Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 107, Issue 22, Pages 10214-10219Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0914209107
Keywords
cell necrosis; apoptosis; insulin
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Funding
- National Institutes of Health [R01 HL059888, R01 DK031842]
- Radioimmunoassay and Morphology Cores of the Diabetes Research and Training Center of Washington University [GP60 DK-20579]
- Washington University Digestive Diseases Research Center Morphology Core [P30 DK052574]
- Clinical and Translational Science Award to Washington University [RR024992]
- Blum Kovler Foundation
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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.
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