Prevention of Autoimmune Diabetes in NOD Mice by Dimethyl Fumarate

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.

Determination of carboxylic acids content in the herbal mixtures by HPLC

“…The high content of succinic acid found in the studied herbal mixtures may indicate the ability of these mixtures to prevent the development of mitochondrial dysfunction, and at the same time the development of oxidative stress, which is the main pathogenic mechanism of diabetic angiopathies. Fumaric acid has pronounced antioxidant properties, which is expressed by the cytoprotective ability against the harmful effects of lipid peroxidation and the development of oxidative stress, which underlie the development and progression of diabetic complications [24,25]. Fumaric acid, which has been identified and quantified in all studied herbal mixtures, also has the ability to increase the function of the immune system and reduce inflammation [26,27].…”

Dysregulation of β-Cell Proliferation in Diabetes: Possibilities of Combination Therapy in the Development of a Comprehensive Treatment

“…Lastly, in support of these findings, we previously reported that DMF significantly delayed the onset of T1DM in non-obese diabetic mice and reduced the onset of autoimmune DM. The insulitis score was significantly lower, and these results were accompanied by a significant reduction in serum level of proinflammatory cytokines and chemokines [ 132 ]. Thus, combination therapy with DMF is a novel approach that may augment the efficacy of proliferation agents by providing protection from autoreactive immune cell destruction.…”

Anti-Oxidative Therapy in Islet Cell Transplantation

“…Meanwhile, ascorbic acid only partially reduced oxidative damage 30 min after reperfusion [ 43 ]. Dimethyl fumarate has also been shown to improve islet yield from rats if administered orally for two days prior to procurement and islet isolation [ 44 ]. Similar to DMF, dh404 treatment of Sprague–Dawley rats enhanced nuclear translocation of nuclear factor erythroid factor-related factor 2(Nrf2) and elevated heme oxygenase 1 (HO-1) expression in the pancreas and improved islet yield and viability [ 45 ].…”

“…The protective effect of the Nrf2 pathway on islet cells has been extensively studied. We have previously demonstrated that islet cells isolated from rats pretreated with DMF exhibited significantly increased mRNA expression of glutamate-cysteine ligase catalytic subunit (GCLC) and NADPH oxidoreductase 1(NQO1), transcriptional targets of Nrf2, and decreased oxidative stress as indicated by the reduction in 8OHDG positive islet cells [ 44 ]. Dh404, another Nrf2 activator, has been shown to improve the viability of islet cells when treated with H 2 O 2 through the attenuation of oxidative stress by upregulating antioxidative enzymes such as NQO1, HO-1 and GCLC [ 124 ].…”

“…While there are a plethora of Nrf2 activators that protect islet cells, DMF has been the most evaluated for its immunosuppressive effects. DMF treatment successfully reduce the onset of spontaneous diabetes in NOD mice, a type 1 DM model, suggesting its potent immunomodulatory effects [ 44 ]. In fact, DMF has been used in a clinical trial for the treatment of multiple sclerosis (MS), in which DMF treatment significantly decreased both T and B cell counts in MS patients [ 125 ].…”