Death effectors of β-cell apoptosis in type 1 diabetes

Abstract

While it is generally agreed that apoptosis of pancreatic β-cells is the most important and final step in the progression of type 1 diabetes without which clinical diabetes does not develop, it has not been elucidated which molecule(s) are the real culprit(s) in type 1 diabetes. Perforin, FasL, TNFα, IL-1, IFNγ, and NO have been claimed as the effector molecules; however, they, as a single agent, might explain only part of β-cell death in type 1 diabetes. While FasL was initially considered as a strong candidate for the most important death effector, following experiments cast doubt on such a hypothesis. Combinations or synergism between IFNγ and TNFα or IL-1β are being revisited as the death effectors, and molecular mechanism explaining such a synergism was addressed in several recent papers. The role of NF-κB for pancreatic β-cell death in type 1 diabetes is also controversial. While NF-κB plays anti-apoptotic roles in most other death models, its role in type 1 diabetes might be different probably due to the involvement of multiple cytokines at different stages of the disease progression and the peculiarity of pancreatic β-cells. Recent papers also suggested a role for Ca 2+ in cytokine-mediated pancreatic β-cell death. Such participation of Ca 2+ in β-cell death appears to have a close relevance to the mitochondrial events or ER stress that constitutes an important part of cell death machinery recently identified.