Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Many diabetic patients suffer from a cardiomyopathy that cannot be explained by poor coronary perfusion. Reactive oxygen species (ROS) have been proposed to contribute to this cardiomyopathy. Consistent with this we found evidence for induction of the antioxidant genes for catalase in diabetic OVE26 hearts. To determine whether increased antioxidant protection could reduce diabetic cardiomyopathy, we assessed cardiac morphology and contractility, Ca(2+) handling, malondialdehyde (MDA)-modified proteins, and ROS levels in individual cardiomyocytes isolated from control hearts, OVE26 diabetic hearts, and diabetic hearts overexpressing the antioxidant protein catalase. Diabetic hearts showed damaged mitochondria and myofibrils, reduced myocyte contractility, slowed intracellular Ca(2+) decay, and increased MDA-modified proteins compared with control myocytes. Overexpressing catalase preserved normal cardiac morphology, prevented the contractile defects, and reduced MDA protein modification but did not reverse the slowed Ca(2+) decay induced by diabetes. Additionally, high glucose promoted significantly increased generation of ROS in diabetic cardiomyocytes. Chronic overexpression of catalase or acute in vitro treatment with rotenone, an inhibitor of mitochondrial complex I, or thenoyltrifluoroacetone, an inhibitor of mitochondrial complex II, eliminated excess ROS production in diabetic cardiomyocytes. The structural damage to diabetic mitochondria and the efficacy of mitochondrial inhibitors in reducing ROS suggest that mitochondria are a source of oxidative damage in diabetic cardiomyocytes. We also found that catalase overexpression protected cardiomyocyte contractility in the agouti model of type 2 diabetes. These data show that both type 1 and type 2 diabetes induce damage at the level of individual myocytes, and that this damage occurs through mechanisms utilizing ROS.
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PMID:Catalase protects cardiomyocyte function in models of type 1 and type 2 diabetes. 1511 4

Increased oxidative stress and impaired anti-oxidant defense have been suggested as contributory factors for initiation and progression of complications in diabetes mellitus. Aging itself has been shown to be along with increased oxidative stress and lower anti-oxidant defense. We aimed at investigating oxidative stress and anti-oxidant enzymes in 61 elderly subjects. Fifteen healthy individuals (group 1, mean age 72.2 +/- 5.13), 13 glucose intolerant patients (group 2, mean age 71.7 +/- 4.9), 19 patients with type 2 diabetes mellitus (T2DM) without any complication (group 3, mean age 70.0 +/- 6.0), and 14 patients with T2DM with at least one complication (group 4, mean age 69.8 +/- 4.7) were included in the study. Whilst plasma levels for malondialdehyde (MDAP) and erythrocyte malondialdehyde (MDAE) were measured as markers of oxidative stress, activity of erythrocyte superoxide dismutase (SOD), glutathion peroxidase (GSH-Px), and catalase (CAT) were taken as markers of oxidative defense system. MDAP level was significantly elevated in group 4 (P = 0.001). MDAE was elevated in patients with T2DM, particularly in group 4, however, the difference between the groups was of borderline significance (P = 0.07). Whilst CAT was elevated in groups 3 and 4 compared to control subjects (P = 0.025 and 0.002, respectively), no difference was found for SOD between the groups. GSH-Px activity was found to be increased in groups 2, 3 and 4, it did not reach statistical significance (P = 0.106). There were significant correlations between CAT and MDAE (P < 0.0001, r = 0.056) and MDAP (P = 0.016, r = 0.306). These results suggest that there was an increased oxidative stress in elderly diabetics, however, this is not due to reduced erythrocyte antioxidant defense potential but, rather, increased free radical production possibly due to hyperglycemia.
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PMID:Oxidative stress and antioxidant status in elderly diabetes mellitus and glucose intolerance patients. 1538 45

Several properties of pancreatic beta-cells in type 2 diabetes (T2D) were studied by using islets isolated from T2D subjects. Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase, and changes in mRNA expression of manganese- superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase. Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.
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PMID:Pancreatic islets from type 2 diabetic patients have functional defects and increased apoptosis that are ameliorated by metformin. 1553 8

