Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function

Mysore, Tharun; Shinkel, Trixie A.; Collins, James E.; Salvaris, Evelyn; Fisicaro, Nella; Murray‐Segal, Lisa; Johnson, Lucinda E A; Lepore, Diana A.; Walters, Stacey N.; Stokes, Rebecca; Chandra, Abhilash P.; O’Connell, Philip J.; d’Apice, Anthony J.F.; Cowan, Peter J.

doi:10.2337/diabetes.54.7.2109

Cited by 96 publications

(75 citation statements)

References 45 publications

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“…It is striking that seemingly beneficial effects of GPX1 on these two key factors, beta cell mass, and insulin synthesis and secretion eventually led to chronic hyperinsulinaemia. Apparently, our in vivo results are in stark contrast to the transient benefits of upregulating antioxidant capacity as shown in vitro [6,7] or during short-term situations [23]. Therefore, this study reveals a long-term metabolic risk of disturbing the balance between intracellular antioxidant defence and ROS formation [9] and cautions against antioxidant strategies to prevent or treat diabetes [9,50].…”

Section: Discussionmentioning

confidence: 58%

“…Scale bar, 10 µm. Magnification, 40× insulin concentration nor insulin gene expression in islets was altered by overexpressing catalase by up to 50-fold [9], two forms of metallothionein by up to 30-fold [9,42] or three forms of superoxide dismutase enzymes by up to 10-fold [5,7]. Furthermore, overproduction of metallothionein and catalase in beta cells actually accelerated cytokineinduced beta cell death [9].…”

Section: Discussionmentioning

confidence: 99%

“…However, overproduction of antioxidant proteins in animals, either specifically in pancreatic beta cells [5,6] or ubiquitously in various tissues [7,8], has generated highly variable or even negative phenotypes [9]. Most strikingly, we have observed spontaneous development of hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity in mice overproducing Se-dependent cellular glutathione peroxidase-1 (GPX1), a major intracellular antioxidant enzyme [10].…”

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confidence: 95%

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Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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Aims/hypothesis We previously observed hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity in Gpx1-overexpressing mice (OE). Here we determined whether these phenotypes were eliminated by diet restriction, subsequently testing whether hyperinsulinaemia was a primary effect of Gpx1 overexpression and caused by dysregulation of pancreatic duodenal homeobox 1 (PDX1) and uncoupling protein-2 (UCP2) in islets. Methods First, 24 male OE and wild-type (WT) mice (2 months old) were given 3 g (diet-restricted) or 5 g (fullfed) feed per day for 4 months to compare their glucose metabolism. Thereafter, several mechanistic experiments were conducted with pancreas and islets of the two genotypes (2 or 6 months old) to assay for beta cell mass, reactive oxygen species (ROS) levels, mitochondrial membrane potential (Δ= m ) and expression profiles of regulatory proteins. A functional assay of islets was also performed. Results Diet restriction eliminated obesity but not hyperinsulinaemia in OE mice. These mice had greater pancreatic beta cell mass (more than twofold) and pancreatic insulin content (40%) than the WT, along with an enhanced Δ= m and glucose-stimulated insulin secretion in islets. With diminished ROS production, the OE islets displayed hyperacetylation of H3 and H4 histone in the Pdx1 promoter, elevated PDX1 and decreased UCP2. Conclusions/interpretation Overproduction of the major antioxidant enzyme, glutathione peroxidase 1, caused seemingly beneficial changes in pancreatic PDX1 and UCP2, but eventually led to chronic hyperinsulinaemia by dysregulating islet insulin production and secretion.

