Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Low density lipoprotein (LDL) oxidation is a crucial step in the atherosclerotic process. High density lipoprotein (HDL)-associated enzymes such as paraoxonase could exert a protective effect on LDL oxidation in the arterial wall, an effect which could be impaired in Type 2 diabetes mellitus (T2DM). We studied copper-induced oxidation in LDL and HDL isolated from 17 T2DM patients with fair glycaemic control and HDL-cholesterol within normal range and 17 healthy normolipidaemic control subjects. To evaluate the effect of HDL on LDL oxidation in diabetic and control subjects, we assessed copper-induced oxidation in HDL/LDL mixtures, with each lipoprotein isolated from the same subject. Relationships with HDL chemical composition, alpha-tocopherol content and serum paraoxonase activity were investigated. Oxidation was promoted by lipoprotein incubation with copper and then thiobarbituric acid reactive substances (TBARS), conjugated diene production and electrophoretic mobility in agarose gel were measured. In T2DM subjects HDL oxidation was higher than in controls. However, HDL from diabetics was as effective as control HDL to inhibit LDL oxidation. Neither HDL chemical composition nor serum paraoxonase activity showed any difference as compared to control subjects. In contrast, HDL from T2DM subjects showed a higher alpha-tocopherol content which positively correlated with HDL oxidability. Paraoxonase activity positively and strongly correlated with HDL inhibitory effect on LDL oxidation in patients and controls belonging to the heterozygous activity phenotype. Besides, LDL oxidability showed no differences between patients and controls. These results suggest that fairly-controlled T2DM patients with HDL-cholesterol levels within normal range show: 1) normal HDL ability to inhibit LDL oxidation related to normal paraoxonase activity; 2) higher HDL oxidability in spite of its high alpha-tocopherol content, which could favour tocopherol-mediated peroxidation and 3) normal LDL oxidability possibly due to the lack of significant lipoprotein structural alterations.
Diabetes Nutr Metab 2001 Feb
PMID:HDL oxidability and its protective effect against LDL oxidation in Type 2 diabetic patients. 1134 63

Oxidized LDL (oxLDL) is a key mediator in atherogenesis and a marker of coronary artery disease (CAD). Type 2 diabetes is associated with excessive cardiovascular morbidity and mortality. Because atherogenesis starts before diabetes is diagnosed, we investigated whether circulating oxLDL levels are increased in impaired glucose tolerance (IGT). OxLDL levels were measured in 376 subjects with normal glucose tolerance (NGT), 113 patients with IGT, and 54 patients with newly diagnosed type 2 diabetes. After correction for age and BMI, serum levels of oxLDL were significantly increased in IGT versus NGT subjects (P = 0.002). OxLDL levels were not associated with the following parameters of the oxidative/antioxidative balance in the blood: total antioxidant capacity, urate-to-allantoin ratio, and circulating phagocyte oxygenation activity. In stepwise multivariate analysis, LDL cholesterol (P < 0.0005) and triglycerides (P < 0.0005) were the strongest predictors of circulating oxLDL levels, followed by HDL cholesterol (P = 0.003), 2-h postchallenge C-peptide (P = 0.011), fasting free fatty acids (P = 0.013), and serum paraoxonase activity (P = 0.035). The strong correlation of oxLDL with LDL cholesterol and triglycerides indicates that LDL oxidation in IGT is preferentially associated with dyslipidemia. OxLDL increase may explain the high atherogenic potency of dyslipidemia in the prediabetic state.
Diabetes 2002 Oct
PMID:In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance. 1235 54

