Oxidative and nitrosative stress in β-cell apoptosis: their contribution to β-cell lossin type 1 diabetes mellitus

Abstract

The loss of beta-cell mass consequential to the activation of pro-apoptotic signalling events is increasingly recognised as a causal and committed stage in the development of autoimmune, type 1, diabetes mellitus (DM). While the mechanisms responsible for targeted beta-cell loss are multifaceted and difficult to define at a prediabetic stage, there is a need, from a therapeutic perspective, to understand the molecular mechanisms involved. Over recent years the use of animal and cell-line models of DM, together with investigations in isolated ex vivo human islets, have greatly increased our understanding of the processes involved in the pathogenesis of type 1 DM. From this work, several biochemical pathways have emerged that may have future potential for therapeutic intervention. This review looks at the current opinions on the role of apoptosis in beta-cell loss at the molecular level, focusing on a central mechanism for oxidative and nitrosative stress, and suggests biochemical pathways that may have future potential for therapeutic intervention.

Reactive Oxygen Species-Triggered Trophoblast Apoptosis Is Initiated by Endoplasmic Reticulum Stress via Activation of Caspase-12, CHOP, and the JNK Pathway in Toxoplasma gondii Infection in Mice

“…Oxidative stress is described as an imbalance between ROS generation and antioxidant capacity, and such stress triggers apoptosis through a variety of signaling pathways, such as ERS response and the activation of the ASK1/JNK pathway (21). These pathological processes can be simultaneously observed in some diseases, such as diabetes, cadmium poisoning, and neurodegenerative diseases (24,30,45). Additionally, there is growing evidence that oxidative stress plays an important role in infection-induced apoptosis (11,31,41).…”

Proproliferative and antiapoptotic action of exogenously introduced YAP in pancreatic β cells

“…It has emerged as a key element linking redox regulation to the pathogenesis of several diseases (64). Oxidative stress has been recognized as one of the common underlying mechanisms of β cell failure in the pathogenesis of both types of diabetes (40)(41)(42). In vivo β cell-specific overexpression of Trx1 protects mice from development of diabetes in both T1D and T2D rodent models, demonstrating the efficacy of Trx1 to halt the progressive β cell demise (65,66).…”

“…Since oxidative stress is an underlying mechanism of β cell destruction in diabetes (40)(41)(42) and ROS-associated signaling is regulated by YAP in other cell types (43,44), we tested whether YAP overexpression would change expression of ROS-related genes. To identify YAP-regulated genes involved in the antioxidant system, we analyzed a panel of 25 ROS-related genes in the constitutively active YAP mutant-expressing or GFP-control-expressing INS-1E cells (data not shown).…”

Roles of Hydrogen Sulfide in the Pathogenesis of Diabetes Mellitus and Its Complications

“…Expression of the MHC proteins induces an insulitis, whereby the islet is islet infiltrated by mononuclear cells, including lymphocytes, macrophages, and plasma cells. The actual trigger for the process of b-cell destruction is still unknown, but it has been proposed that it is an external factor (viral, chemical) or an internal stimulus (cytokines, free radical) which damages a proportion of the b-cells, leading to release of specific b-cell proteins, which can be taken up by antigen presenting cells and processed to antigenic peptides (37,38,70).…”