Death effectors of beta-cell apoptosis in type 1 diabetes.

While it is generally agreed that apoptosis of pancreatic beta-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, TNFalpha, IL-1, IFNgamma, and NO have been claimed as the effector molecules; however, they, as a single agent, might explain only part of beta-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 IFNgamma and TNFalpha or IL-1beta are being revisited as the death effectors, and molecular mechanism explaining such a synergism was addressed in several recent papers. The role of NF-kappaB for pancreatic beta-cell death in type 1 diabetes is also controversial. While NF-kappaB 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 beta-cells. Recent papers also suggested a role for Ca2+ in cytokine-mediated pancreatic beta-cell death. Such participation of Ca2+ in beta-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.