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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have been investigating the effects of preventing oxidative stress on pathogenesis and complications of type 1 diabetes in the NOD mouse model. Our studies have shown that damage caused by oxidative stress is higher in islets and vascular tissue of NOD mice than in nonautoimmune controls or a diabetes-resistant NOD mouse. In addition, phagocytic function and cytokine production by macrophages are aberrant in the NOD. We have demonstrated that treatment of prediabetic NOD mice for 2 weeks with a metalloporphyrin superoxide dismutase (SOD) mimetic results in marked reduction of oxidative stress in islets and vascular tissue and a reversal of macrophage defects.
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PMID:Oxidative stress in type 1 diabetes. 1467 39

Reactive oxygen species (ROS) is involved in autoimmune destruction of islet beta cells, which has been proven to be an important underlying pathogenesis for insulin dependent diabetes mellitus (IDDM). Calcitonin gene-related peptide (CGRP) is a widely distributed neuropeptide, which has been found to play an important role in protecting myocytes from ROS. We hypothesized that exogenous CGRP gene administration before the pathogenic stage of insulitis might suppress the production of ROS and provide a hopeful therapeutic intervention for autoimmune diabetes. We performed CGRP gene transfer by injecting naked plasmid directly into skeletal muscles of mice with electroporation enhancement to achieve a continuous expression of CGRP in skeletal muscles, and thereby its secretion into the circulation. The effect of CGRP gene transfer on the pathogenesis of diabetes was studied in autoimmune diabetic mice induced by multiple low dose streptozotocin (MLDS). The CGRP gene therapy decreased morbidity of autoimmune diabetes, and significantly ameliorated hyperglycemia in these mice. CGRP gene transfer inhibited the production of ROS and malondialdehyde (MDA). In addition, it enhanced the activity of catalase (CAT) and superoxide dismutase (SOD) significantly. The data suggest that intramuscular CGRP gene transfer ameliorates autoimmune destruction of islet beta cells, resulting in significant reduction in diabetes incidence of MLDS diabetes mice. CGRP benefits might be mediated at least in part by inhibiting the oxidative stress in islet beta cells of these mice.
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PMID:Calcitonin gene-related peptide gene therapy suppresses reactive oxygen species in the pancreas and prevents mice from autoimmune diabetes. 1469 77

Oxidative stress plays a key role in the development of microvascular complications of diabetes mellitus (DM). Antioxidant enzymes protect against the rapid onset of diabetic polyneuropathy (DPN) by reducing oxidative stress. Genetic variations that affect activity or expression levels of the antioxidant enzymes may therefore be associated with susceptibility to DPN. We examined polymorphic markers Ala(-9)Val in SOD2 gene and Arg213Gly in SOD3 gene for possible relation to DPN in Russian type 1 diabetic patients. Four hundred Russian white patients with type 1 diabetes were studied using neurological examination according to recommendations of the San Antonio Conference on Diabetic Neuropathy. Two groups were formed from the general sample. Definition of frequency distribution of the polymorphic markers was performed in these groups using the polymerase chain reaction. Genes encoding the enzymes Mn-SOD and extracellular superoxide dismutase (EC-SOD) were found to be associated with the pathogenesis of DPN.
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PMID:Predisposing genetic factors for diabetic polyneuropathy in patients with type 1 diabetes: a population-based case-control study. 1470 72

In the nonobese diabetic (NOD) mouse model of type 1 diabetes, we have found that there are increased markers of oxidative stress in islet beta cells in prediabetic animals when compared with control strains. Treatment of these mice with a superoxide dismutase (SOD) mimetic can markedly reduce the level of nitrotyrosine found in islets. In a diabetes-resistant NOD congenic mouse, the NOD.Lc7 mouse, we found increased beta cell proliferation and decreased apoptosis in islets. There are also lower levels of nitrotyrosine in islets of NOD.Lc7 mice than in NOD mice, suggesting that NOD.Lc7 islets are less susceptible to oxidative damage. We hypothesize that there may be a link between the ability of islet cells to regenerate and their resistance to oxidative stress.
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PMID:Role for oxidative stress in the regeneration of islet beta cells? 1498 69

