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Glucolipid metabolism disorder in diabetes mellitus (DM) causes human endothelial injury and autophagy dysfunction is an important cause of endothelial dysfunction (ED). Selenoprotein S (SelS) could protect endothelium from oxidative stress, inflammatory responses, and apoptosis. This study assessed the effect of SelS on autophagy in glucolipid metabolic disorders and protection of the resulted vascular endothelial injury. The results showed that high glucose (HG), high oxidized low-density lipoprotein (HL), and HG combined with HL (HGL) could reduce viability of human aortic endothelial cells (HAECs), induce HAECs injury and increase SelS expression in a time-dependent manner. HG, HL, and HGL also initially induced autophagy but later reduced it in HAECs, while activity of the Akt/mTOR signaling was inhibited, especially in HGL culture of HAECs. SelS overexpression reduced the endothelial injury and autophagy and activated the Akt/mTOR signaling in HG, HL and HGL-cultured HAECs, compared to the control. Conversely, knockdown of SelS expression had the opposite effects on HAECs. In conclusion, SelS demonstrated a protective effect on endothelial injury induced by high glucose and/or ox-LDL and the underlying molecular events might be related to its regulation of HAECs autophagy by activating the Akt/mTOR signaling. SelS could be a potential intervention target in prevention and treatment of diabetic vascular complications., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Defects in the development, maintenance or expansion of β-cell mass can result in impaired glucose metabolism and diabetes. N 6 -methyladenosine affects mRNA stability and translation efficiency, and impacts cell differentiation and stress response. To determine if there is a role for m 6 A in β-cells, we investigated the effect of Mettl14, a key component of the m 6 A methyltransferase complex, on β-cell survival and function using rat insulin-2 promoter-Cre-mediated deletion of Mettl14 mouse line (βKO). We found that βKO mice with normal chow exhibited glucose intolerance, lower levels of glucose-stimulated insulin secretion, increased β-cell death and decreased β-cell mass. In addition, HFD-fed βKO mice developed glucose intolerance, decreased β-cell mass and proliferation, exhibited lower body weight, increased adipose tissue mass, and enhanced insulin sensitivity due to enhanced AKT signaling and decreased gluconeogenesis in the liver. HFD-fed βKO mice also showed a decrease in de novo lipogenesis, and an increase in lipolysis in the liver. RNA sequencing in islets revealed that Mettl14 deficiency in β-cells altered mRNA expression levels of some genes related to cell death and inflammation. Together, we showed that Mettl14 in β-cells plays a key role in β-cell survival, insulin secretion and glucose homeostasis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

As the most conserved branch of the unfolded protein response (UPR), the inositol-requiring enzyme 1a (IRE1a)/X-box binding protein 1 (XBP1) pathway plays crucial roles in cell survival and cell death by upregulating UPR-associated genes involved in protein entry into the endoplasmic reticulum (ER) and ER-associated degradation (ERAD). Selenoprotein S (SelS) is localized to the ER membrane and involved in ERAD. Although SelS plays an important role in restoring ER stress, the SelS-dependent protective mechanisms against cell death remain unclear. Here, using an inducible SelS knockdown (KD) 3T3-L1 cell model, we showed that SelS KD resulted adipocyte death, which was associated with imbalance of the Bcl-2 family members. Furthermore, SelS KD decreased spliced XBP1 (sXBP1), increased IRE1α and p-JNK, suggesting a role of SelS in the modulation of the IRE1α-sXBP1 pathway. Moreover, adipocyte death induced by SelS suppression can be inhibited by overexpression of sXBP1. Thus, it is proposed that SelS promotes cell survival through the IRE1α-XBP1 signaling pathway., (Copyright © 2018. Published by Elsevier Inc.)