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Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic β cell death and diabetes
Kei Fujimoto, … , Gerald W. Dorn II, Kenneth S. Polonsky
Kei Fujimoto, … , Gerald W. Dorn II, Kenneth S. Polonsky
Published October 11, 2010
Citation Information: J Clin Invest. 2010;120(11):4031-4039. https://doi.org/10.1172/JCI44011.
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Research Article Metabolism

Loss of Nix in Pdx1-deficient mice prevents apoptotic and necrotic β cell death and diabetes

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Abstract

Mutations in pancreatic duodenal homeobox (PDX1) are linked to human type 2 diabetes and maturity-onset diabetes of the young type 4. Consistent with this, Pdx1-haploinsufficient mice develop diabetes. Both apoptosis and necrosis of β cells are mechanistically implicated in diabetes in these mice, but a molecular link between Pdx1 and these 2 forms of cell death has not been defined. In this study, we introduced an shRNA into mouse insulinoma MIN6 cells to deplete Pdx1 and found that expression of proapoptotic genes, including NIP3-like protein X (Nix), was increased. Forced Nix expression in MIN6 and pancreatic islet β cells induced programmed cell death by simultaneously activating apoptotic and mitochondrial permeability transition–dependent necrotic pathways. Preventing Nix upregulation during Pdx1 suppression abrogated apoptotic and necrotic β cell death in vitro. In Pdx1-haploinsufficient mice, Nix ablation normalized pancreatic islet architecture, β cell mass, and insulin secretion and eliminated reactive hyperglycemia after glucose challenge. These results establish Nix as a critical mediator of β cell apoptosis and programmed necrosis in Pdx1-deficient diabetes.

Authors

Kei Fujimoto, Eric L. Ford, Hung Tran, Burton M. Wice, Seth D. Crosby, Gerald W. Dorn II, Kenneth S. Polonsky

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Figure 1

Pdx1 deficiency induces Nix expression in MIN6 cells.

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Pdx1 deficiency induces Nix expression in MIN6 cells.
(A) Microarray ana...
(A) Microarray analysis of mRNAs in control MIN6 cells and cells in which expression of Pdx1 was knocked down (KD) by exposing the cells to a lentivirus-containing shRNA to Pdx1 (3 independent experiments). Blue, low expression; red, high expression. (B) Gene ontology pie charts illustrating upregulated (left) and downregulated (right) genes. (C) Real-time PCR of Pdx1 and Nix mRNAs in Pdx1 knockdown MIN6 cells. Data represent mean ± SEM; n = 6 per group. (D) Immunoblot of Nix expression in Pdx1 knockdown and control MIN6 cells 5 or 7 days after lentiviral infection.

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