Inhibition of the Keap1/Nrf2 Signaling Pathway Significantly Promotes the Progression of Type 1 Diabetes Mellitus

Abstract

Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by insulin deficiency due to pancreatic β-cell damage and leads to hyperglycemia. The precise molecular mechanisms of the etiology of T1DM are not completely understood. Oxidative stress and the antioxidant status of pancreatic β-cells play a vital role in the pathogenesis and progression of T1DM. The Keap1/Nrf2 signaling pathway plays a critical role in cellular resistance to oxidative stress. This study is aimed at investigating the role of the Keap1/Nrf2 signaling pathway in the progression of T1DM. An alloxan- (ALX-) stimulated T1DM animal model in wild-type (WT) and Nrf2 knockout (Nrf2-/-) C57BL/6J mice and a mouse pancreatic β-cell line (MIN6) were established. Compared with the tolerant (ALX exposure, nondiabetic) WT mice, the sensitive (ALX exposure, diabetic) WT mice exhibited higher blood glucose levels and lower plasma insulin levels. The Keap1/Nrf2 signaling pathway was significantly inhibited in the sensitive WT mice, which was reflected by overexpression of Keap1 and low expression of Nrf2, accompanied by a marked decrease in the expression of the antioxidative enzymes. Compared with WT mice, the Nrf2-/- mice had an increased incidence of T1DM and exhibited more severe pancreatic β-cell damage. The results of in vitro experiments showed that ALX significantly inhibited the viability and proliferation and promoted the apoptosis of MIN6 cells. ALX also markedly increased intracellular ROS production and caused DNA damage in MIN6 cells. In addition, the Keap1/Nrf2 signaling pathway was significantly inhibited in the damaged MIN6 cells. Moreover, Nrf2 silencing by transfection with Nrf2 siRNA markedly exacerbated ALX-induced MIN6 cell injury. Conclusively, this study demonstrates that inhibition of the Keap1/Nrf2 signaling pathway could significantly promote the incidence of T1DM. This study indicates that activation of Keap1/Nrf2 signaling in pancreatic β-cells may be a useful pharmacological strategy for the clinical prevention and treatment of T1DM.

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“…This dysmetabolism is also associated with oxidative stress. A recent study has demonstrated that the inhibition of Nrf2 signalling could significantly promote the incidence of type I diabetes mellitus, and, on the other hand, its reactivation reduces oxidative stress in pancreatic β-cells [ 143 ]. At the same time, the absence of Nrf2 protects from insulin resistance in long-term high-fat diet feeding by decreasing adipose tissue inflammation [ 144 , 145 ].…”

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“…Similarly, obese patients exhibit a lower degree of activated Nrf2 transcription factor [129] . Attesting to its pathological importance, a recent study demonstrated that inhibition of the Keap1/Nrf2 signalling pathway promotes incidence of diabetes mellitus (DM), and conversely, activation reduces oxidative stress in pancreatic β-cells [130] . Endothelial cell dysfunction and thrombosis are cardinal signs of severe COVID-19 [131] , while activation of Nrf2 protects the endothelium from oxidative stress and cytokine storm [132] .…”

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