Progesterone and cilostazol protect mice pancreatic islets from oxidative stress induced by hydrogen peroxide (original) (raw)
Related papers
International Journal of Endocrinology
Gestational diabetes (GD) is a condition defined as carbohydrate intolerance and hyperglycemia beginning in the second trimester of pregnancy, which overlaps with the progesterone exponential increase. Progesterone has been shown to cause pancreatic β-cell death by a mechanism dependent on the generation of reactive oxygen species and oxidative stress. Herein, we studied the effect of this hormone on the expression of 84 genes related to oxidative stress and oxidant defense in pancreatic RINm5F cell lineage. Cells were incubated with 0.1, 1.0, or 100 μM progesterone for 6 or 24 h, in the presence or absence of the vitamins E and C. Among the investigated genes, five of them had their expression increased, at least 2-fold, in two different concentrations independently of the time of incubation, or at the same concentration at the different time points, including those that encode for stearoyl-CoA desaturase 1 (Scd1), dual oxidase 1 (Duox1), glutathione peroxidase 6 (GPx6), heme oxyge...
Control of hyperglycemia significantly improves oxidative stress profile of pancreatic islets
Islets, 2011
Pancreatic islets are known to express low levels of antioxidant enzymes compared to other tissues and are therefore vulnerable to oxidative stress. Enhancing antioxidant defense mechanisms in pancreatic islets help them to cope better with oxidative stress. Persistent hyperglycemia under diabetic condition leads to continuous generation of reactive oxygen species, and different tissues exposed to this are oxidatively damaged depending on their antioxidant defense. Since islet cells are very poor in their antioxidant defense, our interest was to assess their antioxidant profile under normal, diabetic, insulin treated diabetic and untreated diabetic condition. On one hand, antioxidant defense was measured in terms of antioxidant enzymes and antioxidant molecules while on the other, damage caused to biomolecules was estimated. Our data demonstrate that oxidative damage to all biomolecules increased in islets cultured from diabetic animals, which enhanced further in islets from untreated diabetic animals. Insulin treatment significantly improved oxidative stress profile of islets indicating that the control of hyperglycemia leads to improvement in oxidative stress profile. ©2 0 1 1 L a n d e s B i o s c i e n c e. D o n o t d i s t r i b u t e .
Diabetes & Metabolism, 2007
Oxidative stress is a putative mechanism leading to beta-cell damage in type 2 diabetes. We studied isolated human pancreatic islets from type 2 diabetic and non-diabetic subjects, matched for age and body mass index. Evidence of increased oxidative stress in diabetic islets was demonstrated by measuring nitrotyrosine concentration and by electron paramagnetic resonance. This was accompanied by reduced glucose-stimulated insulin secretion, as compared to non-diabetic islets (Stimulation Index, SI: 0.9 ± 0.2 vs. 2.0±0.4, P < 0.01), and by altered expression of insulin (approximately -60%), catalase (approximately +90%) and glutathione peroxidase (approximately +140%). When type 2 diabetic islets were preexposed for 24 h to the new antioxidant bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate di-hydrochloride, nitrotyrosine levels, glucose-stimulated insulin secretion (SI: 1.6 ± 0.5) and gene expressions improved/normalized. These results support the concept that oxidative stress may play a role in type 2 diabetes beta-cell dysfunction; furthermore, it is proposed that therapy with antioxidants could be an interesting adjunctive pharmacological approach to the treatment of type 2 diabetes.
Hormetic and regulatory effects of lipid peroxidation mediators in pancreatic beta cells.
