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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The most commonly used technical approach to isolate human pancreatic islets intended for allotransplants generates a product that is hampered by mechanical and chemical insults, which dramatically reduce the mass of viable and functional transplantable cells. We tested a novel class of antioxidant chemical compounds (SOD mimics: AEOL10113 and AEOL10150) to protect human islets from oxidative stress in order to improve the preservation of the isolated tissue. Addition of SOD mimic in culture, after isolation, allowed for the survival of a significantly higher islet cell mass. Functional behavior and phenotypic cell characteristics of the SOD-treated islet preparations were preserved, as was the capacity to normalize diabetic mice, even when a marginal mass of islets was transplanted. The addition of SOD mimic during isolation, before culture, further reduced early cell loss. These results indicate that prompt interventions aimed at blocking oxidative stress can improve human islet survival, preserving a functional islet mass two- to threefold larger than the one usually obtained without adding any antioxidant compound. The ability to preserve functional islets without a dramatic loss represents a major advantage considering the scarce availability of islet tissue for clinical transplantation.
Diabetes 2002 Aug
PMID:Preservation of human islet cell functional mass by anti-oxidative action of a novel SOD mimic compound. 1214 71

Oxidative stress (OS) plays an important role in the pathogenesis of Type 1 diabetes mellitus (DM). The aim of the study was to compare OS parameters in diabetic children and their first-degree relatives. Fifty diabetic children from the West Bohemian Region were examined as well as their 32 siblings (12 Boys and 20 girls) and 65 of their parents during a period of 6 months. Thirty healthy sex- and age-matched children studied before planned surgeries were normal controls for children, 40 healthy adult volunteers were controls for parents. OS parameters were evaluated in all participants of the study (superoxide dismutase, SOD; glutathione peroxidase, GSHPx; plasma antioxidant capacity, AOC; reduced glutathione, GSH; and malondialdehyde, MDA) and also Type 1 DM-associated antibodies (ICA and GADA). The results in diabetic children showed significantly lower GSHPx and AOC and increased MDA when compared with healthy children. Similar findings were found in their siblings but without statistical significance. It is consequently evident that decreased antioxidative protection and simultaneous free radical (FR) overproduction occur in diabetic children and that there is a similar, but not significant, tendency in their siblings. The findings warrant reducing OS in diabetic children and postponing disease onset in susceptible relatives.
J Diabetes Complications
PMID:Parameters of oxidative stress in children with Type 1 diabetes mellitus and their relatives. 1250 49

Nonenzymatic glycosylation of plasma proteins may contribute to the excess risk of developing atherosclerosis in patients with diabetes mellitus. Although it is believed that high-density lipoprotein (HDL) is glycosylated at an increased level in diabetic individuals, little is known about a possible linkage between glycated HDL and endothelial dysfunction in diabetes. To clarify whether glucose-modified HDL affects the function of endothelial cells, we first examined herein the level of H(2)O(2) generation from cultured human aortic endothelial cells (HAECs) exposed to a glycated oxidized HDL (gly-ox-HDL) prepared in vitro. Incubation for 48 hours with 100 microg/mL of gly-ox-HDL induced significant release of H(2)O(2) from cells and gly-ox-HDL-induced H(2)O(2) formation was inhibited in the presence of diphenyleneiodonium, an inhibitor of NADPH oxidase. In addition, stimulation of HAECs with gly-ox-HDL for 48 hours elicited a marked downregulation of catalase and Cu(2+), Zn(2+)-superoxide dismutase (CuZn-SOD), suggesting H(2)O(2) formation by gly-ox-HDL to be due to a disturbance involving oxidant and antioxidant enzymes in the cells. Treatment of HAECs with gly-ox-HDL attenuated the expression of endothelial nitric oxide synthase (eNOS), but not inducible nitric oxide synthase (iNOS), and this was followed by decreased production of nitric oxide (NO) by the cells. Furthermore, in vitro experiments with glycated HDL (gly-HDL) in the presence of 2 mmol/L EDTA and Cu(2+)-oxidized HDL suggested the effect of gly-HDL on endothelial function to be possibly potentiated by additional oxidative modification. Taking all of the above findings together, gly-ox-HDL may lead to the deterioration of vascular function through altered production of reactive oxygen species and reactive nitrogen species in endothelial cells.
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PMID:Glycated high-density lipoprotein regulates reactive oxygen species and reactive nitrogen species in endothelial cells. 1252 61

