title: Biobreeding rat islets exhibit reduced antioxidative defense and N-acetyl cysteine treatment delays type 1 diabetes.
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.
authors.affiliation: Pacific Northwest Diabetes Research Institute, 720 Broadway, Seattle, Washington 98122, USA.
authors.forename: Marika
authors.initials: M
authors.lastname: Bogdani
authors.forename: Angela M
authors.initials: AM
authors.lastname: Henschel
authors.forename: Sanjay
authors.initials: S
authors.lastname: Kansra
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Fuller
authors.forename: Rhonda
authors.initials: R
authors.lastname: Geoffrey
authors.forename: Shuang
authors.initials: S
authors.lastname: Jia
authors.forename: Mary L
authors.initials: ML
authors.lastname: Kaldunski
authors.forename: Scott
authors.initials: S
authors.lastname: Pavletich
authors.forename: Simon
authors.initials: S
authors.lastname: Prosser
authors.forename: Yi-Guang
authors.initials: YG
authors.lastname: Chen
authors.forename: Ake
authors.initials: A
authors.lastname: Lernmark
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Hessner
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000975:Antioxidants / Q000378:metabolism*; D045744:Cell Line, Tumor; D003545:Cysteine / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D005982:Glutathione Transferase / Q000097:blood / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D010088:Oxidoreductases / Q000378:metabolism; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D000975:Antioxidants; D010088:Oxidoreductases; C121849:superoxide reductase; D010544:Peroxidases; D054464:Peroxiredoxins; D005982:Glutathione Transferase; D003545:Cysteine