Article

Endoplasmic reticulum stress-induced apoptosis and autoimmunity in diabetes

Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, 01605-2324, USA.
Current Molecular Medicine (Impact Factor: 3.61). 03/2006; 6(1):71-7. DOI: 10.2174/156652406775574613
Source: PubMed

ABSTRACT Increasing evidence suggests that stress signaling pathways emanating from the endoplasmic reticulum (ER) are important to the pathogenesis of both type 1 and type 2 diabetes. Recent observations indicate that ER stress signaling participates in maintaining the ER homeostasis of pancreatic beta-cells. Either a high level of ER stress or defective ER stress signaling in beta-cells may cause an imbalance in ER homeostasis and lead to beta-cell apoptosis and autoimmune response. In addition, it has been suggested that ER stress attributes to insulin resistance in patients with type 2 diabetes. It is necessary to study the relationship between ER stress and diabetes in order to develop new therapeutic approaches to diabetes based on drugs that block the ER stress-mediated cell-death pathway and insulin resistance.

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    • "The UPR has been implicated in a number of autoimmune disorders associated with vitiligo such as type I diabetes (Lipson et al., 2006). Similar to our proposed model for vitiligo, in diabetes, it has been suggested that exposure to environmental agents such as toxins may be involved in initiation of excessive ER stress in pancreatic β-cells, triggering an apoptotic cascade by the UPR that leads to autoimmunity (Fonseca et al., 2009; Lipson et al., 2006). "
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    • "Regulated cell death is a crucial event for development and cell physiology, and alteration of this process could result in the occurrence of severe human diseases such as inflammation, cancer, neoplasia, neurodegeneration or autoimmune disorders [1] [2] [3] [4] [5]. Subcellular organelle stress is observed in many pathological processes, where complex signaling responses mediate the adaptation to stress or trigger apoptosis when a critical threshold of damage is reached [6]. "
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    • "For example, gene-expression profiling has demonstrated that the UPR regulates genes involved in protein entry into the ER, folding, glycosylation, ERAD, protein quality control, redox metabolism, autophagy, lipid biogenesis, and vesicular trafficking (Figure 1A). Increasing attention has been given to the regulation of the UPR based on substantial evidence for the involvement of chronic ER stress in many diseases, including neurodegenerative conditions (Matus et al., 2008), cancer (Moenner et al., 2007), diabetes (Lipson et al., 2006), and inflammation (Todd et al., 2008), hence offering new therapeutic targets to treat these diseases. "
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