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Review Article

Endoplasmic reticulum stress and destruction of pancreatic β cells in type 1 diabetes

Cao, Zhao-Hui; Wu, Zhuan; Hu, Cong; Zhang, Min; Wang, Wu-Zhou; Hu, Xiao-Bo

Section Editor(s): Guo, Li-Shao

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doi: 10.1097/CM9.0000000000000583
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Type 1 diabetes (T1D) is an autoimmune-mediated disease with loss of pancreatic β cells, characterized by reduced insulin levels and increased blood glucose. Although genetic predisposition is a main cause for T1D, accumulating epidemiological data suggest that many environmental factors, including viral infection, oxidative stress, chemicals exposure, and inflammation play roles in T1D onset and development.[1,2] Pancreatic islet β cells have an elaborate endoplasmic reticulum (ER) system due to the role of insulin synthesis and secretion. These environmental factors related to T1D lead to ER stress.[1,2] Nevertheless, the extent of ER stress contribution to β cells pathophysiology and T1D development remains largely unclear. This article reviews the relationship between ER stress and T1D, which is helpful to the development of new effective therapeutics for T1D.

ER Stress

The ER plays an indispensable role in protein synthesis, folding, modification and transportation, and cellular calcium storage.[3] When faced with accumulation of excessive misfolded or unfolded proteins in the ER lumen, pancreatic β cells respond to ER stress by activating the unfolded protein response (UPR).[4] Under physiological condition, UPR is a protective mechanism to relieve ER stress and prevent cell death. However, under pathological conditions, this adaptive process may promote cells death due to severe ER stress.

The UPR mainly exerts its positive regulatory effects by three ER-resident transmembrane molecules: (1) protein kinase-like ER kinase (PERK), (2) activating transcription factor 6 (ATF6), (3) inositol-requiring enzyme 1α (IRE1α).[4] In response to ER stress, PERK inactivates eukaryotic translation initiation factor 2α (eIF2α), which inhibits protein translation and reduced ER burden.[5] Additionally, the activated IRE1α splices a 26-nucleotide sequence from X-box binding protein 1 (XBP1) mRNA, resulting in induction of an active transcription factor, called spliced XBP-1 (sXBP1).[6] Similarly, upon ER stress, ATF6 protein is translocated into the Golgi, and it is activated to trigger a UPR.[7] sXBP1 and active ATF6 (ATF6N) subsequently promote many target genes expression that improve ER size and function to relieve ER pressure and prevent cell death.[6,7]

However, under severe ER stress, IRE1α recruits the apoptosis signal-regulating kinase-1 (ASK1) and tumor necrosis factor (TNF) receptor associated factor 2 (TRAF2), activating c-Jun N-terminal kinase (JNK), and caspase-12.[8] Additionally, the PERK-ATF4 pathway augments the expression of C/EBP homologous protein (CHOP).[9] Similarly, IRE1-TRAF-ASK1 pathway also promotes CHOP production, ultimately resulting in cellular damage or even apoptosis. Furthermore, ATF6 can increase expression of CHOP and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) expression associated with cell death.[8]Figure 1 summarized the three branches of the UPR signal pathways.

Figure 1
Figure 1:
Three branches of UPR pathways under physiological and pathological ER stress. Signaling pathways from PERK, IRE1α, and ATF6 contribute to regulation of molecules for cell survival under mild ER stress and for cell death under severe ER stress. ASK1: Apoptosis signal-regulating kinase-1; ATF4: Activating transcription factor 4; ATF6: Activating transcription factor 6; CHOP: C/EBP homologous protein; eIF2α: Eukaryotic translation initiation factor 2α; ER: Endoplasmic reticulum; ERAD: ER-associated degradation; IRE1α: Inositol-requiring enzyme 1α; JNK: C-Jun N-terminal kinase; NF-κB: Nuclear factor kappa-light-chain-enhancer of activated B cells; PERK: Protein kinase-like ER kinase; RIDD: Regulated IRE1-dependent mRNA decay; TRAF2: Tumor necrosis factor (TNF) receptor associated factor 2; UPR: Unfolded protein response; XBP1: X-box binding protein 1.

