Faculty Collaboration Database

Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes. J Endocrinol 2013 Feb;216(2):111-23

Date

11/01/2012

Pubmed ID

23111281

Pubmed Central ID

PMC4077722

DOI

10.1530/JOE-12-0385

Scopus ID

2-s2.0-84874778734 (requires institutional sign-in at Scopus site)   23 Citations

Abstract

Islet-level oxidative stress has been proposed as a trigger for type 1 diabetes (T1D), and release of cytokines by infiltrating immune cells further elevates reactive oxygen species (ROS), exacerbating β cell duress. To identify genes/mechanisms involved with diabetogenesis at the β cell level, gene expression profiling and targeted follow-up studies were used to investigate islet activity in the biobreeding (BB) rat. Forty-day-old spontaneously diabetic lymphopenic BB DRlyp/lyp rats (before T cell insulitis) as well as nondiabetic BB DR+/+ rats, nondiabetic but lymphopenic F344lyp/lyp rats, and healthy Fischer (F344) rats were examined. Gene expression profiles of BB rat islets were highly distinct from F344 islets and under-expressed numerous genes involved in ROS metabolism, including glutathione S-transferase (GST) family members (Gstm2, Gstm4, Gstm7, Gstt1, Gstp1, and Gstk1), superoxide dismutases (Sod2 and Sod3), peroxidases, and peroxiredoxins. This pattern of under-expression was not observed in brain, liver, or muscle. Compared with F344 rats, BB rat pancreata exhibited lower GST protein levels, while plasma GST activity was found significantly lower in BB rats. Systemic administration of the antioxidant N-acetyl cysteine to DRlyp/lyp rats altered abundances of peripheral eosinophils, reduced severity of insulitis, and significantly delayed but did not prevent diabetes onset. We find evidence of β cell dysfunction in BB rats independent of T1D progression, which includes lower expression of genes related to antioxidative defense mechanisms during the pre-onset period that may contribute to overall T1D susceptibility.

Author List

Bogdani M, Henschel AM, Kansra S, Fuller JM, Geoffrey R, Jia S, Kaldunski ML, Pavletich S, Prosser S, Chen YG, Lernmark A, Hessner MJ

Authors

Yi-Guang Chen PhD Professor in the Pediatrics department at Medical College of Wisconsin
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Animals, Genetically Modified
Antioxidants
Cell Line, Tumor
Cysteine
Diabetes Mellitus, Type 1
Flow Cytometry
Gene Expression Profiling
Glutathione Transferase
Insulin-Secreting Cells
Islets of Langerhans
Oxidoreductases
Peroxidases
Peroxiredoxins
Rats
Rats, Inbred F344
Reverse Transcriptase Polymerase Chain Reaction