Several in vitro investigations showed that serum paraoxonase 1 (PON1) that is located on high-density lipoprotein reduces or prevents low-density lipoprotein (LDL) oxidation and therefore retards atherosclerosis. Accordingly, the well documented loss of PON1 activity in patients with overt diabetes mellitus was causally related to the development of micro- and macroangiopathy in the disease course. Because vascular complications start already in prediabetic states, e.g. impaired glucose tolerance (IGT), we investigated serum PON1 activities and circulating levels of oxidized LDL (oxLDL) in 125 IGT subjects, 75 patients with newly diagnosed diabetes mellitus type 2, and 403 individuals with normal glucose tolerance. Using three different substrates (paraoxon, phenylacetate, p-nitrophenylacetate) we found that PON1 activity is not significantly altered in IGT and diabetes mellitus subjects, respectively, when compared with normoglycemic controls. Both IGT subjects and diabetes mellitus patients had significantly increased levels of oxLDL in the circulation. However, serum PON1 activity variations and glutamine/arginine phenotype were not related to the levels of oxLDL. The data suggest that 1) PON1 activity loss is an event occurring later in the course of diabetes mellitus; and 2) PON1 does not affect oxidation of circulating LDL, at least in early diabetes mellitus.
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PMID:Lack of association between serum paraoxonase 1 activities and increased oxidized low-density lipoprotein levels in impaired glucose tolerance and newly diagnosed diabetes mellitus. 1267 62

Human serum paraoxonase (PON1), which is associated with HDL, is an esterase and has been shown to reduce the susceptibility of LDL to lipid peroxidation. The objective of the study was to determine whether genetic polymorphisms of the PON1 gene are associated with insulin sensitivity. Forty-eight Japanese patients with type 2 diabetes were recruited, and euglycemic hyperinsulinemic clamp was performed to assess insulin sensitivity. The PON1 promoter polymorphism C(-108)T was determined by direct sequencing, and the coding region polymorphism Q192R was determined by polymerase chain reaction and digestion of the amplified fragments. No association was observed between the Q192R polymorphism and the glucose infusion rate (GIR), whereas GIR increased with the following order of genotypes: -108TT < -108CT < and -108CC (4.2+/-1.6, 5.1+/-2.5, and 6.9+/-2.5 mg kg(-1) min(-1), respectively; P<0.02, ANCOVA). Stepwise regression analysis revealed that the C(-108)T polymorphism significantly contributed to the GIR. It has been reported that oxidative stress attenuates insulin signaling in vitro. The PON1 promoter polymorphism C(-108)T may influence insulin sensitivity by modulating serum antioxidant capacity.
Diabetes Res Clin Pract 2003 May
PMID:Relationships between polymorphisms of the human serum paraoxonase gene and insulin sensitivity in Japanese patients with type 2 diabetes. 1270 15

Human serum paraoxonase (PON1) has been implicated to play an important role in cardiovascular disease and diabetes. Studies in the literature indicate that PON1 has two different enzyme activities, i.e., esterase and hydroperoxide reducing activities. The objective of this study was to establish the importance of these two activities and to distinguish between them. As the addition of copper immediately inactivated the enzyme, we used auto-oxidation as the model system. Auto-oxidation of HDL resulted in more than 80% reduction of the esterolytic activity, which was protected by antioxidants, Vitamin E (50%) and PDTC (95%) and completely by 1 M glucose. In contrast, the hydroperoxide reducing activity, using unesterified hydroperoxides remained unaffected with time. We also used pNPHPODE (novel substrate) to establish that hydrolysis might be a prerequisite for the enzyme to act on the esterified hydroperoxide. The results indicated that the hydrolysis of the substrate was inhibited under oxidizing conditions with no reduction of the hydroperoxide. Overall, our findings suggest that protecting the esterolytic activity of PON1 by antioxidants might be important in preserving its action on phospholipid peroxides and a concerted reaction involving the esterolytic and hydroperoxide reducing activities might be suggested for the action of PON1.
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PMID:Oxidative inactivation of paraoxonase--implications in diabetes mellitus and atherosclerosis. 1611 60