Nutrient sensing mechanisms of carbohydrates, amino acids and lipids operate distinct pathways that are essential for the adaptation to varying metabolic conditions. The role of nutrient-induced biosynthesis of hormones is paramount for attaining metabolic homeostasis in the organism. Nutrient overload attenuate key metabolic cellular functions and interfere with hormonal-regulated inter- and intra-organ communication, which may ultimately lead to metabolic derangements. Hyperglycemia and high levels of saturated free fatty acids induce excessive production of oxygen free radicals in tissue and cells. This phenomenon, which is accentuated in both type-1 and type-2 diabetic patients, has been associated with the development of impaired glucose tolerance and the etiology of peripheral complications. However, low levels of the same free radicals also induce hormetic responses that protect cells against deleterious effects of the same radicals. Of interest is the role of hydroxyl radicals in initiating peroxidation of polyunsaturated fatty acids (PUFA) and generation of alpha\alphaalpha,$\beta$-unsaturated reactive 4-hydroxyalkenals that avidly form covalent adducts with nucleophilic moieties in proteins, phospholipids and nucleic acids. Numerous studies have linked the lipid peroxidation product 4-hydroxy-2E-nonenal (4-HNE) to different pathological and cytotoxic process. Similarly, two other members of the family, 4-hydroxyl-2E-hexenal (4-HHE) and 4-hydroxy-2E,6Z-dodecadienal (4-HDDE) have also been identified as potential cytotoxic agents. It has been suggested that 4-HNE-induced modifications in macromolecules in cells may alter their cellular functions and modify signaling properties. Yet, it has also been acknowledged that these bioactive aldehydes also function as signaling molecules that directly modify cell functions in a hormetic fashion to enable cells adapt to various stressful stimuli. Recent studies have shown that 4-HNE and 4-HDDE, which activate peroxisome proliferator-activated receptor delta\deltadelta (PPAR$\delta$) in vascular endothelial cells and insulin secreting beta cells, promote such adaptive responses to ameliorate detrimental effects of high glucose and diabetes-like conditions. In addition, due to the electrophilic nature of these reactive aldehydes they form covalent adducts with electronegative moieties in proteins, phosphatidylethanolamine and nucleotides. Normally these non-enzymatic modifications are maintained below the cytotoxic range due to efficient cellular neutralization processes of 4-hydroxyalkenals. The major neutralizing enzymes include fatty aldehyde dehydrogenase (FALDH), aldose reductase (AR) and alcohol dehydrogenase (ADH), which transform the aldehyde to the corresponding carboxylic acid or alcohols, respectively, or by biding to the thiol group in glutathione (GSH) by the action of glutathione-S-transferase (GST). This review describes the hormetic and cytotoxic roles of oxygen free radicals and 4-hdroxyalkenal in beta cells exposed to nutritional challenges and the cellular mechanisms they employ to maintain their level at functional range below the cytotoxic threshold.
Journal of Molecular Medicine-jmm, 2004
It has been proposed that low activities of antioxidant enzymes in pancreatic beta cells may increase their susceptibility to autoimmune attack. We have therefore used the spontaneously diabetic BB/S rat model of type 1 diabetes to compare islet catalase and superoxide dismutase activities in diabetes-prone and diabetes-resistant animals. In parallel studies, we employed the RINm5F beta cell line as a model system (previously validated) to investigate whether regulation of antioxidant enzyme activity by inflammatory mediators (cytokines, nitric oxide) occurs at the gene or protein expression level. Diabetes-prone rat islets had high insulin content at the age used (58–65 days) but showed increased amounts of DNA damage when subjected to cytokine or hydrogen peroxide treatments. There was clear evidence of oxidative damage in freshly isolated rat islets from diabetes-prone animals and significantly lower catalase and superoxide dismutase activities than in islets from age-matched diabetes-resistant BB/S and control Wistar rats. The mRNA expression of antioxidant enzymes in islets from diabetes-prone and diabetes-resistant BB/S rats and in RINm5F cells, treated with a combination of cytokines or a nitric oxide donor, DETA-NO, was analysed semi-quantitatively by real time PCR. The mRNA expression of catalase was lower, whereas MnSOD expression was higher, in diabetes-prone compared to diabetes-resistant BB/S rat islets, suggesting regulation at the level of gene expression as well as of the activities of these enzymes in diabetes. The protein expression of catalase, CuZnSOD and MnSOD was assessed by Western blotting and found to be unchanged in DETA-NO treated cells. Protein expression of MnSOD was increased by cytokines in RINm5F cells whereas the expression of CuZnSOD was slightly decreased and the level of catalase protein was unchanged. We conclude that there are some changes, mostly upregulation, in protein expression but no decreases in the mRNA expression of catalase, CuZnSOD or MnSOD enzymes in beta cells treated with either cytokines or DETA-NO. The lower antioxidant enzyme activities observed in islets from diabetes-prone BB/S rats could be a factor in the development of disease and in susceptibility to DNA damage in vitro and could reflect islet alterations prior to immune attack or inherent differences in the islets of diabetes-prone animals, but are not likely to result from cytokine or nitric oxide exposure in vivo at that stage.
PloS one, 2012
Chronic exposure (24-72 hrs) of pancreatic islets to elevated glucose and fatty acid leads to glucolipoxicity characterized by basal insulin hypersecretion and impaired glucose-stimulated insulin secretion (GSIS). Our aim was to determine the mechanism for basal hypersecretion of insulin. We used mono-oleoyl-glycerol (MOG) as a tool to rapidly increase lipids in isolated rat pancreatic ß-cells and in the clonal pancreatic ß-cell line INS-1 832/13. MOG (25-400 µM) stimulated basal insulin secretion from ß-cells in a concentration dependent manner without increasing intracellular Ca(2+) or O(2) consumption. Like GSIS, MOG increased NAD(P)H and reactive oxygen species (ROS). The mitochondrial reductant ß-hydroxybutyrate (ß-OHB) also increased the redox state and ROS production, while ROS scavengers abrogated secretion. Diazoxide (0.4 mM) did not prevent the stimulatory effect of MOG, confirming that the effect was independent of the K(ATP)-dependent pathway of secretion. MOG was metabo...