KLF11 (TIEG2) is a pancreas-enriched transcription factor that has elicited significant attention because of its role as negative regulator of exocrine cell growth in vitro and in vivo. However, its functional role in the endocrine pancreas remains to be established. Here, we report, for the first time, to our knowledge, the characterization of KLF11 as a glucose-inducible regulator of the insulin gene. A combination of random oligonucleotide binding, EMSA, luciferase reporter, and chromatin immunoprecipitation assays shows that KLF11 binds to the insulin promoter and regulates its activity in beta cells. Genetic analysis of the KLF11 gene revealed two rare variants (Ala347Ser and Thr220Met) that segregate with diabetes in families with early-onset type 2 diabetes, and significantly impair its transcriptional activity. In addition, analysis of 1,696 type 2 diabetes mellitus and 1,776 normoglycemic subjects show a frequent polymorphic Gln62Arg variant that significantly associates with type 2 diabetes mellitus in North European populations (OR = 1.29, P = 0.00033). Moreover, this variant alters the corepressor mSin3A-binding activity of KLF11, impairs the activation of the insulin promoter and shows lower levels of insulin expression in pancreatic beta cells. In addition, subjects carrying the Gln62Arg allele show decreased plasma insulin after an oral glucose challenge. Interestingly, all three nonsynonymous KLF11 variants show increased repression of the catalase 1 promoter, suggesting a role in free radical clearance that may render beta cells more sensitive to oxidative stress. Thus, both functional and genetic analyses reveal that KLF11 plays a role in the regulation of pancreatic beta cell physiology, and its variants may contribute to the development of diabetes.
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PMID:Role of transcription factor KLF11 and its diabetes-associated gene variants in pancreatic beta cell function. 1577 81

The enzyme catalase is the main regulator of hydrogen peroxide metabolism. Recent findings suggest that a low concentration of hydrogen peroxide may act as a messenger in some signalling pathways whereas high concentrations are toxic for many cells and cell components. Acatalasemia is a genetically heterogeneous condition with a worldwide distribution. Yet only two Japanese and three Hungarian syndrome-causing mutations have been reported. A large-scale (23 130 subjects) catalase screening program in Hungary yielded 12 hypocatalasemic families. The V family with four hypocatalasemics (60.6 +/- 7.6 MU/L) and six normocatalasemic (103.6 +/- 23.5 MU/L) members was examined to define the mutation causing the syndrome. Mutation screening yielded four novel polymorphisms. Of these, three intron sequence variations, namely G-->A at the nucleotide 60 position in intron 1, T-->A at position 11 in intron 2, and G-->T at position 31 in intron 12, are unlikely to be responsible for the decreased blood catalase activity. However, the novel G-->A mutation in exon 9 changes the essential amino acid Arg 354 to Cys 354 and may indeed be responsible for the decreased catalase activity. This inherited catalase deficiency, by inducing an increased hydrogen peroxide steady-state concentration in vivo, may be involved in the early manifestation of type 2 diabetes mellitus for the 35-year old proband.
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PMID:Detection of a novel familial catalase mutation (Hungarian type D) and the possible risk of inherited catalase deficiency for diabetes mellitus. 1580 Sep 61

The direct effect and the interaction of diabetic angiopathy and metabolic control on free radical and antioxidant activity indices was investigated in 48 patients with type 2 diabetes mellitus. Conjugated dienes (CD) and thiobarbituric acid-reacting substances (TBARS) levels were 34 and 178% of control values, respectively. An approximate two-fold decrease in plasma thiols (PSH) and erythrocyte lysate thiols (LSH) concentrations, parameters reflecting protein oxidative damage, was found. Impairment of blood antioxidant potential in diabetic patients was reflected by an 81% increase in superoxide dismutase (SOD) activity, a 30% decrease in catalase (CT), 20% decrease in glutathione peroxidase (GPx) and glutathione reductase (GR) activities as well as by lowered total antioxidant status (TAS). CD, TBARS and SOD values were positively correlated with plasma glucose concentration and glycated hemoglobin level. A negative correlation existed between levels of LSH, PSH, CT, GPx or TAS and both glucose and HbA(1c). Blood glucose control and vascular complications had strong independent effects on prooxidant-antioxidant status, apart from blood glucose and GR activity. In addition, glycemic control and diabetic vasculopathy interact in their influence on most of the free radical and antioxidant indices, except for CD, LSH levels and CT activity. Thus, we observed different mechanisms by which vascular complications and glucose control affect blood free radical indices and antioxidant status parameters in type 2 diabetic patients.
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PMID:Effects of metabolic control and vascular complications on indices of oxidative stress in type 2 diabetic patients. 1593 62

Increased oxidative stress might play an important role in the initiation and progression of diabetic complications. The present study has been undertaken to investigate whether there is any relationship between retinopathy degree and leukocyte superoxide dismutase (SOD) and catalase (CAT) activities and lipid peroxidation (LPO) in diabetic individuals with type 2 diabetic retinopathy. Patients were groupped with respect to the degree of retinopathy. Leukocyte malondialdehyde (MDA) levels, and SOD and CAT activities were measured in patients with type 2 diabetes mellitus (n=41) and nondiabetic healthy controls (n=23). Leukocyte LPO of the type 2 diabetic patients with retinopathy was significantly increased (p < 0.001), whereas SOD and CAT activities were decreased (p<0.001 and p<0.001, respectively) compared to those of controls. MDA concentrations rose while SOD and CAT activities fell with increasing severity of diabetic retinopathy, altough there was no significant difference in comprasion of the parameters mentioned above between the diabetic patients with and without retinopathy. Our results show that leukocytes in patients with type 2 diabetic retinopathy are affected by oxidative stress which might be contribute to pathogenesis of diabetic retinopathy. Prospective studies are needed to evaulate the relationship between the leukocyte antioxidants status and DR.
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PMID:Leukocyte lipid peroxidation, superoxide dismutase and catalase activities of type 2 diabetic patients with retinopathy. 1608 Mar 81

