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

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

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

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.

Original languageEnglish
Pages (from-to)4031-4039
Number of pages9
JournalJournal of Clinical Investigation
Volume120
Issue number11
DOIs
StatePublished - Nov 1 2010

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