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

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Chop deletion reduces oxidative stress, improves β cell function, and promotes cell survival in multiple mouse models of diabetes
Published in Volume 118, Issue 10 (October 1, 2008)
J. Clin. Invest. 118(10): 3378-3389 (2008). doi:10.1172/JCI34587.

Benbo Song1, Donalyn Scheuner2, David Ron3, Subramaniam Pennathur4 and Randal J. Kaufman1,2,4

1Howard Hughes Medical Institute and
2Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan, USA.
3Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.
4Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA.

Address correspondence to: Randal Kaufman, University of Michigan Medical Center, Departments of Biological Chemistry and Internal Medicine, H.H.M.I., 4570 MSRB II, 1150 W. Medical Center Dr., Ann Arbor, Michigan 48109-0650, USA. Phone: (734) 763-9037; Fax: (734) 763-9323; E-mail: kaufmanr@umich.edu.

First published September 5, 2008
Received for publication November 27, 2007, and accepted in revised form July 30, 2008.

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.


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Copyright © 2008, The American Society for Clinical Investigation