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

2015 ◽  
Vol 55 (1) ◽  
pp. 21-29 ◽  
Author(s):  
S Lortz ◽  
S Lenzen ◽  
I Mehmeti
Keyword(s):  
Gene Expression ◽  
Hydrogen Peroxide ◽  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Insulin Gene ◽  
Insulin Content ◽  
Insulin Biosynthesis ◽  
Β Cell ◽  
Insulin Gene Expression

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 (H2O2). Because of the high rate of insulin biosynthesis and the low expression of H2O2-inactivating enzymes in pancreatic β cells, it has been proposed that the luminal H2O2concentration might be very high. As the role of this H2O2in 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 H2O2removal 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 H2O2significantly with a threefold increase of the EC50value for H2O2. However, the expression of cytokine-induced ER stress genes and viability after incubation with β cell toxic cytokines (IL1β alone or together with TNFα+IFNγ) 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 H2O2reduced insulin gene expression and insulin content in ER-Catalase N244 expressing cells. These data show that ER-Catalase N244 reduced H2O2toxicity but did not provide protection against pro-inflammatory cytokine-mediated toxicity and ER stress. Insulin secretion was not affected by decreasing H2O2in the ER in spite of a reduced insulin transcription and processing.

scholarly journals Endoplasmic Reticulum Stress-Induced Activation of Activating Transcription Factor 6 Decreases Insulin Gene Expression via Up-Regulation of Orphan Nuclear Receptor Small Heterodimer Partner

Endocrinology ◽  
2008 ◽  
Vol 149 (8) ◽  
pp. 3832-3841 ◽  
Author(s):  
Hye-Young Seo ◽  
Yong Deuk Kim ◽  
Kyeong-Min Lee ◽  
Ae-Kyung Min ◽  
Mi-Kyung Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Er Stress ◽  
Insulin Gene ◽  
Orphan Nuclear Receptor ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Small Heterodimer Partner ◽  
Insulin Gene Expression ◽  
Long Evans ◽  
Activating Transcription Factor

The highly developed endoplasmic reticulum (ER) structure of pancreatic β-cells is a key factor in β-cell function. Here we examined whether ER stress-induced activation of activating transcription factor (ATF)-6 impairs insulin gene expression via up-regulation of the orphan nuclear receptor small heterodimer partner (SHP; NR0B2), which has been shown to play a role in β-cell dysfunction. We examined whether ER stress decreases insulin gene expression, and this process is mediated by ATF6. A small interfering RNA that targeted SHP was used to determine whether the effect of ATF6 on insulin gene expression is mediated by SHP. We also measured the expression level of ATF6 in pancreatic islets in Otsuka Long Evans Tokushima Fatty rats, a rodent model of type 2 diabetes. High glucose concentration (30 mmol/liter glucose) increased ER stress in INS-1 cells. ER stress induced by tunicamycin, thapsigargin, or dithiotreitol decreased insulin gene transcription. ATF6 inhibited insulin promoter activity, whereas X-box binding protein-1 and ATF4 did not. Adenovirus-mediated overexpression of active form of ATF6 in INS-1 cells impaired insulin gene expression and secretion. ATF6 also down-regulated pancreatic duodenal homeobox factor-1 and RIPE3b1/MafA gene expression and repressed the cooperative action of pancreatic duodenal homeobox factor-1, RIPE3b1/MafA, and β-cell E box transactivator 2 in stimulating insulin transcription. The ATF6-induced suppression of insulin gene expression was associated with up-regulation of SHP gene expression. Finally, we found that expression of ATF6 was increased in the pancreatic islets of diabetic Otsuka Long Evans Tokushima Fatty rats, compared with their lean, nondiabetic counterparts, Long-Evans Tokushima Otsuka rats. Collectively, this study shows that ER stress-induced activation of ATF6 plays an important role in the development of β-cell dysfunction.