ER Stress and T1D

T1D is an autoimmune-mediated disease with pancreatic β cells deficiency. As professional secretory cells, pancreatic islets β cells are rich in ER networks, required for the folding, modification, exporting, and processing of newly synthesized insulin. Accumulative evidence has supported that ER stress and impaired UPR are associated with pancreatic β cells dysfunction and T1D in in vitro and in vivo.

In cell models

In insulinoma INS-1E and Min6 cells, Rondas et al[10] investigated that cytokine interleukin (IL)-1β and interferon (IFN)-γ stimulates glucose-regulated protein 78 (GRP78) membrane translocation and activates the PERK-eIF2α-CHOP pathway. In addition, expression and activity of peptidylarginine deiminase 2, a candidate gene for T1D are increased in pre-diabetic non-obese diabetic (NOD) mice, indicating that ER stress was activated in T1D. Hu et al[11] found that silenced CHOP by small interfering RNA (siRNA) ameliorated high glucose-induced apoptosis in pancreatic islets β cells. Additionally, in INS-1 cells, ATF6α knockdown by siRNA activated JNK and p38 kinase pathways and promoted cell death. However, inhibition of JNK or p38 kinases prevented cell apoptosis in the absence of ATF6α, which suggested that ATF6α is necessary for β-cell viability.[12]

In animal models

In experimental animal models, mutation in genes important for ER function results in pancreatic β cells loss and severe diabetes. It has been demonstrated that PERK gene conventional knockout (KO) mice showed some permanent abnormalities soon after birth, such as hyperglycemia, hypoinsulinemia, and pancreatic β cell dysfunction because of the inability to maintain ER integrity.[13] In addition, mice with a mutation in eIF2α displayed a severe β cell failure, leading to perinatal death because of hypoglycemia due to defective gluconeogenesis.[14]IRE1α conditional KO mice exhibited hyperglycemia, hypoinsulinemia, and a decreasing serum immunoglobulin level. Furthermore, IRE1α deficiency caused histological abnormality of exocrine tissues, such as pancreatic glands and salivary glands.[15] Tersey et al[16] demonstrated that isolated islets from NOD mice displayed upregulation of ER stress parameters, ER structure alterations, and activation of the NF-κB target genes associated with ER stress.

In diabetic patients

In human, PERK gene deficiency caused Wolcott-Rallison syndrome, characterized by permanent neonatal diabetes mellitus, demonstrating that PERK activity is crucial for normal β cell function.[17] In addition, mutations in the Wolfram syndrome (WFS1) gene, which encodes an ER transmembrane protein to mitigate ER stress, is also associated with insulin-dependent diabetes.[18] Recently, Wang et al[19] showed that another mutation of L35Q in the Insulin (INS) gene was linked to neonatal diabetes. Since L35 residue is involved in its hydrophobic core of the molecule, the L35Q specific mutation is likely to affect the formation of B19-A20 disulfide bond then leads to conformational alterations, finally resulting in pancreatic β cell loss by initiating ER stress. Table 1 summarizes the recent publications associated with ER stress in the regulation of β-cell dysfunction.

Table 1
Table 1:
Publications associated with ER stress in the regulation of β-cell dysfunction.

ER Stress Mediated Possible Mechanism in T1D

In T1D, autoimmune responses lead to production of cytokines that cause an inflammatory state in β cells. Chronic inflammation can disturb calcium homeostasis, protein folding, and redox status in the ER leading to ER stress. Recent evidence suggests ER stress is linked to inflammation and autoimmune, and these processes are tightly interconnected and related to the pathogenesis of T1D.

ER stress and inflammation

Chronic ER stress and the three typical pathways of the UPR are demonstrated to elevate inflammation through activation of JNK-AP1 and inhibitor of NF-κB kinase signaling pathways.[28] Increased JNK and NF-κB signaling molecules induced other inflammatory mediators associated with T1D. Additionally, ER stress-mediated UPR increases proinflammatory cytokines expression, such as IL-6, IL-1β, TNFα, and IFN-γ, which further aggravates ER stress and tissue damage.[29] These inflammatory cytokines successively can induce ER stress through reactive oxygen species (ROS) and nitric oxide (NO). The accumulation of ROS was proved to aggravate ER stress in turn.[30] In addition, excessive NO leads to the loss of ER calcium and attenuation of ER chaperone function resulting in pancreatic β cells apoptosis. Notably, exposure to TNF-α can initiate ER stress, while ER stress in turn can cause the increasing of TNF-α and other inflammatory responses. On the other hand, these cytokines have been displayed to impair insulin response pathway through regulation of the suppressors of cytokine signaling proteins expression, and induction of the degradation of insulin receptor substrate.[31]