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.
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PMID:Antioxidant enzyme activity and mRNA expression in the islets of Langerhans from the BB/S rat model of type 1 diabetes and an insulin-producing cell line. 1500 13

Defective intracellular antioxidant enzyme production (IAP) has been demonstrated in adults with diabetic nephropathy. To evaluate the effects on IAP of vitamin E administration in adolescents with type 1 diabetes and early signs of microangiopathy, 12 adolescents (aged 11-21 y; diabetes duration 10-18) were studied. Eight had retinopathy [background (four), preproliferative (three), or proliferative (one)], four had persistent microalbuminuria, and seven had both. Skin fibroblasts were obtained by biopsies and cultured in Dulbecco's modified Eagle's medium. CuZn superoxide dismutase (SOD), MnSOD, catalase (CAT), and glutathione-peroxidase (GPX) activity and mRNA expression were measured before and after 3 mo of synthetic vitamin E supplementation (600 mg twice daily); on both occasions, IAP was evaluated at different ex vivo glucose concentrations (5 and 22 mM). Ten adolescents with type 1 diabetes (aged 12-20 y) without angiopathy and eight healthy volunteers (aged 15-22 y) participated as control subjects. Vitamin E serum levels were measured throughout the study. In normal glucose concentrations, CuZnSOD, MnSOD, CAT, and GPX activity and mRNA expression were not different among the groups. In high glucose, CuZnSOD activity and mRNA increased similarly in all groups [angiopathics: 0.96 +/- 0.30 U/mg protein; 9.9 +/- 3.2 mRNA/glyceraldehyde-3-phosphate dehydrogenase). CAT and GPX activity and mRNA did not increase in high glucose only in adolescents with angiopathy (0.35 +/- 0.09; 4.2 +/- 0.1 and 0.52 +/- 0.14; 2.4 +/- 0.9, respectively). MnSOD did not change in any group. Vitamin E supplementation had no effect on any enzymatic activity and mRNA in both normal and hyperglycemic conditions. Adolescents with early signs of diabetic angiopathy have defective IAP and activity, which are not modified by vitamin E.
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PMID:Effects of vitamin E supplementation on intracellular antioxidant enzyme production in adolescents with type 1 diabetes and early microangiopathy. 1534 73

Reactive oxygen species, such as superoxide, and nitrogen oxides, such as peroxynitrite, are thought to contribute to beta-cell destruction during the disease process that leads to type 1 diabetes. EUK-8 is a member of a new class of synthetic salen-manganese compounds with low toxicity that possess catalytic superoxide dismutase, peroxidase, and catalase activity that can inactivate superoxide and nitrogen oxides (e.g., peroxynitrite and nitrogen dioxide). We observed that EUK-8 administration inhibited the adoptive transfer of type 1 diabetes to NOD mice. In addition, administration of EUK-8 to NOD mice with established autoimmunity completely prevented the development of type 1 diabetes for up to 1 year in age, even though the treatment was discontinued after 35 weeks of age. EUK-8 treatment also prolonged the survival of islet allografts in newly diabetic NOD mice. Thus, reactive oxygen and nitrogen species contribute to the pathoetiology of both spontaneous type 1 diabetes and allograft rejection. In cultures of NIT-1 cells, EUK-8 inhibited cytotoxicity caused by superoxide as well as nitric oxide. Collectively, our findings implicate a greater role for nitrogen oxides (other than peroxynitrite) in beta-cell damage. Antioxidants designed to prevent the formation of both cytotoxic reactive oxygen and nitrogen species may effectively protect beta-cells from spontaneous autoimmunity and alloresponses.
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PMID:A salen-manganese catalytic free radical scavenger inhibits type 1 diabetes and islet allograft rejection. 1544 86

