**6. Conclusions and future directions**

in the β cells also induce ER stress which in turn exacerbates β cell dysfunction and pro‐ motes disease progression. Collectively, there is convincing evidence that ER stress plays an

The primary purpose of ER stress response is to compensate the damage caused by the dis‐ turbances of normal ER function. However, persistence of ER dysfunction would eventually render cells undergoing apoptosis. The mechanisms underlying ER stress induced cell death are not fully elucidated, due to the fact that multiple potential participants involved but lit‐ tle clarity on the dominant death effectors in a particular cellular context. Generally, the process of cell death by ER stress can be illustrated in three phases: adaptation, alarm, and

The adaptation response phase is to protect cells from damage induced by the disturban‐ ces of ER function and restore the homeostasis of ER. As described earlier, UPR signaling involves three axes of responses: IRE1, PERK, and ATF6. These axes interact between each other and form a feedback regulatory mechanism to control the activity of UPR. The accumulation of unfolded proteins in ER results in the engagement of ER resident chaper‐ on BiP, and as a consequence, IRE1, PERK, and ATF6 are released from BiP. Therefore, over-expression of BiP can prevent cell death induced by oxidative stress, Ca2+ disturban‐ ces, and hypoxia (107). Upon ER stress, the transcription of BiP is enhanced by ATF6p50, the cleaved form of ATF6 (108). PERK is oligomerized and phosphorylated upon the re‐ lease from BiP. Activated PERK inactivates eIF2α to reduce mRNA translation and pro‐ tein load on ER. Therefore, PERK deficiency results in an abnormally elevated protein synthesis in response to ER stress, and renders cells highly sensitive to ER stress-induced apoptosis (109). Consistently, as a downstream molecule of PERK, eIF2α is required for cell survival upon the insult of ER stress. A mutation at the phosphorylation site of eIF2α (Ser51Ala) abolishes the translational suppression in response to ER stress (41). When re‐ leased from BiP, IRE1 becomes dimerized and activated. Activated IRE1 then induces XBP-1 by promoting the splicing of its mRNA (44). XBP-1 is responsible for the transcrip‐ tion of many adaptation genes implicated in UPR. Unlike PERK and IRE1, ATF6 translo‐ cates into the Golgi apparatus once released from BiP. The transmembrane domain of ATF6 is cleaved in the Golgi apparatus and is then relocated into the nucleus, by which it

During the alarm phase, many signal pathways are activated to alert the system. For in‐ stance, the cytoplasmic part of IRE1 can bind to TNF receptor-associated factor 2 (TRAF2), a key adaptor mediating TNF-induced innate immune response. TRAF2 then activates NFκB pathway via activating IKK and activates the signaling for c-Jun N-terminal kinas‐ es (JNK) by apoptosis signal-regulating kinase 1 (Ask1). It is reported that dominant neg‐ ative TRAF2 suppresses the activation of JNK in response to ER stress (110). In addition, TRAF2 is also a critical component for E3 ubiquitin-protein ligase complex (111). E3 ubiq‐ uitin-protein ligase complex binds to Ubc13 and mediates the noncanonical ubiquitina‐ tion of substrates, which is suggested to be required for the activation of JNK (112).

essential role in β cell destruction during the course of type 1 diabetes.

**5.2. Mechanisms underlying ER stress-induced β cell death**

apoptosis (39).

208 Type 1 Diabetes

regulates gene expression (51).

Although exogenous insulin therapy partly compensates the function of β cells, it cannot regulate blood glucose as accurately as the action of endogenous insulin. As a result, long-term improperly control of blood glucose homeostasis predisposes patients with type 1 diabetes to the development of diverse complications such as diabetic retinopathy (125-127), nephropathy (128;129), neuropathy (130-132), foot ulcers (133-135), and cardio‐ vascular diseases (136-138). Due to the long-term health consequences of diabetes, impact of insulin dependence on life quality, and increasing appearance in both young and old populations, understanding the pathophysiology of diabetes and finding a better way to treat diabetes has become a high priority. Although the underlying mechanisms leading to type 1 diabetes have yet to be fully addressed, accumulating evidence suggests that ER stress plays a critical role in autoimmune-mediated β cell destruction during the course of type 1 diabetes. ER stress in β cells can be triggered by either autoimmune responses against β-cell self-antigens or the increase of compensated insulin synthesis. During the course of type 1 diabetes, autoreactive immune cells secrete copious amount of inflamma‐ tory cytokines, leading to excessive production of nitric oxygenand β cell destruction in an ER stress-dependent pathway. ER stress also regulates the functionality of immune cells with implications in autoimmune progression. The inadequate insulin secretion in patients with type 1 diabetes renders the residual β cells for compensated insulin secre‐ tion to maintain blood glucose homeostasis. This increase in insulin biosynthesis could overwhelm the folding capacity of ER, and exacerbate β cell dysfunction by inducing ER stress in β cells.

**Author details**

Guangdong, China

Columbus, Ohio, USA

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Address all correspondence to: zhongjixin620@163.com

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1 Department of Medicine, Affiliated Hospital of Guangdong Medical College, Zhanjiang,

Endoplasmic Reticulum (ER) Stress in the Pathogenesis of Type 1 Diabetes

http://dx.doi.org/10.5772/52644

211

2 Davis Heart & Lung Research Institute, The Ohio State University College of Medicine,

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Jixin Zhong1,2

Although ER stress is a critical factor involved in the pathogenesis of type 1 diabetes, it should be kept in mind that the mechanisms underlying autoimmune-mediated β cell de‐ struction in type 1 diabetes are complex, and ER stress is unlikely the exclusive mechanism implicated in disease process. Despite recent significant progress in this area, there are still many questions yet to be addressed. Are there additional factors inducing ER stress in β cells during type 1 diabetes development? Can ER stress be served as a biomarker for β cell destruction and autoimmune progression in the clinic setting? Does blockade of ER stress in immune cells attenuate autoimmune progression and protect β cells? Future studies aimed to dissect these questions would provide a deep insight for type 1 diabetes pathogenesis and would have great potential for developing novel therapeutic strategies against this devastat‐ ing disorder.