Naringin (4′,5,7-Trihydroxyflavanone 7-Rhamnoglucoside) Attenuates β-Cell Dysfunction in Diabetic Rats through Upregulation of PDX-1

2018 ◽  
Vol 206 (3) ◽  
pp. 133-143 ◽  
Author(s):  
Manickam Subramanian ◽  
Balaji Thotakura ◽  
Swathi Priyadarshini Chandra Sekaran ◽  
Ashok kumar Jyothi ◽  
Indumathi Sundaramurthi
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Insulin Secretion ◽  
Protein Expression ◽  
Serum Insulin ◽  
Diabetic Rats ◽  
Insulin Gene ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Gene Expression

Background: Pancreatic duodenal homeobox-1 (PDX-1) is a key transcription factor which regulates Insulin gene expression and insulin secretion in adult β-cells and helps to maintain β-cells mass. Naringin, a flavanone, owing to its anti­oxidant property, is reported to have antidiabetic effects. Objectives: The present study tries to evaluate the role of naringin on the β-cell-specific transcription factor PDX-1 in diabetic rats. Methods: Diabetes was induced in male rats using streptozotocin and treated with naringin (100 mg/kg) orally for 4 and 8 weeks. Serum insulin level, Pdx-1 and Insulin gene expression, and PDX-1 protein expression were assessed in the rat pancreas. Histopathological and ultrastructural changes in the islet and β-cells were observed. Results: Naringin prevented leukocytic infiltration in the pancreas of diabetic rats and recouped the β-cells with adequate secretory granules. Naringin-treated diabetic rats showed significantly increased mRNA expression of Pdx-1 and Insulin genes, increased expression of transcription factor PDX-1, and higher serum insulin levels than the diabetic control animals. These changes were more pronounced in the 8-week naringin-treated diabetic animals. Conclusions: Naringin was found to be an effective antidiabetic agent which increased Insulin gene expression and insulin secretion by upregulating the PDX-1 gene and protein expression.

scholarly journals β-Cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid as a glutamate dehydrogenase activator in db/db mice

2011 ◽  
Vol 212 (3) ◽  
pp. 307-315 ◽  
Author(s):  
Seung Jin Han ◽  
Sung-E Choi ◽  
Sang-A Yi ◽  
Soo-Jin Lee ◽  
Hae Jin Kim ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Death ◽  
Insulin Secretion ◽  
Carboxylic Acid ◽  
Glucose Tolerance ◽  
Glutamate Dehydrogenase ◽  
Insulin Gene ◽  
Β Cells ◽  
Β Cell ◽  
Insulin Gene Expression

2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is an activator of glutamate dehydrogenase (GDH), which is a mitochondrial enzyme with an important role in insulin secretion. We investigated the effect of BCH on the high-glucose (HG)-induced reduction in glucose-stimulated insulin secretion (GSIS), the HG/palmitate (PA)-induced reduction in insulin gene expression, and HG/PA-induced β-cell death. We also studied whether long-term treatment with BCH lowers blood glucose and improves β-cell integrity indb/dbmice. We evaluated GSIS, insulin gene expression, and DNA fragmentation in INS-1 cells exposed to HG or HG/PA in the presence or absence of BCH. Anin vivostudy was performed in which 7-week-old diabeticdb/dbmice were treated with BCH (0.7 g/kg,n=10) and placebo (n=10) every other day for 6 weeks. After treatment, an intraperitoneal glucose tolerance test and immunohistological examinations were performed. Treatment with BCH blocked HG-induced GSIS inhibition and the HG/PA-induced reduction in insulin gene expression in INS-1 cells. In addition, BCH significantly reduced HG/PA-induced INS-1 cell death and phospho-JNK level. BCH treatment improved glucose tolerance and insulin secretion indb/dbmice. BCH treatment also increased the ratio of insulin-positive β-cells to total islet area (P<0.05) and reduced the percentage of β-cells expressing cleaved caspase 3 (P<0.05). In conclusion, the GDH activator BCH improved glycemic control indb/dbmice. This anti-diabetic effect may be associated with improved insulin secretion, preserved islet architecture, and reduced β-cell apoptosis.

scholarly journals Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

2008 ◽  
Vol 199 (1) ◽  
pp. 41-50 ◽  
Author(s):  
Ernest Sargsyan ◽  
Henrik Ortsäter ◽  
Kristofer Thorn ◽  
Peter Bergsten
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
Cell Function ◽  
Β Cells ◽  
Β Cell ◽  
Eukaryotic Translation ◽  
Β Cell Function ◽  
Activating Transcription Factor ◽  
The Unfolded Protein Response

Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of β-cell function and impaired insulin secretion observed in these individuals. A strategy to improve β-cell function in individuals with T2DM has been intermittent administration of KATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of KATP channels improve β-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in β-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic β-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and β-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves β-cell function.