The hallmark of immune-mediated type 1 diabetes is T cell-mediated destruction of the insulin-producing beta cells in the islets, which results from an imbalance between disease promoting factors and protective elements. The precise mechanisms of beta cell destruction leading to diabetes remain unclear. There are many molecules, including Fas ligand (FasL) and cytokines, such as IL-1, TNF-alpha and IFN-gamma that cause release of other cytokine-mediators that have potential to damage the beta cells. The beta cell-death appears to ultimately be caused by receptor (Fas/FasL)-mediated mechanisms and/or by secretion of cytotoxic molecules (e.g., granzymes, perforin). FasL-mediated beta cell damage might play a role in promoting insulitis and beta cell destruction in autoimmune diabetes in addition to toxic molecules, such as reactive oxygen species (superoxide, hydroxy radical, nitric oxide) or perforin. Furthermore, DNA damage in beta cells leads to poly (ADP-ribose) polymerase-activation which will increase NAD consumption and rapid depletion of NAD compromise ATP production in the cells. Nicotinamide inhibits poly (ADP-ribose) polymerase and reduces nitric oxide accumulation in the NOD pancreas and protect beta cells against radical-induced necrosis. Transgenic mice with beta cell specific overexpression of copper, zinc superoxide dismutase, or thioredoxin are resistant to autoimmune and STZ-induced diabetes. It is apparent that a number of different mechanisms of beta cell destruction are operative in type 1 diabetes. Blockage of multiple pathways, rather than a single pathway, of beta cell-death may, therefore be necessary to fully protect beta cells from destruction and thereby prevent type 1 diabetes.
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PMID:Prevention of type 1 diabetes: from the view point of beta cell damage. 1556 75

Diabetic pregnancy is often complicated by a number of pathological conditions among which is increased oxidative stress. This study was conducted to investigate the parameters of oxidative stress in 90 patients divided into the three groups: pregnant women with Type 1 diabetes mellitus, healthy pregnant women and non-pregnant women. In pregnancy groups all parameters were followed in 1st, 2nd and 3rd trimester. Diabetic control was monitored by fasting blood glucose and glycosylated hemoglobin (HbA(1c)) and these values, as well as measured biochemical parameters (urea, creatinine, total cholesterol and uric acid), were appropriate throughout the study. The concentration of TBARS, as a measure of lipid peroxidation, and activity of antioxidant enzymes superoxide dismutase (Cu, Zn-SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) were investigated in hemolysate of erythrocytes. TBARS concentration increased significantly in pregnant women when compared with control group (non-pregnant women), as well as in pregnant diabetics compared with healthy pregnant women. The SOD activity was gradually increased in the group of normal pregnant women vs. non-pregnant group, but decreased significantly in the group of diabetic pregnant women. Catalase activity was significantly increased only in 3rd trimester diabetic pregnant women. Increased lipid peroxidation and reduced antioxidant status, despite good diabetic control, show that pregnant women are exposed to oxidative stress to a greater degree than controls.
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PMID:Oxidative stress in diabetic pregnancy: SOD, CAT and GSH-Px activity and lipid peroxidation products. 1562 58

To counterbalance the restricted availability of pancreatic islet tissue for transplant in Type 1 Diabetes Mellitus (T1DM), new methods to provide viable and functional islet cells need to be established. We report on our approach to enhance in vitro viability and function of isolated neonatal pancreatic porcine cell clusters (NPCCs) by co-culturing them with PLGA microsphere entrapped, slowly release superoxide dismutase and catalase. These powerful antioxidizing agents were shown to significantly improve morphology, viability and function, as assessed by microscopy, molecular, biochemical and functional studies, of the incubated NPCCs, as compared to control. Preliminarily, in vitro exposure of isolated NPCCs to slow release microsphere-embedded SOD and CAT could permit or contribute to overcome hurdles associated with scarcity in islet tissue procurement for transplant in T1DM.
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PMID:Long-term delivery of superoxide dismutase and catalase entrapped in poly(lactide-co-glycolide) microspheres: in vitro effects on isolated neonatal porcine pancreatic cell clusters. 1599 7


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