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 95%

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Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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“…We performed FDA/PI staining to confirm the viability of control and stored islets. This provided evidence for stable membrane integrity and the presence of functional enzymatic activities of the islets [33]. FDA was used to stain live cells with green fluorescence, and to confirm the presence of esterase enzyme [20], and we used PI to fluoresce the dead cells red.…”

Section: Discussionmentioning

confidence: 99%

High Recovery of Functional Islets Stored at Low and Ultralow Temperatures

2014

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■ AbstractBACKGROUND: Poor recovery of islets upon cryopreservation is the main hurdle in islet banking. Pancreatic islets have a poor antioxidative defense mechanism, and exposure of islets to low temperature leads to oxidative stress. AIM: We aimed to investigate whether known compounds such as metformin, γ aminobutyric acid (GABA), docosahexanoic acid (DHA), or eicosapentaenoic acid (EPA) alone or in combination are capable of reducing oxidative stress for better islet recovery upon storage at suboptimal temperatures. METHODS: Islets isolated from mouse pancreas were stored at low temperature (4°C) for 15 days and at ultralow temperature (-196°C) for 30 days with or without additives. After revival from cold storage, islets were assessed by using three methods: (1) specificity by dithizone (DTZ), (2) viability by fluorescein diacetate/propidium iodide (FDA/PI) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and (3) functionality by glucose-stimulated insulin secretion (GSIS). The oxidative status of the islets stored at suboptimal temperatures was determined by both intracellular free radical release (fluorometric analysis) and lipid peroxidation (enzymatic determination). RESULTS: Supplementation with additives led to an improvement in islet survival upon storage at suboptimal temperatures, without depletion of insulin secretory activity, which was comparable to that of controls. The additives acted as cryoprotectants and antioxidants as revealed by high recovery of viable islets and reduction in total reactive oxygen species (ROS) and malonidealdehyde (MDA), respectively. CONCLUSIONS: Our results demonstrate for the first time that supplementation with EPA, DHA, and metformin may lead to higher islet recovery from -196°C storage, enabling proper islet banking.

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“…CAT has also exhibited a protective effect against H 2 O 2 and streptozotocin-induced oxidative stress in vivo (31). Additionally, combinatorial overexpression of CAT and GSH-px has been shown to have a protective effect against ROS-induced oxidative stress through improving the activity of CuZnSOD or MnSOD (32)(33)(34)(35).…”

Section: Discussionmentioning

confidence: 99%

Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells

Song

Zhao

Wang

et al. 2013

Molecular Medicine Reports

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Abstract. Reactive oxygen species (ROS)-induced pancreatic β cell death affects insulin secretion and is important in the pathogenesis of diabetes. Lagerstroemia speciosa, a traditional folk medicine, has been used for t he prevention and treatment of diabetes. However, whether Lagerstroemia speciosa has a cytoprotective effect on pancreatic β cells remains to be elucidated. The present study aimed to investigate the cytoprotective effects of hot water extracts from Lagerstroemia speciosa leaves (LWE) on 3-morpholinosydnonimine (SIN-1)-induced oxidative damage in Syrian hamster pancreatic insulinoma HIT-T15 cells. The HIT-T15 cells were first treated with SIN-1 (50 µM) for 24 h and then co-incubated with LWE for 48 h. SIN-1 significantly decreased HIT-T15 cell viability (P<0.05); however, LWE did not exert a significant cytotoxic effect and increased the viability of HIT-T15 cells in a dose-dependent manner. To further investigate the protective effects of LWE on SIN-1-induced oxidative stress in HIT-T15 cells, the cellular levels of ROS, lipid peroxidation and endogenous antioxidant enzymes, including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-px), were determined. LWE decreased the intracellular levels of ROS and lipid peroxidation, and increased the activities of antioxidant enzymes. These results suggest that LWE has a cytoprotective effect against SIN-1-induced oxidative stress in HIT-T15 cells through the inhibition of lipid peroxidation, a decrease in ROS levels and an increase in antioxidant enzyme activity. In addition, LWE increased insulin secretion in SIN-1-treated HIT-T15 cells. Our results suggested that LWE were effective in the treatment of diabetes. Further studies are required to study the anti-diabetic molecular mechanism in a cell model.

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Overexpression of Glutathione Peroxidase With Two Isoforms of Superoxide Dismutase Protects Mouse Islets From Oxidative Injury and Improves Islet Graft Function

Cited by 96 publications

References 45 publications

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

High Recovery of Functional Islets Stored at Low and Ultralow Temperatures

Protective effects of Lagerstroemia speciosa on 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in HIT-T15 pancreatic β cells

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