enhancer in macrophages. Journal of Immunology18523242330. (doi:10.4049/jimmunol.0903052)

    • Search Google Scholar
    • Export Citation
  • ZhangSKimKH1995TNF-alpha inhibits glucose-induced insulin secretion in a pancreatic beta-cell line (INS-1). FEBS Letters377237239. (doi:10.1016/0014-5793(95)01272-9)

    • Search Google Scholar
    • Export Citation
  • ZhangKWongHNSongBMillerCNScheunerDKaufmanRJ2005The unfolded protein response sensor IRE1alpha is required at 2 distinct steps in B cell lymphopoiesis. Journal of Clinical Investigation115268281. (doi:10.1172/JCI200521848)

    • Search Google Scholar
    • Export Citation
  • ZhangZTongNGongYQiuQYinLLvXWuX2011Valproate protects the retina from endoplasmic reticulum stress-induced apoptosis after ischemia-reperfusion injury. Neuroscience Letters5048892. (doi:10.1016/j.neulet.2011.09.003)

    • Search Google Scholar
    • Export Citation
  • ZiogasAMudersMHEconomopoulouMSprottDGrossklausSSiegertGBarettonGBMitroulisIChavakisT2015Endothelial-specific X-box binding protein 1 deficiency limits tumor necrosis factor-induced leukocyte recruitment and vasculitis. Arthritis & Rheumatology6732793285. (doi:10.1002/art.39309)

    • Search Google Scholar
    • Export Citation

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    Schematic representation of the possible cross talks between UPR and pro-inflammatory pathways in pancreatic β-cells under ER stress. Pro-inflammatory cytokines (IL1β, TNF, IFN, IL23, and IL24), lipids (free fatty acids), IAPP aggregates, and Serca2 blockers induce ER stress by diverse mechanisms such as NO formation, ROS production, and ER calcium depletion leading to UPR activation in pancreatic β-cells. UPR-mediated activation of IRE1α (by its dimerization and phosphorylation) may lead to the recruitment of the adaptor protein tumor necrosis factor receptor-associated factor 2 (TRAF2) leading to activation of NF-κB (via IκBα degradation) and JNK. JNK activation in turn increases AP1 activity and both AP1 and NF-κB migrate to the nucleus to induce expression of pro-inflammatory genes. Under pro-inflammatory stimulation, JNK (via AP1) upregulates CHOP expression, consequently increasing IκBα degradation, NF-κB activation and elevated NO production further potentiating ER stress responses. Furthermore, IRE1α induces the alternative splicing of XBP1s, which may increase NF-κB activation via its inhibitory effect on FOX01. Finally, IRE1α increases degradation of miRNA that targets Txnip, leading to increased activation of the NLRP3 inflammasome and IL1β production, under certain conditions. Activation of the PERK arm in ER-stressed β-cells might activate NF-κB via ATF4-mediated increase in the expression of CHOP. Moreover, PERK inhibits general protein translation (via phosphorylation and activation of eIF2α), which may also increase NF-κB activation, due to inhibition of de novo IκBα expression. Finally, PERK was also shown to contribute to the activation of the NLRP3 inflammasome and IL1β release. Furthermore, cytokine-induced ER stress stimulates translocation of citrullinated BiP to the plasma membrane where it may activate the immune system, thereby contributing to the inflammatory response in the islets. This ER stress-mediated inflammatory state contributes to the maintenance of ER stress and probably leads to β-cell demise. Additional information and supporting references are provided in the text.

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    ER stress-targeting therapies. Several strategies to improve ER function in pancreatic β-cells are emerging. (1) The use of the chemical chaperones 4-phenyl butyric acid (4-PBA) and taurine-conjugated ursodeoxycholic acid (TUDCA) show promising results regarding diabetes therapy, although their mode of action remains largely unknown. (2) Several compounds such as valproic acid (VPA) or BiP inducer X (BiX) may promote the expression of endogenous chaperones, thereby reducing ER stress and apoptosis. (3) Two novel compounds, namely telithromycin and RH01687, were shown to inhibit CHOP and promote β-cell function and survival during ER stress. (4) Strategies aimed at blocking pro-apoptotic UPR pathway such as ASK1 or JNK activity downstream of IRE1α have been shown to protect against ER stress-mediated cell death. Notably, the anti-apoptotic properties of GLP1 are partly mediated by reduced ER stress through actions on ASK1 and the transcription factor JunB downstream JNK (5). GLP1 may also stimulate BiP expression. (6) Finally, other anti-diabetic therapies such as pioglitazone, metformin, or resveratrol have been shown to reduce ER stress in β-cells through unknown mechanisms.