The paraoxonase (PON) gene cluster maps to human chromosome 7q21-22. In the PON 1 gene, several polymorphisms in the promoter and coding regions have been identified and are known to influence gene expression levels. Promoter polymorphisms have been shown to have the strongest influence on paraoxonase activity levels. Paraoxonase, a high-density lipoprotein associated enzyme, protects lipoproteins from oxidation. Lipid oxidation may play an important role in the development of micro- and macrovascular disease. There is evidence that paraoxonase activity is reduced in patients with diabetes. We therefore hypothesise that PON 1genotypes influence paraoxonase activity levels and increase the risk of microvascular disease in type 1 diabetes. Genotyping of 156 Caucasian adolescents with diabetes for seven PON 1 polymorphisms was performed, including that of a novel PON 1 promoter polymorphism A(-1074)G. PON genotypes were related to paraoxonase and arylesterase activities and diabetes complication status. There was strong linkage disequilibrium between the PON 1 promoter polymorphisms. Both promoter and coding region polymorphisms strongly influenced activity levels and were associated with diabetes complications. PON 1 genotypes Leu/Leu 54, AA(-162) and GG(-1074) were associated with higher urinary albumin loss, while the genotype GG(-907) was protective for retinopathy.
J Diabetes Complications
PMID:Association between PON 1 polymorphisms, PON activity and diabetes complications. 1694 20

Human serum paraoxonase 1 (PON1) is associated with high-density lipoprotein and inhibits oxidative modification of low-density lipoprotein in vitro. Therefore, PON1 is expected to protect against atherosclerosis in vivo. We and other investigators have shown that PON1 enzymatic activity is decreased in diabetic patients; however, an alteration in hepatic PON1 synthesis under hyperglycemic conditions remains unclear. We previously demonstrated that Sp1 is a positive regulator of PON1 transcription and that an interaction between Sp1 and protein kinase C (PKC) is a crucial mechanism for the effect of Sp1 on PON1 transcription in cultured HepG2 cells. Because several PKC isoforms are activated under hyperglycemic conditions, we examined the effect of d-glucose, which can activate the diacylglycerol-PKC pathway, on the transcription and expression of PON1. For a reporter gene assay, Huh7 human hepatocyte cell line incorporated with PON1 (-1232/-6)-luciferase expression vector was established using a cationic lipid method. d-Glucose dose dependently enhanced PON1 promoter activity. d-Glucose also enhanced both messenger RNA and protein expression of PON1. Increased PON1 expression was also detected in primary human hepatocytes treated with high d-glucose concentrations. Bisindolylmaleimide, a PKC inhibitor, significantly inhibited d-glucose-induced transactivation of PON1; and mithramycin, an inhibitor of Sp1, completely abrogated the transactivation. Our data suggest that high glucose concentrations transactivate the PON1 gene through Sp1 activation by PKC in cultured hepatocytes. Up-regulated hepatic PON1 expression under high glucose conditions may be a compensatory mechanism in diabetes in which antioxidant capacity, including PON1 enzymatic activity, is attenuated.
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PMID:High glucose induces transactivation of the human paraoxonase 1 gene in hepatocytes. 1901 97

Paraoxonase 1 (PON1) is a high-density lipoprotein-associated enzyme that is believed to be involved in the protection against oxidative stress. There is evidence that paraoxonase activity is reduced in patients with diabetes and cataract. In the current study, we analyzed mRNA expression of PON1 as well as other members of the paraoxonase family, PON2 and PON3, in human cataractous lens samples. Our results indicate that only PON1 is expressed at the gene and protein levels in human lens tissues. We quantified MDA levels and measured PON1 (paraoxonase/arylesterase) enzymatic activities in subjects suffering from cataract due to aging and diabetes. Decreased PON1 activity was more pronounced in diabetic patients (p< 0.001) compared to senile subjects, which may be due to glycation and increased oxidative insult. To examine the structural alterations that occur in response to glycation, we constructed a three-dimensional model of PON1 and its glycated variant. Glycation at Lys70 and Lys75 is predicted to cause hindrance in binding of substrate to the active site of the enzyme.
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PMID:Expression and activity of paraoxonase 1 in human cataractous lens tissue. 1943 27

