Peroxiredoxin 6 Attenuates Alloxan-Induced Type 1 Diabetes Mellitus in Mice and Cytokine-Induced Cytotoxicity in RIN-m5F Beta Cells

Abstract

Type 1 diabetes is associated with the destruction of pancreatic beta cells, which is mediated via an autoimmune mechanism and consequent inflammatory processes. In this article, we describe a beneficial effect of peroxiredoxin 6 (PRDX6) in a type 1 diabetes mouse model. The main idea of this study was based on the well-known data that oxidative stress plays an important role in pathogenesis of diabetes and its associated complications. We hypothesised that PRDX6, which is well known for its various biological functions, including antioxidant activity, may provide an antidiabetic effect. It was shown that PRDX6 prevented hyperglycemia, lowered the mortality rate, restored the plasma cytokine profile, reversed the splenic cell apoptosis, and reduced the β cell destruction in Langerhans islets in mice with a severe form of alloxan-induced diabetes. In addition, PRDX6 protected rat insulinoma RIN-m5F β cells, cultured with TNF-α and IL-1β, against the cytokine-induced cytotoxicity and reduced the apoptotic cell death and production of ROS. Signal transduction studies showed that PRDX6 prevented the activation of NF-κB and c-Jun N-terminal kinase signaling cascades in RIN-m5F β cells cultured with cytokines. In conclusion, there is a prospect for therapeutic application of PRDX6 to delay or even prevent β cell apoptosis in type 1 diabetes.

Hyperglycemic Conditions Promote Rac1-Mediated Serine536 Phosphorylation of p65 Subunit of NFκB (RelA) in Pancreatic Beta Cells

“…Investigations by Nano et al have documented protective effects of islet neogenesis associated protein (INGAP) against proinflammatory cytokineinduced metabolic defects, including accelerated NFκB signaling S536 phosphorylation and nuclear accumulation of p65 [70]. Novoselova and coworkers studied potential protective effects of peroxiredoxin 6 (Prx6) against metabolic dysfunction in rat insulinoma RIN-m5F cells following exposure to high glucose or proinflammatory cytokines [71]. Based on data accrued from a series of complementary studies, these investigators surmised that NF-κB signaling module, specifically S536 phosphorylation of p65, as a target for Prx6 mediated protective effects.…”

The Possible Role of Β-Cell Senescence in the Development of Type 2 Diabetes Mellitus

“…Interestingly, the insulin-stimulating activity of Prx6 in vitro was detected both when RIN-m5F β-cells were cultivated under normal conditions and under stressful conditions, inducing cell death [99]. In an alloxan-or streptozotocin-induced mouse model of diabetes, intravenous administration of recombinant Prdx6 prevented hyperglycemia, reduced mortality, restored the plasma cytokine profile, and reduced β-cell destruction in the islets of Langerhans in the mouse pancreas [100][101][102].…”

Role of Innate Immunity and Oxidative Stress in the Development of Type 1 Diabetes Mellitus. Peroxiredoxin 6 as a New Anti-Diabetic Agent

“…Systematic studies evaluating the role for Prdx6 in protection against T1D consequences in in vivo and in vitro were conducted. Using alloxan model of severe murine diabetes allowed us to show that the intravenous ly administered recombinant Prdx6 prevents hyper glycemia, decreases mortality rate, restores serum cytokine profile, and reduces destruction of beta cells in the pancreatic islets of Langerhans [79]. Moreover, in vitro experiments with Prdx6 showed that it protects rat insulinoma (RIN m5F) beta cells exposed to TNF α and IL 1β by decreasing ROS production and cell apoptosis.…”