Journal of Endocrinology, 1994
The aim of the present investigation was to evaluate the putative involvement of oxygen free radicals in interleukin-1β (IL-1β)-induced suppression of islet glucose oxidation. Isolated adult rat pancreatic islets were exposed for 1 h to liposomally encapsulated superoxide dismutase (SOD; 10 mg/ml), catalase (CAT; 10 mg/ml) and glutathione peroxidase (GPX; 5 mg/ml), after which IL-1β (25 U/ml) or hydrogen peroxide (H2O2; 0·1 mm) was added, and the incubation was continued overnight. The following day, samples were taken from the incubation media for nitrite determinations, and islet glucose oxidation rates were measured. The CAT activity increased fourfold after addition of CAT-containing liposomes. It was found that IL-1β induced a marked increase in islet nitrite production, as an index of nitric oxide formation, and that this was paralleled by a decrease in islet glucose oxidation rates. H2O2-treated islets exhibited a modest decrease in glucose oxidation rates and a minor increas...
Lipid peroxidation and antioxidant status in experimental diabetes
Clinica Chimica Acta, 1999
Oxidative stress is currently suggested as a mechanism underlying diabetes. The present study was designed to evaluate the oxidative stress related parameters in streptozotocin-induced diabetes in rats using different complementary approaches: susceptibility to in vitro oxidation (lipid peroxidation induction in liver homogenate, red blood cells hemolysis), blood antioxidant status (total antioxidant capacity by two approaches), and plasma isoprostane measurement, a new marker of lipid peroxidation in vivo. We have shown that induced liver thiobarbituric acid reactive substances increased after 4 weeks of diabetes, in spite of increased liver vitamin E content. Red blood cells hemolysis was significantly delayed after 4 weeks of diabetes. Plasma antioxidant capacity (AOC) tended to increase after 4 weeks of diabetes and was correlated with plasma vitamin E levels. Total antioxidant activity (TAA) significantly decreased after 1 week and a significant correlation was observed with plasma albumin levels. Plasma isoprostane (8-epiprostaglandinF2alpha) concentrations were not modified significantly 1 week or 4 weeks after the induction of diabetes. Levels of vitamin E in the diet and changes in its distribution among the body seems to play an important role in the development of oxidative stress during diabetes and its consequences.
PLOS ONE, 2016
Mitochondria and NADPH oxidase are important sources of reactive oxygen species in particular the superoxide radical (ROS) in pancreatic islets. These molecules derived from molecular oxygen are involved in pancreatic β-cells signaling and control of insulin secretion. We examined the involvement of ROS produced through NADPH oxidase in the leucine-and/or glucose-induced insulin secretion by pancreatic islets from fed or 48-hour fasted rats. Glucose-stimulated insulin secretion (GSIS) in isolated islets was evaluated at low (2.8 mM) or high (16.7 mM) glucose concentrations in the presence or absence of leucine (20 mM) and/or NADPH oxidase inhibitors (VAS2870-20 μM or diphenylene iodonium -DPI-5 μM). ROS production was determined in islets treated with dihydroethidium (DHE) or MitoSOX Red reagent for 20 min and dispersed for fluorescence measurement by flow cytometry. NADPH content variation was examined in INS-1E cells (an insulin secreting cell line) after incubation in the presence of glucose (2.8 or 16.7 mM) and leucine (20 mM). At 2.8 mM glucose, VAS2870 and DPI reduced net ROS production (by 30%) and increased GSIS (by 70%) in a negative correlation manner (r = -0.93). At 16.7 mM glucose or 20 mM leucine, both NADPH oxidase inhibitors did not alter insulin secretion neither net ROS production. Pentose phosphate pathway inhibition by treatment with DHEA (75 μM) at low glucose led to an increase in net ROS production in pancreatic islets from fed rats (by 40%) and induced a marked increase (by 144%) in islets from 48-hour fasted rats. The NADPH/NADP + ratio was increased when INS-1E cells were exposed to high glucose (by 4.3-fold) or leucine (by 3-fold). In conclusion, increased ROS production through NADPH oxidase prevents the occurrence of hypoglycemia in fasting conditions, however, in the presence of high glucose or high leucine levels, the increased production of NADPH and the consequent enhancement of the activity of the antioxidant defenses mitigate the excess of ROS production and allow the secretory process of insulin to take place.
Cell journal, 2014
Pancreatic islets have fewer antioxidant enzymes than other tissues and thus are vulnerable to oxidative stress. In the present study, the effects of nine specifically selected Iranian medical plants on the mitochondria function and survival of isolated rat islets were examined. In this experimental study, following laparotomy, pancreases of rats were removed and the islets isolated and incubated in vitro for 24 hours. Logarithmic doses of plant materials were added to the islets and incubated for an additional 24 hours after which the viability of the cells and production of reactive oxygen species (ROS) were measured. Levels of insulin production in relation to static and stimulated glucose concen- trations were also determined. The tested compounds markedly increased survival of the islet cells, their mi- tochondrial activity, and insulin levels at the same time as reducing production of ROS. Greatest effects were observed in the following order: Peganum harmala, Glycyrrhiza glab...