期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2010
卷号：107
期号：22
页码：10214-10219
DOI：10.1073/pnas.0914209107
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Mutations of the pancreatic duodenal homeobox gene-1, Pdx1, cause heritable diabetes in humans and mice. A central abnormality with Pdx1 deficiency is increased death of {beta}-cells, leading to decreased {beta}-cell mass. We show that lentiviral suppression of Pdx1 increases death of mouse insulinoma MIN6 {beta}-cells associated with dissipation of the mitochondrial inner membrane electrochemical gradient, {Delta}{psi}m. Preventing mitochondrial permeability transition pore opening with the cyclophilin D inhibitor cyclosporin A restored {Delta}{psi}m and rescued cell viability. Reduced {beta}-cell mass, markers of {beta}-cell apoptosis, necrosis, and decreased proliferation are present in Pdx1 haploinsufficient mice. Genetic ablation of the Ppif gene, encoding cyclophilin D, restored {beta}-cell mass and decreased TUNEL and complement complex labeling without affecting {beta}-cell proliferation. In adult mice maintained on a high-fat diet, Ppif ablation normalized fasting glucose and glucose and insulin responses to acute glucose challenge. Thus, cyclophilin D and the mitochondrial permeability transition are critical regulators of {beta}-cell death caused by Pdx1 insufficiency.
