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 diabeto-genesis 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.

Long-term intake of a high-protein diet increases liver triacylglycerol deposition pathways and hepatic signs of injury in rats

“…Moreover, the production of free radicals associated with these metabolic pathways could be responsible for the increased expression levels of Gstm7, Nqo1, and Gstm4. These genes code for enzymes involved in the detoxification of, among others, endogenous electrophilic compounds to prevent cytotoxicity and cellular damage [54][55][56]. Oxidative stress and the consequent organelle damage may play a critical role in the progression of hepatic injury.…”

Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program

“…Our analysis also revealed an overexpression of five genes encoding glutathione-dependent enzymes (Idh2, Gsta3, Gstm2, Gstm7 and Odc1) that have already been related to antioxidant and anti-apoptotic effects in various cell types, such as CGNs 30–34 ( Supplementary Figure S1D ).…”

Early deficits in insulin secretion, beta cell mass and islet blood perfusion precede onset of autoimmune type 1 diabetes in BioBreeding rats

“…In prediabetic NOD mice, beta cell dysfunction is suggested to occur as a consequence of early immune cell infiltration and activation of inflammatory cascades [ 39 ]. However, the DR Lyp/Lyp rats do not display any major infiltration by mononuclear cells until a few days prior to clinical onset of type 1 diabetes [ 13 ]. We confirmed this, and islets from DR Lyp/Lyp rats did not show increased infiltration of CD3 + cells in pancreatic sections.…”

“…However, positive staining of infiltrating monocytes remains to be shown at this age [ 11 ]. Additionally, islets from 40-day-old DR Lyp/Lyp animals express lower levels of genes involved in the metabolism of reactive oxygen species (ROS) [ 13 ] and are more sensitive to changes in redox balance [ 14 ]. Over time, such an inherent sensitivity could contribute to accumulation of the ROS that diminish beta cell function, rendering cells more sensitive to immune cell attack.…”