Peroxiredoxin 4 Improves Insulin Biosynthesis and Glucose-induced Insulin Secretion in Insulin-secreting INS-1E Cells

Mehmeti, Ilir; Lortz, Stephan; Elsner, Matthias; Lenzen, Sigurd

doi:10.1074/jbc.m114.568329

Cited by 52 publications

(55 citation statements)

References 52 publications

(65 reference statements)

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“…This is in contrast to previous findings after Prdx4 overexpression, which increased insulin 1 and 2 mRNA expression, insulin content and glucose-induced insulin secretion (Mehmeti et al 2014). These results indicate that efficient removal of H 2 O 2 as such by ER-Catalase N244 does not favour proinsulin protein folding.…”

Section: Discussioncontrasting

confidence: 56%

“…The threefold increase of the EC 50 value for H 2 O 2 toxicity documents convincingly the high H 2 O 2 inactivation capacity of ER-Catalase N244, also when compared with the overexpression of Prdx4 (Mehmeti et al 2012, Mehmeti et al 2014 or the targeted expression of a WT catalase cDNA in the ER (Margittai et al 2012).…”

Section: Discussionmentioning

confidence: 90%

“…These results indicate that efficient removal of H 2 O 2 as such by ER-Catalase N244 does not favour proinsulin protein folding. ER-Catalase N244 expression could not replicate the positive effects of Prdx4 overexpression on gene expression, biosynthesis and secretion of insulin (Mehmeti et al 2014).…”

Section: Discussionmentioning

confidence: 99%

“…States of increased insulin demand, such as insulin resistance in type 2 diabetes, require a further increase of the insulin secretory capacity (DeFronzo et al 1989). In addition, the expression of H 2 O 2 -degrading enzymes such as catalase and glutathione peroxidase and also of the ER-resident H 2 O 2 -metabolising enzyme Prdx4 is very low in insulin-secreting cells (Tiedge et al 1998, Mehmeti et al 2014. Thus, a possible effect of luminal H 2 O 2 on oxidative protein folding is likely to be particularly prominent in insulin-secreting cells.…”

Section: Discussionmentioning

confidence: 99%

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Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

Lortz

Lenzen

Mehmeti

2015

Journal of Molecular Endocrinology

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Oxidative folding of nascent proteins in the endoplasmic reticulum (ER), catalysed by one or more members of the protein disulfide isomerase family and the sulfhydryl oxidase ER oxidoreductin 1 (ERO1), is accompanied by generation of hydrogen peroxide (H 2 O 2 ). Because of the high rate of insulin biosynthesis and the low expression of H 2 O 2 -inactivating enzymes in pancreatic b cells, it has been proposed that the luminal H 2 O 2 concentration might be very high. As the role of this H 2 O 2 in ER stress and proinsulin processing is still unsolved, an ER-targeted and luminal-active catalase variant, ER-Catalase N244, was expressed in insulin-secreting INS-1E cells. In these cells, the influence of ER-specific H 2 O 2 removal on cytokine-mediated cytotoxicity and ER stress, insulin gene expression, insulin content and secretion was analysed. The expression of ER-Catalase N244 reduced the toxicity of exogenously added H 2 O 2 significantly with a threefold increase of the EC 50 value for H 2 O 2 . However, the expression of cytokine-induced ER stress genes and viability after incubation with b cell toxic cytokines (IL1b alone or together with TNFaCIFNg) was not affected by ER-Catalase N244. In control and ER-Catalase N244 expressing cells, insulin secretion and proinsulin content was identical, while removal of luminal H 2 O 2 reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H 2 O 2 toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H 2 O 2 in the ER in spite of a reduced insulin transcription and processing.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

Lortz

Lenzen

Mehmeti

2015

Journal of Molecular Endocrinology

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“…Similarly, H 2 O 2 in the range of 25-100 μM, given for 24 h, induced a significant increase in cell death (as measured by LDH release). These concentrations of H 2 O 2 are in accord with those used in other studies on pancreatic β cells (Mehmeti et al 2014, Wali et al 2014, Fu et al 2015, Lortz et al 2015. Accordingly, in subsequent studies, we examined effects of 100 nM insulin and 50-100 μM H 2 O 2 given for 24 h.…”