ER stress and autoimmunity

Disturbances in the ER homeostasis lead to improper post-translational modifications (PTMs) of many proteins, which may contribute to autoimmune disorders. Indeed, these proteins such as insulin, GRP78, chromogranin A, and glutamic acid decarboxylase 65 are changed into neoantigens owning to improper PTMs.[32] These neoantigens with increased immunogenicity produced from ER-stressed pancreatic β cells may induce autoimmunity leading to pathological conditions. Mannering et al[33] showed that CD4+ T cells from a T1D patient recognized an oxidized epitope of human insulin. Additionally, the T cell recognition was dependent on a disulfide bond between two adjacent cysteine residues, as cysteine mutated to serine, T cell responses against this peptide is abolished. It demonstrated that a neoantigen activates CD4+ T cells and pathology ensues. Moreover, immune responsiveness must closely intersect with pathways mediating protein synthesis, folding, assembling, and modification to ensure synthesis and normal processing of secretory proteins for meeting the needs of their function.[33] Whether ER stress can initiate autoimmunity or can be induced as a consequence of autoimmunity in T1D still remains unknown.

ER as a Therapeutic Target in T1D

As evidence accumulates, ER stress could induce the pathologic pathway leading to T1D resulting from islet β cell death. Therefore, reducing ER stress and restoring ER function is expected to be therapeutic. Intuitively there are several approaches for targeting UPR in ER stress conditions. One drug target is to mitigate ER stress directly, such as exogenous chemical chaperones including taurineconjugated ursodeoxycholic acid (TUDCA) and 4-phenylbutyric acid (PBA).[34,35] TUDCA and PBA have been considered in therapeutic strategies for diabetes and metabolic disease ( Identifier: NCT02218619, NCT00771901, NCT03462940). As the calcium homeostasis in the β cell plays a key role in cellular survival, a second approach is to maintain ER calcium concentration during ER stress. Ryanodinc receptor blocker has been shown to maintain ER calcium levels and prevent β cell apoptosis.[36] In addition, enhancing the ability of specific protective UPR to efficiently deal with ER stress is also a treatment for diabetes. For example, binding-immunoglobulin protein-inducible factor X can increase expression of GRP78, which has been shown to protects cells against ER stress-associated apoptosis.[37] Alternatively, prevention of UPR hyperactivation is another therapeutic approach. IRE1α kinase-inhibiting RNase attenuators protects β cells, increases insulin secretion, and decrease glucose level in Akita diabetic mice.[38] Besides synthetic chemicals, some naturally compounds also have been reported in alleviating ER stress such as curcumin and resveratrol.[39,40]Table 2 summarizes the recent identified small compounds in improving ER stress.

Table 2
Table 2:
Small molecules/compounds targeting various components of UPR signaling in diabetes models.

Future Perspectives

In summary, ER stress has been confirmed to be closely related to pancreatic β-cell destruction and T1D. There is currently no effective prevention of T1D, thus raising the urgency for developing novel treatments for this disorder. The challenge is how and when and why the transition from “physiological” to “pathological” UPR occurs? Can ER stress be served as a clinical biomarker to predict T1D development? How can we safely regulate ER stress and UPR signaling to prevent or treat T1D? Therefore, in the future, studies aimed at solving these questions would provide a new avenue of treatment for T1D.


This work was supported by grants from the National Natural Science Foundation of China (No. 41877390), the Nature Science Fund of Hunan Province (Nos. 2016JJ2113, 2018JJ3458, 2019JJ40241), the Science Fund of Hunan Provincial Education Department (No. 16A186), the Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study (No. 0223-0002-0002000-54), and the Graduate Education and Innovation Fund of University of South China (No. 2017JG022).

Conflicts of interest



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    Endoplasmic reticulum stress; Inflammation; Autoimmunity; Type 1 diabetes

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