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

10.5772/52644 ◽  
2013 ◽  
Author(s):  
Jixin Zhong
Keyword(s):  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Er Stress

scholarly journals Mild Endoplasmic Reticulum Stress Augments the Proinflammatory Effect of IL-1β in Pancreatic Rat β-Cells via the IRE1α/XBP1s Pathway

Endocrinology ◽  
2012 ◽  
Vol 153 (7) ◽  
pp. 3017-3028 ◽  
Author(s):  
Michela Miani ◽  
Maikel L. Colli ◽  
Laurence Ladrière ◽  
Miriam Cnop ◽  
Decio L. Eizirik
Keyword(s):  
Fatty Acids ◽  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Inflammatory Response ◽  
Er Stress ◽  
Low Dose ◽  
Β Cells ◽  
Β Cell ◽  
Tnf Α

The prevalence of obesity and type 1 diabetes in children is increasing worldwide. Insulin resistance and augmented circulating free fatty acids associated with obesity may cause pancreatic β-cell endoplasmic reticulum (ER) stress. We tested the hypothesis that mild ER stress predisposes β-cells to an exacerbated inflammatory response when exposed to IL-1β or TNF-α, cytokines that contribute to the pathogenesis of type 1 diabetes. INS-1E cells or primary rat β-cells were exposed to a low dose of the ER stressor cyclopiazonic acid (CPA) or free fatty acids, followed by low-dose IL-1β or TNF-α. ER stress signaling was inhibited by small interfering RNA. Cells were evaluated for proinflammatory gene expression by RT-PCR and ELISA, gene reporter activity, p65 activation by immunofluorescence, and apoptosis. CPA pretreatment enhanced IL-1β- induced, but not TNF-α-induced, expression of chemokine (C-C motif) ligand 2, chemokine (C-X-C motif) ligand 1, inducible nitric oxide synthase, and Fas via augmented nuclear factor κB (NF-κB) activation. X-box binding protein 1 (XBP1) and inositol-requiring enzyme 1, but not CCAAT/enhancer binding protein homologous protein, knockdown prevented the CPA-induced exacerbation of NF-κB-dependent genes and decreased IL-1β-induced NF-κB promoter activity. XBP1 modulated NF-κB activity via forkhead box O1 inhibition. In conclusion, rat β-cells facing mild ER stress are sensitized to IL-1β, generating a more intense and protracted inflammatory response through inositol-requiring enzyme 1/XBP1 activation. These observations link β-cell ER stress to the triggering of exacerbated local inflammation.

scholarly journals The Role of Endoplasmic Reticulum Stress in Autoimmune-Mediated Beta-Cell Destruction in Type 1 Diabetes

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Jixin Zhong ◽  
Xiaoquan Rao ◽  
Jun-Fa Xu ◽  
Ping Yang ◽  
Cong-Yi Wang
Keyword(s):  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Er Stress ◽  
Autoimmune Response ◽  
Potential Implication ◽  
Beta Cell Destruction ◽  
Cell Destruction

Unlike type 2 diabetes which is caused by the loss of insulin sensitivity, type 1 diabetes (T1D) is manifested by the absolute deficiency of insulin secretion due to the loss ofβmass by autoimmune response againstβ-cell self-antigens. Although significant advancement has been made in understanding the pathoetiology for type 1 diabetes, the exact mechanisms underlying autoimmune-mediatedβ-cell destruction, however, are yet to be fully addressed. Accumulated evidence demonstrates that endoplasmic reticulum (ER) stress plays an essential role in autoimmune-mediatedβ-cell destruction. There is also evidence supporting that ER stress regulates the functionality of immune cells relevant to autoimmune progression during T1D development. In this paper, we intend to address the role of ER stress in autoimmune-mediatedβ-cell destruction during the course of type 1 diabetes. The potential implication of ER stress in modulating autoimmune response will be also discussed. We will further dissect the possible pathways implicated in the induction of ER stress and summarize the potential mechanisms underlying ER stress for mediation ofβ-cell destruction. A better understanding of the role for ER stress in T1D pathoetiology would have great potential aimed at developing effective therapeutic approaches for the prevention/intervention of this devastating disorder.

scholarly journals The Endoplasmic Reticulum and Calcium Homeostasis in Pancreatic Beta Cells

Endocrinology ◽  
2019 ◽  
Vol 161 (2) ◽  
Author(s):  
Irina X Zhang ◽  
Malini Raghavan ◽  
Leslie S Satin
Keyword(s):  
Type 2 Diabetes ◽  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Beta Cell ◽  
Er Stress ◽  
Beta Cells ◽  
Unfolded Protein ◽  
Protein Response

Abstract The endoplasmic reticulum (ER) mediates the first steps of protein assembly within the secretory pathway and is the site where protein folding and quality control are initiated. The storage and release of Ca2+ are critical physiological functions of the ER. Disrupted ER homeostasis activates the unfolded protein response (UPR), a pathway which attempts to restore cellular equilibrium in the face of ER stress. Unremitting ER stress, and insufficient compensation for it results in beta-cell apoptosis, a process that has been linked to both type 1 diabetes (T1D) and type 2 diabetes (T2D). Both types are characterized by progressive beta-cell failure and a loss of beta-cell mass, although the underlying causes are different. The reduction of mass occurs secondary to apoptosis in the case of T2D, while beta cells undergo autoimmune destruction in T1D. In this review, we examine recent findings that link the UPR pathway and ER Ca2+ to beta cell dysfunction. We also discuss how UPR activation in beta cells favors cell survival versus apoptosis and death, and how ER protein chaperones are involved in regulating ER Ca2+ levels. Abbreviations: BiP, Binding immunoglobulin Protein ER; endoplasmic reticulum; ERAD, ER-associated protein degradation; IFN, interferon; IL, interleukin; JNK, c-Jun N-terminal kinase; KHE, proton-K+ exchanger; MODY, maturity-onset diabetes of young; PERK, PRKR-like ER kinase; SERCA, Sarco/Endoplasmic Reticulum Ca2+-ATPases; T1D, type 1 diabetes; T2D, type 2 diabetes; TNF, tumor necrosis factor; UPR, unfolded protein response; WRS, Wolcott–Rallison syndrome.

