Targeting cyclophilin D and the mitochondrial permeability transition enhances β-cell survival and prevents diabetes in Pdx1 deficiency

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 β-cells, leading to decreased β-cell mass. We show that lentiviral suppression increases mouse insulinoma MIN6 β-cells associated dissipation mitochondrial inner membrane electrochemical gradient, Δψm. Preventing permeability transition pore opening cyclophilin D inhibitor cyclosporin restored Δψm rescued cell viability. Reduced mass, markers apoptosis, necrosis, proliferation are present haploinsufficient Genetic ablation Ppif gene, encoding D, mass TUNEL complement complex labeling without affecting proliferation. In adult mice maintained on a high-fat diet, normalized fasting glucose insulin responses acute challenge. Thus, critical regulators caused by insufficiency.