Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Abstract

Aims: Glutathione peroxidase (GPX) mimic ebselen and superoxide dismutase (SOD) mimic copper diisopropylsalicylate (CuDIPs) were used to rescue impaired glucose-stimulated insulin secretion (GSIS) in islets of GPX1 and(or) SOD1-knockout mice. Results: Ebselen improved GSIS in islets of all four tested genotypes. The rescue in the GPX1 knockout resulted from a coordinated transcriptional regulation of four key GSIS regulators and was mediated by the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a)-mediated signaling pathways. In contrast, CuDIPs improved GSIS only in the SOD1 knockout and suppressed gene expression of the PGC-1a pathway. Innovation: Islets from the GPX1 and(or) SOD1 knockout mice provided metabolically controlled intracellular hydrogen peroxide (H 2 O 2 ) and superoxide conditions for the present study to avoid confounding effects. Bioinformatics analyses of gene promoters and expression profiles guided the search for upstream signaling pathways to link the ebselen-initiated H 2 O 2 scavenging to downstream key events of GSIS. The RNA interference was applied to prove PGC-1a as the main mediator for that link. Conclusion: Our study revealed a novel metabolic use and clinical potential of ebselen in rescuing GSIS in the GPX1-deficient islets and mice, along with distinct differences between the GPX and SOD mimics in this regard. These findings highlight the necessities and opportunities of discretional applications of various antioxidant enzyme mimics in treating insulin secretion disorders. Redox Signal. 20,[191][192][193][194][195][196][197][198][199][200][201][202][203]

Ebselen suppresses inflammation induced by Helicobacter�pylori lipopolysaccharide via the p38 mitogen-activated protein kinase signaling pathway

“…However, ebselen treatment did not affect TLR4 expression, suggesting that ebselen may inhibit H. pylori LPS-induced ROS production via GPX2/4 expression as opposed to TLR4 signaling. This may be due to the fact that ebselen acts as an oxidant at redox-modulatory sites, which mimics the activity of endogenous GPX, therefore partially restores GPX antioxidant capacity (20,21). Furthermore, the present study demonstrated that phosphorylation of p38 MAPK was significantly increased following H. pylori LPS treatment and that LPS-induced phosphorylation of p38 MAPK was inhibited by treatment with ebselen.…”

Selenium and Selenoproteins in Adipose Tissue Physiology and Obesity

“…Dietary Se deficiency and(or) diet restriction partially alleviated the negative impacts of GPX1 overexpression on lipid and glucose metabolism in male mice [184,185]. In contrast, the GPX mimetic could restore partially the impaired glucose-stimulated insulin secretion and related signaling in the GPX1 −/− mice [186].…”

Selenium and Metabolic Disorders: An Emphasis on Type 2 Diabetes Risk

“…Thus, hepatic GPx1 may prevent hepatic steatosis indirectly by regulating ROS levels. Further supporting the protective function of GPx1, the GPx mimetic, ebselen, was found to restore islet function in GPx1-/- mice through a PGC-1α dependent mechanism [ 82 ]. Nrf2 is a transcription factor that controls the transcription of antioxidant enzymes by interacting with an antioxidant response element (ARE).…”