ER stress, cytokines, and beta-cell death

Insulin dependent diabetes mellitus (IDDM) is an autoimmune disease characterized by the selective destruction of insulin secreting beta-cells found in the pancreatic islets of Langerhans. The ability of beta-cells to secrete insulin in a response to a glucose challenge is essential to maintain whole body glucose homeostasis. Because of the loss of beta-cell mass in IDDM, patients must rely on exogenous insulin for survival. Diabetes development is preceded by insulitis and infiltration of T cells, B cells, and macrophages into the islets. Cytokines, such as interleukin-1 and interferon-gamma, released from these immune cells are believed to participate in beta-cell dysfunction and destruction by a mechanism dependent upon beta-cell expression of the inducible isoform of nitric oxide synthase (iNOS) and the subsequent production of nitric oxide. Nitric oxide impairs glucose oxidation to carbon dioxide by inhibiting iron sulfur center containing enzymes such as the Krebs cycle enzyme aconitase and electron transport chain complexes I and II, resulting in the reduction of intracellular ATP levels by 4-fold. Glucose stimulated insulin secretion requires the accumulation of ATP to close the ATP-sensitive potassium channels resulting in beta-cell depolarization, calcium entry, and calcium-dependent exocytosis. The reduction in mitochondrial function by nitric oxide is one mechanism by which cytokines induce beta-cell dysfunction.;The purpose of these studies was to determine the role of endoplasmic reticulum (ER) stress and cytokines in beta-cell death. Our results suggest that Peroxisome Proliferator-Activated Receptor (PPAR)-gamma ligands induce beta-cell apoptosis by a mechanism that correlates with prolonged activation of the Unfolded Protein Response (UPR). In addition, we have determined that cytokines induce UPR activation; however the UPR does not mediate cytokine-induced beta-cell death, as disruption of UPR signaling cascades fails to change the amount of cell death that is observed in response to cytokines. Finally, we provide evidence to suggest that short exposures of beta-cells to cytokines (when nitric oxide production is high) induces death by a necrotic pathway; however as the rate of nitric oxide production decreases, the mechanism of cytokine-induced beta-cell death switches to apoptosis, as evidenced by caspase-3 cleavage and activation.