Reactive oxygen species (ROS) have been implicated in the pathogenesis of vascular dysfunction in diabetes mellitus, and NAD(P)H oxidase is known as the most important source of ROS in the vasculatures. To determine whether NAD(P)H oxidase is a major participant in the critical intermediary signaling events in high glucose (HG, 25 mM)-induced proliferation of vascular smooth muscle cells (VSMC), we investigated in explanted aortic VSMC from rats the role of NAD(P)H oxidase on the HG-related cellular proliferation and superoxide production. VSMC under HG condition had increased proliferative capacity that was inhibited by tiron (1 mM), a cell membrane permeable superoxide scavenger, but not by SOD, which is not permeable to cell membrane. The nitroblue tetrazolium staining in the HG-exposed VSMC was more prominent than that of VSMC under normal glucose (5.5 mM) condition, which was significantly inhibited by DPI (10 microM), an NAD(P)H oxidase inhibitor, but not by inhibitors for other oxidases such as NADH dehydrogenase, xanthine oxidase, and nitric oxide synthase. In the VSMC under HG condition, the enhanced NAD(P)H oxidase activity with increased membrane translocation of Rac1 was observed, but the protein expression of p22phox and gp91phox was not increased. These data suggest that HG-induced changes in VSMC proliferation are related to the intracellular production of superoxide through enhanced activity of NAD(P)H oxidase.
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PMID:NAD(P)H oxidase participates in the signaling events in high glucose-induced proliferation of vascular smooth muscle cells. 1267 89

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive "causal" antioxidant therapy. New low-molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase beta isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.
Diabetes Care 2003 May
PMID:New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy. 1271 23

Magnesium deficit and oxidative stress are common features of the diabetic state. This concept supported by another observation that magnesium deficiency is also a state of increased oxidative stress prompted us to study the effect of magnesium supplementation on magnesium status and oxidative stress in diabetic rats. For this purpose, male Wistar rats were made diabetic with a single intraperitoneal injection of Alloxan. Experimental diabetes caused a significant decrease in serum and red blood cell magnesium levels and increased urinary excretion of magnesium. Marked increase in plasma malondialdehyde and corresponding decrease in vitamins C & E, uric acid and total thiols was observed in the diabetic rats as compared to control group. In liver, MDA levels were increased significantly with concomitant decrease in vitamin C, non-protein thiols and antioxidant enzymes (SOD & GST). Magnesium supplementation for four weeks restored serum and RBC magnesium levels to near normal levels with marginal but significant decrease in blood glucose levels. Plasma and liver MDA levels were reduced significantly and vitamin C and total thiols were increased significantly with magnesium supplementation. Antioxidant enzyme activity was also increased significantly with magnesium supplementation in diabetic rats. Our data clearly demonstrates that alloxanic diabetes is associated with decreased magnesium status and increased oxidative stress and that magnesium supplementation can in part restore the antioxidant parameters and decrease the oxidative stress in experimental diabetic rats.
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PMID:Effect of magnesium supplementation on oxidative stress in alloxanic diabetic rats. 1273 78

Oxidative stress and modulation of anti-oxidant enzymes may contribute to the deleterious consequences of diabetes mellitus and to the effects of chronic (i.e. 21 day) stress in the CNS. We therefore compared the effects of short- and long-term exposure to diabetes-induced hyperglycemia, restraint stress and the combined effects of restraint stress and diabetes upon parameters of oxidative stress in the rat hippocampus. Whereas 7 days of restraint stress or hyperglycemia, or the combination, produced similar increases in oxidative stress markers 4-hydroxy-2-nonenal (HNE) and malondialdehyde (MDA) throughout the hippocampus, 21 days of stress or hyperglycemia did not increase these markers in the dentate gyrus. In contrast, Ammon's horn still showed elevated levels of these lipid peroxidation products, especially in diabetic rats subjected to 21 days of restraint stress. The expression of two anti-oxidant enzymes, copper/zinc superoxide dismutase (Cu/Zn-SOD) and manganese SOD, was also differentially regulated by stress and hyperglycemia in a time- and region-specific manner in the rat hippocampus. Although long-term stress decreased both SOD isoforms, diabetes increased Cu/Zn-SOD expression in DG with or without 21 days of repeated stress. These increases may account for the finding that protein-conjugated HNE and MDA levels returned to control levels between 7 days and 21 days of hyperglycemia or the combination of diabetes and stress. These results suggest that while other anti-oxidant pathways may account for decreases in oxidative stress in the long-term stress paradigm, increases in Cu/Zn-SOD expression may contribute to the region-specific attenuation of oxidative stress in the diabetic rat hippocampus.
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PMID:Region specific increases in oxidative stress and superoxide dismutase in the hippocampus of diabetic rats subjected to stress. 1294 6