Protein calorie restriction has opposite effects on glucose metabolism and insulin gene expression in fetal and adult rat endocrine pancreas

2004 ◽  
Vol 286 (4) ◽  
pp. E542-E550 ◽  
Author(s):  
M. A. Martín ◽  
E. Fernández ◽  
A. M. Pascual-Leone ◽  
F. Escrivá ◽  
C. Alvarez
Keyword(s):  
Gene Expression ◽  
Glucose Metabolism ◽  
Food Restriction ◽  
Cell Mass ◽  
Insulin Gene ◽  
Mrna Levels ◽  
Β Cell ◽  
Adult Age ◽  
Insulin Gene Expression ◽  
Insulin Mrna

We previously demonstrated that fetuses from undernourished pregnant rats exhibited increased β-cell mass and hyperinsulinemia, whereas keeping food restriction until adult age caused reduced β-cell mass, hypoinsulinemia, and decreased insulin secretion. Because these alterations can be related to insulin availability, we have now investigated early and long-term effects of protein calorie food restriction on insulin mRNA levels as well as the possible mechanisms that could modulate the endogenous insulin mRNA content. We used fetuses at 21.5 days of gestation proceeding from food-restricted rats during the last week of pregnancy and 70-day-old rats undernourished from day 14 of gestation until adult age and with respective controls. Insulin mRNA levels, glucose transporters, and total glycolysis and mitochondrial oxidative fluxes were evaluated. We additionally analyzed undernutrition effects on signals implicated in glucose-mediated insulin gene expression, especially pancreatic duodenal homeobox-1 (PDX-1), stress-activated protein kinase-2 (p38/SAPK2), and phosphatidylinositol 3-kinase. Undernourished fetuses showed increased insulin mRNA, oxidative glucose metabolism, and p38/SAPK2 levels, whereas undernutrition until adult age provoked a decrease in insulin gene expression, oxidative glucose metabolism, and PDX-1 levels. The results indicate that food restriction caused changes in insulin gene expression and content leading to alterations in glucose-stimulated insulin secretion. The molecular events, increased p38/SAPK2 levels in fetuses and decreased PDX-1 levels in adults, seem to be the responsible for the altered insulin mRNA expression. Moreover, because PDX-1 activation appears to be regulated by glucose-derived metabolite(s), the altered glucose oxidation caused by undernutrition could in some manner affect insulin mRNA expression.

scholarly journals γ-Oryzanol Protects Pancreatic β-Cells Against Endoplasmic Reticulum Stress in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (4) ◽  
pp. 1242-1250 ◽  
Author(s):  
Chisayo Kozuka ◽  
Sumito Sunagawa ◽  
Rei Ueda ◽  
Moritake Higa ◽  
Hideaki Tanaka ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
Insulin Secretion ◽  
Er Stress ◽  
High Fat Diet ◽  
Diabetic Mice ◽  
High Fat ◽  
Β Cells ◽  
Β Cell ◽  
Pancreatic Β Cells ◽  
Glucose Stimulated Insulin Secretion

Abstract Endoplasmic reticulum (ER) stress is profoundly involved in dysfunction of β-cells under high-fat diet and hyperglycemia. Our recent study in mice showed that γ-oryzanol, a unique component of brown rice, acts as a chemical chaperone in the hypothalamus and improves feeding behavior and diet-induced dysmetabolism. However, the entire mechanism whereby γ-oryzanol improves glucose metabolism throughout the body still remains unclear. In this context, we tested whether γ-oryzanol reduces ER stress and improves function and survival of pancreatic β-cells using murine β-cell line MIN6. In MIN6 cells with augmented ER stress by tunicamycin, γ-oryzanol decreased exaggerated expression of ER stress-related genes and phosphorylation of eukaryotic initiation factor-2α, resulting in restoration of glucose-stimulated insulin secretion and prevention of apoptosis. In islets from high-fat diet-fed diabetic mice, oral administration of γ-oryzanol improved glucose-stimulated insulin secretion on following reduction of exaggerated ER stress and apoptosis. Furthermore, we examined the impact of γ-oryzanol on low-dose streptozotocin-induced diabetic mice, where exaggerated ER stress and resultant apoptosis in β-cells were observed. Also in this model, γ-oryzanol attenuated mRNA level of genes involved in ER stress and apoptotic signaling in islets, leading to amelioration of glucose dysmetabolism. Taken together, our findings demonstrate that γ-oryzanol directly ameliorates ER stress-induced β-cell dysfunction and subsequent apoptosis, highlighting usefulness of γ-oryzanol for the treatment of diabetes mellitus.

scholarly journals Transcription Factor Glis3, a Novel Critical Player in the Regulation of Pancreatic β-Cell Development and Insulin Gene Expression