scholarly journals ER stress and development of type 1 diabetes

2016 ◽  
Vol 64 (1) ◽  
pp. 2-6 ◽  
Author(s):  
Feyza Engin
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Molecular Mechanisms ◽  
Adaptive Responses ◽  
Β Cell ◽  
Cellular Homeostasis ◽  
Unfolded Protein

Type 1 diabetes (T1D) results from an autoimmune-mediated destruction of pancreatic β cells. The incidence of T1D is on the rise globally around 3% to 5% per year and rapidly increasing incidence in younger children is of the greatest concern. currently, there is no way to cure or prevent T1D; hence, a deeper understanding of the underlying molecular mechanisms of this disease is essential to the development of new effective therapies. The endoplasmic reticulum (ER) is an organelle with multiple functions that are essential for cellular homeostasis. Excessive demand on the ER, chronic inflammation, and environmental factors lead to ER stress and to re-establish cellular homeostasis, the adaptive unfolded protein response (UPR) is triggered. However, chronic ER stress leads to a switch from a prosurvival to a proapoptotic UPR, resulting in cell death. Accumulating data have implicated ER stress and defective UPR in the pathogenesis of inflammatory and autoimmune diseases, and ER stress has been implicated in β-cell failure in type 2 diabetes. However, the role of ER stress and the UPR in β-cell pathophysiology and in the initiation and propagation of the autoimmune responses in T1D remains undefined. This review will highlight the current understanding and recent in vivo data on the role of ER stress and adaptive responses in T1D pathogenesis and the potential therapeutic aspect of enhancing β-cell ER function and restoring UPR defects as novel clinical strategies against this disease.

scholarly journals Deletion of the RNLS Gene using CRISPR/Cas9 as Pancreatic Cell β Protection against Autoimmune and ER Stress for Type 1 Diabetes Mellitus

2021 ◽  
Vol 9 (F) ◽  
pp. 613-619
Author(s):  
Aufa Baraja ◽  
Fadhilla Rachmawati Sunarto ◽  
Arga Setyo Adji ◽  
Fitri Handajani ◽  
Firman Suryadi Rahman
Keyword(s):  
Diabetes Mellitus ◽  
Type 1 Diabetes ◽  
B Cells ◽  
Er Stress ◽  
Type 1 Diabetes Mellitus ◽  
Genome Editing ◽  
Immune Recognition ◽  
Pancreatic Cell ◽  
The Unfolded Protein Response

BACKGROUND: Type 1 diabetes mellitus (T1DM) is a chronic disease in children which is usually caused by autoimmunity that damages pancreatic a and b cells which have functions as blood glucose regulators. Some studies stated that Renalase (RNLS) gene deletion will protect these b cells from autoimmune reactions and Endoplasmic Reticulum (ER) stress. RNLS deletion by genome editing Clustered Regular interspersed Short Palindromic Repeats-CRISPR-related (CRISPR/Cas9) is believed to have the potential to be a therapy for T1DM Patients. AIM: This research was conducted to know the potential of RNLS deletion using the CRISPR/Cas9 as an effective therapy and whether it has a permanent effect on T1DM patients. METHODS: The method applied in this research summarized articles by analyzing the titles and abstracts of various predetermined keywords. In this case, the author chose a full-text article published within the past 10 years by prioritizing searches in the last 5 years through PubMed, Google Scholar, Science Direct, Cochrane, American Diabetes Association, and official guidelines from IDAI. RESULTS: RNLS deletion using CRISPR/Cas9 in mice weakened the response of polyclonal -cell-reactive CD8+ T cells and disrupted the immune recognition to cells so that autoimmune killing did occur. In addition, such deletion prevents RNLS ER stress by increasing the threshold, triggering the unfolded protein response so that ER stress is difficult to occur. RNLS mutations in b cells also increase b cell survivability to oxidative stress. CONCLUSION: b cells RNLS deletion by genome editing CRISPR/Cas9 is effective in protecting b cells from autoimmune reactions and RE stress. However, further research is needed to determine the side effects and safety of its use.

scholarly journals Pathological 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

Diabetologia ◽  
2013 ◽  
Vol 56 (12) ◽  
pp. 2638-2646 ◽  
Author(s):  
Chaoxing Yang ◽  
Philip diIorio ◽  
Agata Jurczyk ◽  
Bryan O’Sullivan-Murphy ◽  
Fumihiko Urano ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Type 1 Diabetes ◽  
Endoplasmic Reticulum Stress ◽  
Beta Cell ◽  
Rat Model ◽  
Cell Apoptosis ◽  
Beta Cell Apoptosis

scholarly journals ER Stress as a Trigger for  -Cell Dysfunction and Autoimmunity in Type 1 Diabetes

Diabetes ◽  
2012 ◽  
Vol 61 (4) ◽  
pp. 780-781 ◽  
Author(s):  
B. O'Sullivan-Murphy ◽  
F. Urano
Keyword(s):  
Type 1 Diabetes ◽  
Er Stress ◽  
Cell Dysfunction
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