Abstract
Oxidative stress plays critical roles in the pathogenesis of diabetes. This study tested the hypothesis that by protecting β-cells against oxidative stress and inflammation, an Nrf2 activator, dimethyl fumarate (DMF), may prevent or delay the onset of type 1 diabetes in non-obese diabetic (NOD) mice. Firstly, islet isolation was conducted to confirm the antioxidative effects of DMF oral administration on islet cells. Secondly, in a spontaneous diabetes model, DMF (25 mg/kg) was fed to mice once daily starting at the age of 8 weeks up to the age of 22 weeks. In a cyclophosphamide-induced accelerated diabetes model, DMF (25 mg/kg) was fed to mice twice daily for 2 weeks. In the islet isolation study, DMF administration improved the isolation yield, attenuated oxidative stress and enhanced GCLC and NQO1 expression in the islets. In the spontaneous model, DMF significantly reduced the onset of diabetes compared to the control group (25% vs. 54.2%). In the accelerated model, DMF reduced the onset of diabetes from 58.3% to 16.7%. The insulitis score in the islets of the DMF treatment group (1.6 ± 0.32) was significantly lower than in the control group (3.47 ± 0.21). The serum IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-9, IL-12p70, IFN-γ, TNF-α, MCP-1 and CXCL16 levels in the DMF-treated group were lower than in the control group. In conclusion, DMF may protect islet cells and reduce the incidence of autoimmune diabetes in NOD mice by attenuating insulitis and proinflammatory cytokine production.
Highlights
It is generally accepted that reactive oxygen species (ROS) contribute to the autoimmunemediated destruction of pancreatic β-cells in the islets of Langerhans and loss of insulin secretion [1]
B, both the islet yield and count were significantly higher in the dimethyl fumarate (DMF)-treated group when compared to the vehicle-treated group (IEQ: 2136 ± 620 vs. 1231 ± 468; IC: 1032 ± 45 vs. 770 ± 57; p < 0.05). This was associated with a fourfold increase in the mRNA expression of the antioxidant enzymes glutamate-cysteine ligase catalytic subunit (GCLC) and NQO1 in the DMF-treated group (Figure 2A)
GCLC and NQO1 have been reported as putative transcriptional targets of Nrf2 and upregulated by cellular stress
Summary
It is generally accepted that reactive oxygen species (ROS) contribute to the autoimmunemediated destruction of pancreatic β-cells in the islets of Langerhans and loss of insulin secretion [1]. Antigen-specific T cells mediate the infiltration of inflammatory cells into the pancreas, which leads to the production of inflammatory cytokines and ROS and eventually promotes β-cell destruction. It is well known that innate immune cells, such as macrophages and dendritic cells, are the first cells that enter the islets during insulitis [2,3]. The ROS generated by the initial insult to the islets induce the activation of macrophages, redox-dependent NF-kB and other transcription factors [4]. Activated macrophages secrete a mixture of proinflammatory cytokines such as TNF-α, IL-6 and IL-1β, and produce ROS, which can damage the pancreatic β-cells [5,6,7]. The activation of macrophages and T cells triggers oxidative stress, which leads to the progression of type I diabetes [8]
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