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

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 5

Preservation of β cell mass and islet architecture in Pdx1+/–Nix–/– mice.

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Preservation of β cell mass and islet architecture in Pdx1+/–Nix–/– mice...
(A) Islet morphology in adult WT, Pdx1+/–, Pdx1+/–Nix–/–, and Nix–/– mice (9–11 weeks of age) after 6–8 weeks on a high-fat diet; α cells are stained red (anti-glucagon) and β cells are stained green (anti-insulin). Quantitation of group data for β cell area per pancreas area and β cell/α cell ratio are shown (n = 4–6 per group). (B) TUNEL labeling of adult pancreatic β cells; quantitative TUNEL data are shown at right (n = 5, each group). (C) Pancreatic islets from 1-day-old mice comparing α cells (red; anti-glucagon) and β cells (green; anti-insulin); quantitative group data are shown at right (n = 5 per group). (D) TUNEL labeling of neonatal β cells; quantitative data are shown at right (n = 5 per group). Original magnification, ×600 (including insets). Data represent mean ± SEM.