Section: Insulin Increases Death Of Min6 Cellssupporting

confidence: 58%

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

Bucris

Beck

Boura‐Halfon

et al. 2016

Journal of Endocrinology

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Insulin resistance results from impaired insulin signaling in target tissues that leads to increased levels of insulin required to control plasma glucose levels. The cycle of hyperglycemia and hyperinsulinemia eventually leads to pancreatic β cell deterioration and death by a mechanism that is yet unclear. Insulin induces ROS formation in several cell types. Furthermore, death of pancreatic β cells induced by oxidative stress could be potentiated by insulin. Here, we investigated the mechanism underlying this phenomenon. Experiments were done on pancreatic β cell lines (Min-6, RINm, INS-1), isolated mouse and human islets, and on cell lines derived from nonpancreatic sources. Insulin (100 nM) for 24 h selectively increased the production of ROS in pancreatic β cells and isolated pancreatic islets, but only slightly affected the expression of antioxidant enzymes. This was accompanied by a time-and dose-dependent decrease in cellular reducing power of pancreatic β cells induced by insulin and altered expression of several ER stress response elements including a significant increase in Trb3 and a slight increase in iNos. The effect on iNos did not increase NO levels. Insulin also potentiated the decrease in cellular reducing power induced by H 2 O 2 but not cytokines. Insulin decreased the expression of MCL-1, an antiapoptotic protein of the BCL family, and induced a modest yet significant increase in caspase 3/7 activity. In accord with these findings, inhibition of caspase activity eliminated the ability of insulin to increase cell death. We conclude that prolonged elevated levels of insulin may prime apoptosis and cell death-inducing mechanisms as a result of oxidative stress in pancreatic β cells.

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The pro-radical hydrogen peroxide as a stable hydroxyl radical distributor: lessons from pancreatic beta cells

2022

Self Cite

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The toxic potential of H2O2 is limited, even if intracellular concentrations of H2O2 under conditions of oxidative stress increase to the micromolar concentration range. Its toxicity is mostly restricted to the oxidation of highly reactive thiol groups, some of which are functionally very important. Subsequently, the HO· radical is generated spontaneously from H2O2 in the Fenton reaction. The HO· radical is extremely toxic and destroys any biological structure. Due to the high reactivity, its action is limited to a locally restricted site of its generation. On the other hand, H2O2 with its stability and long half-life can reach virtually any site and distribute its toxic effect all over the cell. Thereby HO·, in spite of its ultra-short half-life (10–9 s), can execute its extraordinary toxic action at any target of the cell. In this oxidative stress scenario, H2O2 is the pro-radical, that spreads the toxic action of the HO· radical. It is the longevity of the H2O2 molecule allowing it to distribute its toxic action from the site of origin all over the cell and may even mediate intercellular communication. Thus, H2O2 acts as a spreader by transporting it to sites where the extremely short-lived toxic HO· radical can arise in the presence of “free iron”. H2O2 and HO· act in concert due to their different complementary chemical properties. They are dependent upon each other while executing the toxic effects in oxidative stress under diabetic metabolic conditions in particular in the highly vulnerable pancreatic beta cell, which in contrast to many other cell types is so badly protected against oxidative stress due to its extremely low H2O2 inactivating enzyme capacity.

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Peroxiredoxin 4 Improves Insulin Biosynthesis and Glucose-induced Insulin Secretion in Insulin-secreting INS-1E Cells

Cited by 52 publications

References 52 publications

Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

Impact of scavenging hydrogen peroxide in the endoplasmic reticulum for β cell function

Prolonged insulin treatment sensitizes apoptosis pathways in pancreatic β cells

The pro-radical hydrogen peroxide as a stable hydroxyl radical distributor: lessons from pancreatic beta cells

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