2010 ◽  
Vol 30 (7) ◽  
pp. 1864-1864
Author(s):  
Hong Soon Kang ◽  
Yong-Sik Kim ◽  
Gary ZeRuth ◽  
Ju Youn Beak ◽  
Kevin Gerrish ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Cell Development ◽  
Insulin Gene ◽  
Pancreatic Β Cell ◽  
Β Cell ◽  
Insulin Gene Expression

TCF7L2 controls insulin gene expression and insulin secretion in mature pancreatic β-cells

2008 ◽  
Vol 36 (3) ◽  
pp. 357-359 ◽  
Author(s):  
Merewyn K. Loder ◽  
Gabriela da Silva Xavier ◽  
Angela McDonald ◽  
Guy A. Rutter
Keyword(s):  
Gene Expression ◽  
Insulin Secretion ◽  
Human Islets ◽  
Insulin Gene ◽  
Nucleotide Polymorphisms ◽  
Cellular Mechanisms ◽  
Gene Encoding ◽  
Risk Alleles ◽  
Insulin Gene Expression ◽  
Glucagon Like Peptide 1

Genetic studies have linked the risk of Type 2 diabetes with SNPs (single nucleotide polymorphisms) in the gene encoding the Wnt signalling-associated transcription factor, TCF7L2 (T-cell factor 7-like 2). The risk alleles have been associated with reduced glucose and GLP-1 (glucagon-like peptide 1)-stimulated insulin secretion. Recent evidence has suggested that inheritance of the at-risk T allele at SNP rs7903146 may increase the expression of TCF7L2 in adult human islets. However, the cellular mechanisms by which changes in TCF7L2 levels may affect insulin secretion are unclear. In the present paper, we describe the use of RNA silencing to investigate the role of TCF7L2 on insulin secretion and gene expression in rodent islets. We find that reduced TCF7L2 expression reduces glucose-simulated insulin secretion and insulin gene expression while slightly potentiating glucose stimulated changes in intracellular free Ca2+ concentrations.

scholarly journals The Vascular Basement Membrane: A Niche for Insulin Gene Expression and β Cell Proliferation

2006 ◽  
Vol 10 (3) ◽  
pp. 397-405 ◽  
Author(s):  
Ganka Nikolova ◽  
Normund Jabs ◽  
Irena Konstantinova ◽  
Anna Domogatskaya ◽  
Karl Tryggvason ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Basement Membrane ◽  
Insulin Gene ◽  
Β Cell ◽  
Vascular Basement Membrane ◽  
Insulin Gene Expression

scholarly journals Oxidative and endoplasmic reticulum stress in β-cell dysfunction in diabetes

2015 ◽  
Vol 56 (2) ◽  
pp. R33-R54 ◽  
Author(s):  
Sumaira Z Hasnain ◽  
Johannes B Prins ◽  
Michael A McGuckin
Keyword(s):  
Oxidative Stress ◽  
Endoplasmic Reticulum ◽  
Er Stress ◽  
Inflammatory Cytokines ◽  
Cell Stress ◽  
Insulin Biosynthesis ◽  
Central Feature ◽  
Β Cells ◽  
Β Cell ◽  
Cell Dysfunction

The inability of pancreatic β-cells to make sufficient insulin to control blood sugar is a central feature of the aetiology of most forms of diabetes. In this review we focus on the deleterious effects of oxidative stress and endoplasmic reticulum (ER) stress on β-cell insulin biosynthesis and secretion and on inflammatory signalling and apoptosis with a particular emphasis on type 2 diabetes (T2D). We argue that oxidative stress and ER stress are closely entwined phenomena fundamentally involved in β-cell dysfunction by direct effects on insulin biosynthesis and due to consequences of the ER stress-induced unfolded protein response. We summarise evidence that, although these phenomenon can be driven by intrinsic β-cell defects in rare forms of diabetes, in T2D β-cell stress is driven by a range of local environmental factors including increased drivers of insulin biosynthesis, glucolipotoxicity and inflammatory cytokines. We describe our recent findings that a range of inflammatory cytokines contribute to β-cell stress in diabetes and our discovery that interleukin 22 protects β-cells from oxidative stress regardless of the environmental triggers and can correct much of diabetes pathophysiology in animal models. Finally we summarise evidence that β-cell dysfunction is reversible in T2D and discuss therapeutic opportunities for relieving oxidative and ER stress and restoring glycaemic control.

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