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IL-1 plus IFN-Оі), the length of cytokine exposure (24вЂ“48 h vs. Factors contributing to ОІ-cell death include the type of cytokines present (IL-1 alone vs. There have been many reports suggesting that cytokines stimulate ОІ-cell apoptosis ( 16, 17) and that NO may or may not participate in this process. It is this reduction in ATP that is responsible for the inhibitory actions of cytokines on insulin secretion, as glucose-induced insulin secretion requires the ATP-dependent inhibition of K + channel activity, allowing for depolarization and Ca 2+-dependent exocytosis ( 14, 15).ДЄlthough it has been well established that NO is the primary mediator of the inhibitory actions of cytokines on ОІ-cell function, the mechanisms responsible for the loss of ОІ-cell viability in response to cytokines have not been fully identified. NO exerts its inhibitory effects on ОІ-cell function by targeting iron-sulfurвЂ“containing enzymes, such as aconitase of the Krebs cycle and the electron transport chain, resulting in the inhibition of glucose oxidation to CO 2 ( 12) and reductions in cellular levels of ATP ( 9, 13). In response to IL-1 or combinations of IL-1 and IFN-Оі, the insulin-secreting ОІ-cell is the primary islet source of iNOS and NO ( 8, 11). Interleukin (IL)-1 alone is sufficient to stimulate iNOS expression in rat islets, while IL-1 plus interferon (IFN)-Оі are the minimal combination of cytokines required to stimulate iNOS expression and NO production in mouse and human islets ( 2, 9, 10). The mechanism by which cytokines impair ОІ-cell function includes the expression of the inducible isoform of nitric oxide (NO) synthase (iNOS), resulting in the production of high levels of NO ( 4вЂ“ 8). Cytokines, released during insulitis, have been shown to inhibit ОІ-cell function and to induce islet destruction ( 2, 3). Type 1 diabetes is an autoimmune disease characterized by an inflammatory reaction in and around pancreatic islets of Langerhans that results in the selective destruction of insulin-secreting ОІ-cells ( 1). In contrast, neither the absence of PERK nor the expression of the S51A eIF2О± mutant affects the levels of cytokine-induced death.Д¬ONCLUSIONS-While cytokine-induced ОІ-cell death temporally correlates with UPR activation, the lack of caspase activity and the ability of NO to attenuate caspase activity suggest that prolonged UPR activation does not mediate cytokine-induced ОІ-cell death.

In addition, cell death is enhanced by в€ј35% in tunicamycin-treated cells expressing an S51A eIF2О± mutant that cannot be phosphorylated or in cells lacking PERK (protein kinase regulated by RNA/endoplasmic reticulumвЂ“like kinase).

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Cell death in response to the classical UPR activator is associated with a 2.5-fold increase in caspase-3 activity, while IL-1 fails to stimulate caspase-3 activity.

Importantly, cytokines and tunicamycin, a classical UPR activator, induce ОІ-cell death by different mechanisms. NO mediates both cytokine-induced UPR activation and ОІ-cell death as NO synthase inhibitors attenuate each of these IL-1вЂ“stimulated events. RESULTS-UPR activation correlates with ОІ-cell death in interleukin (IL)-1вЂ“treated rat islets. RESEARCH DESIGN AND METHODS-The effects of cytokine treatment of rat and human islets and RINm5F cells on UPR activation, NO production, and cell viability were examined using molecular and biochemical methodologies. In this study, the role of UPR activation in cytokine-induced ОІ-cell death was examined. The UPR, activated by cytokine-induced nitric oxide (NO) production, has been proposed to mediate ОІ-cell death in response to cytokines. OBJECTIVE-The unfolded protein response (UPR) is a conserved cellular response designed to alleviate damage and promote survival of cells experiencing stress however, prolonged UPR activation can result in apoptotic cell death. Institutional Subscriptions and Site Licenses.Special Edition Series: Disrupting Therapeutic Inertia in Diabetes Management.Special Edition: SGLT2 Inhibitors and Diabetic Kidney Disease.Special Edition Series: SGLT2 Inhibitors in Type 2 Diabetes: Cardiovascular and Renal Outcomes.Special Edition Series: Diabetes and Influenza.Special Edition: Painful Diabetic Peripheral Neuropathy.Special Edition Series: COVID-19 and Diabetes.

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