Oxidative stress is an important pathogenic constituent in diabetic endothelial dysfunction. The aim of this study was to investigate whether an increase in oxidative stress related to xanthine oxidoreductase occurs in diabetes. Liver, brain, heart, and kidney xanthine oxidase (XO), xanthine dehydrogenase (XDH), antioxidant enzymes (glutathione peroxidase, superoxide dismutase, catalase), and nitrite levels were measured in control and early and late diabetic rat models. Although diabetes had no impact on liver XO and XDH activity, XDH activity in heart, kidney, and brain was significantly greater in late diabetic rats than in controls. Selenium glutathione peroxidase (GPx) activity was found to be lower in the liver, brain, kidney, and heart of late diabetic rats than in controls. The measured decrease in selenium GPx activity was also observed in early diabetic heart, kidney, and brain. No significant change was observed in liver, brain, and kidney copper/zinc superoxide dismutase (Cu/Zn SOD) activity in early and late diabetic rat models compared with that in controls, whereas heart Cu/Zn SOD activity was significantly decreased in both early and late diabetic rats. Liver and brain catalase activity remained similar among the different experimental groups, whereas increased heart and kidney catalase activity was observed in both early and late diabetic rats. Liver, kidney, and brain nitrite levels were found to be increased in early diabetic rat models compared with those in controls. These data suggest that the increased XDH and decreased selenium GPx activity observed in the later stages of diabetes leads to enhanced oxidative stress in the heart, kidney, and brain, resulting in secondary organ damage associated with the disease.
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PMID:Activities of xanthine oxidoreductase and antioxidant enzymes in different tissues of diabetic rats. 1453 5

The effects of overexpression of Cu(2+)/Zn(2+) superoxide dismutase-1 (SOD-1) on indexes of renal injury were compared in 5-month-old nontransgenic (NTg) db/db mice and db/db mice hemizygous for the human SOD-1 transgene (SOD-Tg). Both diabetic groups exhibited similar hyperglycemia and weight gain. However, in NTg-db/db mice, albuminuria, glomerular accumulation of immunoreactive transforming growth factor-beta, collagen alpha1(IV), nitrotyrosine, and mesangial matrix were all significantly increased compared with either nondiabetic mice or SOD-Tg-db/db. SOD-1 activity and reduced glutathione levels were higher, whereas malondialdehyde content was lower, in the renal cortex of SOD-Tg-db/db compared with NTg-db/db mice, consistent with a renal antioxidant effect in the transgenic mice. Inulin clearance (C(IN)) and urinary excretion of guanosine 3',5'-cyclic monophosphate (U(cGMP)) were increased in SOD-Tg-db/db mice compared with corresponding values in nondiabetic mice or NTg-db/db mice. C(IN) and U(cGMP) were suppressed by Nomega-nitro-L-arginine methyl ester in SOD-Tg-db/db but not in NTg-db/db mice, implying nitric oxide (NO) dependence of these increases and enhanced renal NO bioactivity in SOD-Tg-db/db. Studies of NO-responsive cGMP in isolated glomeruli supported greater quenching of NO in glomeruli from NTg-db/db compared with SOD-Tg-db/db mice. Evidence of increased NO responsiveness and the suppression of glomerular nitrotyrosine may both reflect reduced NO-superoxide interaction in SOD-Tg-db/db mice. The results implicate superoxide in the pathogenesis of diabetic nephropathy.
Diabetes 2004 Mar
PMID:Attenuation of renal injury in db/db mice overexpressing superoxide dismutase: evidence for reduced superoxide-nitric oxide interaction. 1498 62

Mutations in the hepatocyte nuclear factor (HNF)-1 beta lead to type 5 maturity-onset diabetes of the young (MODY5). HNF-1 beta forms a homodimer or a heterodimer with HNF-1 alpha and regulates various target genes. HNF-1 beta mutations are rare, and no functional analysis has been performed in conjunction with HNF-1 alpha. HNF-1 beta is expressed in the liver and biliary system and controls liver-specific and bile acid-related genes. Moreover, liver-specific Hnf-1 beta knockout mice present with severe jaundice. However, no patients with HNF-1 beta mutations have biliary manifestations. In this report, we found a novel missense mutation in the HNF-1 beta gene in a patient with neonatal cholestasis and liver dysfunction together with the common features of MODY5. Functional analysis revealed that the mutant HNF-1 beta had diminished transcriptional activity by loss of the DNA binding activity. The mutant had a promoter-specific dominant-negative transcriptional effect on wild-type HNF- and inhibited its DNA binding. Moreover, the mutant had a promoter- and cell-specific transcriptional repressive effect on HNF-1 alpha and a promoter-specific inhibitory effect on HNF-1 alpha DNA binding. From these results, we considered that the different phenotype of patients with HNF-1 beta mutations might be caused by the different HNF-1 beta activity in conjunction with the different repression of HNF-1 alpha activity in selected promoters and tissues.
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PMID:Promoter-specific repression of hepatocyte nuclear factor (HNF)-1 beta and HNF-1 alpha transcriptional activity by an HNF-1 beta missense mutant associated with Type 5 maturity-onset diabetes of the young with hepatic and biliary manifestations. 1500 36


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