Melatonin, which is synthesized in the pineal gland and other tissues, has a variety of physiological, immunological, and biochemical functions. It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. Melatonin also reduces serum lipid levels in mammalian species, and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. This review will focus on the physiological and metabolic effects of melatonin and highlight its potential use for the treatment of cholesterol/lipid and carbohydrate disorders.
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PMID:Metabolic effects of melatonin on oxidative stress and diabetes mellitus. 1621 26

Oxidative stress has been defined as a loss of counterbalance between free radical or reactive oxygen species (ROS) production and antioxidant systems. It is involved in the pathogenesis of different chronic diseases. High levels of ROS production via different biochemical mechanisms accompany diseases like type 2 diabetes mellitus (DM) and end-stage renal disease (ESRD). Elevated oxidative status and reduced antioxidant defence systems in patients with DM and ESRD accelerate the prevalence of atherosclerosis and other chronic complications. Our aim was to reveal the effects of diabetes and haemodialysis (HD) separately and together on oxidative stress. In our study, we included 20 diabetic (DM) patients with no renal disease, 20 non-diabetic haemodialysis (HD), 20 diabetic haemodialysis (DHD) patients and 20 healthy volunteers. We have determined the levels of lipid peroxidation expressed as thiobarbituric acid-reactive substances (TBARS), oxidative protein damage as indicated by protein carbonyl (PCO) content and activities of antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSHPx) in all patient groups and healthy subjects. We found enhanced oxidative stress in all patient groups due to an increase in lipid peroxidation (TBARS) and increased oxidative protein damage in terms of PCO content and reduced activities of SOD, CAT and GSH-Px. Oxidative stress was more profound in diabetic patients undergoing haemodialysis. We conclude that both diabetes and dialysis increase oxidative stress and their combined effect on oxidative stress is the highest in magnitude as observed in diabetic patients undergoing haemodialysis.
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PMID:Effect of haemodialysis on the oxidative stress and antioxidants in diabetes mellitus. 1625 35

Post-translational modifications of lens proteins play a crucial role in the formation of cataract during ageing. The aim of our study was to analyze protein composition of the cataractous lenses by electrophoretic and high-performance liquid chromatographic (HPLC) methods. Samples were obtained after extracapsular cataract surgery performed by phacoemulsification technique from cataract patients with type 2 diabetes mellitus (DM CAT, n = 22) and cataract patients without diabetes (non-DM CAT, n = 20), while non-diabetic non-cataractous lenses obtained from cadaver eyes served as controls (CONTR, n = 17). Lens fragments were derived from the surgical medium by centrifugation. Samples were homogenized in a buffered medium containing protease inhibitor. Soluble and insoluble protein fractions were separated by centrifugation. The electrophoretic studies were performed according to Laemmli on equal amounts of proteins and were followed by silver intensification. Oxidized amino acid and Phe content of the samples were also analyzed by HPLC following acid hydrolysis of proteins. Our results showed that soluble proteins represented a significantly lower portion of the total protein content in cataractous lenses in comparison with the control group (CONTR, 71.25%; non-DM CAT, 32.00%; DM CAT, 33.15%; p < 0.05 vs CONTR for both). Among the proteins, the crystallin-like proteins with low-molecular weight can be found both in the soluble and insoluble fractions, and high-molecular weight aggregates were found mainly in the total homogenates. In our HPLC analysis, oxidatively modified derivatives of phenylalanine were detected in cataractous samples. We found higher levels of m-Tyr, o-Tyr and DOPA in the total homogenates of cataractous samples compared to the supernatants. In all three groups, the median Phe/protein ratio of the total homogenates was also higher than that of the supernatants (total homogenates vs supernatants, in the CONTR group 1102 vs 633 micromol/g, in the DM CAT group 1187 vs 382 micromol/g and in the non-DM CAT group 967 vs 252 micromol/g; p < 0.05 for all). In our study we found that oxidized amino acids accumulate in cataractous lenses, regardless of the origin of the cataract. The accumulation of the oxidized amino acids probably results from oxidation of Phe residues of the non-water soluble lens proteins. We found the presence of high-molecular weight protein aggregates in cataractous total homogenates, and a decrease of protein concentration in the water-soluble phase of cataractous lenses. The oxidation of lens proteins and the oxidative modification of Phe residues in key positions may lead to an altered interaction between protein and water molecules and thus contribute to lens opacification.
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PMID:Accumulation of the hydroxyl free radical markers meta-, ortho-tyrosine and DOPA in cataractous lenses is accompanied by a lower protein and phenylalanine content of the water-soluble phase. 1629 66


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