  • AkiyamaMHatanakaMOhtaYUedaKYanaiAUeharaYTanabeKTsuruMMiyazakiMSaekiS2009Increased insulin demand promotes while pioglitazone prevents pancreatic beta cell apoptosis in Wfs1 knockout mice. Diabetologia52653663. (doi:10.1007/s00125-009-1270-6)

    • Search Google Scholar
    • Export Citation
  • AllagnatFChristuliaFOrtisFPirotPLortzSLenzenSEizirikDLCardozoAK2010Sustained production of spliced X-box binding protein 1 (XBP1) induces pancreatic beta cell dysfunction and apoptosis. Diabetologia5311201130. (doi:10.1007/s00125-010-1699-7)

    • Search Google Scholar
    • Export Citation
  • AllagnatFCunhaDMooreFVanderwindenJMEizirikDLCardozoAK2011Mcl-1 downregulation by pro-inflammatory cytokines and palmitate is an early event contributing to beta-cell apoptosis. Cell Death and Differentiation18328337. (doi:10.1038/cdd.2010.105)

    • Search Google Scholar
    • Export Citation
  • AllagnatFFukayaMNogueiraTCDelarocheDWelshNMarselliLMarchettiPHaefligerJAEizirikDLCardozoAK2012C/EBP homologous protein contributes to cytokine-induced pro-inflammatory responses and apoptosis in beta-cells. Cell Death and Differentiation1918361846. (doi:10.1038/cdd.2012.67)

    • Search Google Scholar
    • Export Citation
  • AndradeJMParaisoAFde OliveiraMVMartinsAMNetoJFGuimaraesALde PaulaAMQureshiMSantosSH2014Resveratrol attenuates hepatic steatosis in high-fat fed mice by decreasing lipogenesis and inflammation. Nutrition30915919. (doi:10.1016/j.nut.2013.11.016)

    • Search Google Scholar
    • Export Citation
  • AngelPSzabowskiASchorpp-KistnerM2001Function and regulation of AP-1 subunits in skin physiology and pathology. Oncogene2024132423. (doi:10.1038/sj.onc.1204380)

    • Search Google Scholar
    • Export Citation
  • AriyamaYTanakaYShimizuHShimomuraKOkadaSSaitoTYamadaEOyadomariSMoriM2008The role of CHOP messenger RNA expression in the link between oxidative stress and apoptosis. Metabolism5716251635. (doi:10.1016/j.metabol.2008.06.019)

    • Search Google Scholar
    • Export Citation
  • AzadmehrAZiaeeAGhaneiLFallah HuseiniHHajiaghaeeRTavakoli-FarBKordafshariG2014A randomized clinical trial study: anti-oxidant, anti-hyperglycemic and anti-hyperlipidemic effects of olibanum gum in type 2 diabetic patients. Iranian Journal of Pharmaceutical Research1310031009.

    • Search Google Scholar
    • Export Citation
  • BackSHScheunerDHanJSongBRibickMWangJGildersleeveRDPennathurSKaufmanRJ2009Translation attenuation through eIF2alpha phosphorylation prevents oxidative stress and maintains the differentiated state in beta cells. Cell Metabolism101326. (doi:10.1016/j.cmet.2009.06.002)

    • Search Google Scholar
    • Export Citation
  • BlassSUnionARaymackersJSchumannFUngethumUMuller-SteinbachSDe KeyserFEngelJMBurmesterGR2001The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis and Rheumatism44761771.

    • Search Google Scholar
    • Export Citation
  • BonnyCObersonANegriSSauserCSchorderetDF2001Cell-permeable peptide inhibitors of JNK: novel blockers of beta-cell death. Diabetes507782. (doi:10.2337/diabetes.50.1.77)

    • Search Google Scholar
    • Export Citation
  • BownCDWangJFChenBYoungLT2002Regulation of ER stress proteins by valproate: therapeutic implications. Bipolar Disorders4145151. (doi:10.1034/j.1399-5618.2002.bib1-1-40201.x)