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.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Irwon-dong Kangnam-ku, Seoul 135-710, Republic of Korea. mslee@smc.samsung.co.kr
Myung-Shik
MS
Lee
Inik
I
Chang
Sunshin
S
Kim
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000473:pathology*; D053222:Fas Ligand Protein; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D007375:Interleukin-1; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D052899:Pore Forming Cytotoxic Proteins; D014409:Tumor Necrosis Factor-alpha; D054353:Perforin; D009569:Nitric Oxide; D007371:Interferon-gamma; D002118:Calcium