Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes
Benbo Song, … , Subramaniam Pennathur, Randal J. Kaufman
Benbo Song, … , Subramaniam Pennathur, Randal J. Kaufman
Published September 5, 2008
Citation Information: J Clin Invest. 2008;118(10):3378-3389. https://doi.org/10.1172/JCI34587.
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Research Article Metabolism

Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes

Abstract

The progression from insulin resistance to type 2 diabetes is caused by the failure of pancreatic β cells to produce sufficient levels of insulin to meet the metabolic demand. Recent studies indicate that nutrient fluctuations and insulin resistance increase proinsulin synthesis in β cells beyond the capacity for folding of nascent polypeptides within the endoplasmic reticulum (ER) lumen, thereby disrupting ER homeostasis and triggering the unfolded protein response (UPR). Chronic ER stress promotes apoptosis, at least in part through the UPR-induced transcription factor C/EBP homologous protein (CHOP). We assessed the effect of Chop deletion in multiple mouse models of type 2 diabetes and found that Chop–/– mice had improved glycemic control and expanded β cell mass in all conditions analyzed. In both genetic and diet-induced models of insulin resistance, CHOP deficiency improved β cell ultrastructure and promoted cell survival. In addition, we found that isolated islets from Chop–/– mice displayed increased expression of UPR and oxidative stress response genes and reduced levels of oxidative damage. These findings suggest that CHOP is a fundamental factor that links protein misfolding in the ER to oxidative stress and apoptosis in β cells under conditions of increased insulin demand.

Authors

Benbo Song, Donalyn Scheuner, David Ron, Subramaniam Pennathur, Randal J. Kaufman

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Figure 1

Chop-null mutation increases β cell mass, improves β cell function, and prevents glucose intolerance in HF diet–fed eIF2αS/A mice.

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Chop-null mutation increases β cell mass, improves β cell function, and...
Mice of the indicated genotypes were fed a 45% HF diet for 35–41 weeks. (A and B) Body mass and glucose tolerance tests; n = 8–10 mice per condition. Significant differences between eIF2αS/AChop+/+ and eIF2αS/AChop–/– are indicated. (C) Islet morphology shown by H&E and immunofluorescence staining. Scale bars: 400 μm (top), 50 μm (bottom). (D and E) β cell ultrastructure from TEM and insulin granule content quantified by analysis of similar total areas from TEM images from 2 mice per condition. ER, rough ER; M: mitochondria. Scale bar: 1 μm. (F) Analysis of serum insulin levels; n = 8–10 mice per condition. (G) Analysis of GSIS. Islets from 2 animals per condition were analyzed in duplicate. H, high glucose (16.7 mM); L, low glucose (3.3 mM). *P < 0.05, **P < 0.01, ***P < 0.001.