The aim of this study was to investigate the modulating effect of atorvastatin on serum paraoxonase 1 enzyme (PON1) activity in type 2 diabetic Egyptian patients with or without nephropathy. The present study was carried out on the following groups: control group, which consisted of 30 healthy persons; Group I, which consisted of 20 type 2 diabetic patients without nephropathy; and Group II, which consisted of 20 type 2 diabetic patients with nephropathy. All the patients selected were under an antidiabetic regimen of insulin, and patients receiving antihypertensive agents were excluded from the follow-up study to avoid drug interaction fallacies. Twenty-two patients (15 without nephropathy and seven with nephropathy) received atorvastatin in individually adjusted oral dosage (range 10-20 mg) once per day for 12 weeks. All cases were subjected to thorough clinical examination and history taking and measurement of serum levels of PON1 activity, malondialdehyde (MDA), glutathione reductase activity, fasting glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL), urea, and creatinine. Urine samples were collected for determination of proteinuria. The obtained results showed that PON1 activity and HDL significantly decreased and fasting glucose significantly increased in Group I and Group II when compared to the control group, with significant difference in their levels between Group II and Group I. MDA, total cholesterol, and LDL levels significantly increased and glutathione reductase activity significantly decreased in Group I and Group II when compared to the control group. Urea, creatinine, and proteinuria levels showed significant increase in Group II when compared to the control group and Group I, with nonsignificant difference between control group and Group I. Atorvastatin therapy caused a significant increase in PON1 activity, and serum levels of MDA and glutathione reductase activity were significantly decreased and increased, respectively. Also, total cholesterol, triglyceride and LDL-cholesterol levels were significantly reduced with a significant increase in HDL-cholesterol levels. There was a significant modest reduction in serum urea and creatinine levels as well as in proteinuria level. Fasting glucose level was significantly reduced under the antidiabetic regimen of insulin through the follow-up period. PON1 activity showed a significant negative correlation with glucose and LDL, and a significant positive correlation with HDL in all the studied groups. It could be concluded that atorvastatin with its pleiotropic effects could provide optimal therapeutic intervention to control not only dyslipidemia, but also oxidative stress status with consequent improvement in the course of type 2 diabetes and diabetic nephropathy. More specifically, restoration of PON1 activity by atorvastatin opens a window to investigate other drugs that could provide a new adjuvant therapeutic line for better control of diabetes and diabetic nephropathy. Further research is also recommended to study the distribution of PON1 genetic polymorphism among the Egyptian population to explain the variability in its activity and its relationship with other factors that associate diabetes and its complications.
J Diabetes Complications
PMID:Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy. 1955 42

The aim of the present study is to evaluate the extent of DNA damage in diabetes and metabolic syndrome and to assess the variations after supplementation with antioxidants. We used comet assay to measure DNA damage in freshly isolated lymphocytes from a total of 12 rabbits, distributed into four experimental groups (n = 3 rabbits per group): non-diabetic (control, G1), diabetic (G2), diabetic supplemented with vitamin C (G3), and diabetic supplemented with vitamin E (G4). Also their serum was isolated for estimation of parameters that contribute to metabolic syndrome. Malondialdehyde (MDA), the marker of oxidative stress was also assessed. Mean values of DNA damage (tail length, expressed as mum), lipid peroxidation and concentration of blood glucose, MDA, C-reactive protein, and triglycerides were higher in G2; whereas the mean values of concentration of high-density lipoprotein, serum paraoxonase-1 activity and small dense low-density lipoprotein oxidation time were reduced in G2 followed by G3, G4, and G1. A significant positive correlation was observed between the DNA damage and elevated parameters of metabolic syndrome (r = 0.66, 0.96, 0.89, 0.75, 0.88, 0.92, 0.99, P < 0.05) and a significant negative correlation (r = -0.91, -0.75, -0.98, P < 0.05) was found between the DNA damage and declined parameters of metabolic syndrome. These data indicate that the extent of DNA damage is more in diabetic rabbits as compared to the non-diabetic or antioxidant supplemented group. Abnormal metabolic parameters and their correlation with DNA damage, suggest the risk of development of metabolic syndrome in diabetic group but a possibility of repression by antioxidants because of their ability to counteract oxidative stress.
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PMID:Evaluation of DNA damage and metabolic syndrome parameters in diabetic rabbits supplemented with antioxidants. 1964 14


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