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)

Paraoxonase (PON) is an antioxidative enzyme, which eliminates lipid peroxides. PON has two common polymorphisms (M/L55 and R/Q192) that influence PON concentration and activity. We studied whether the M/L55 or R/Q192 genotype relates with the severity of atherosclerosis of the abdominal aorta, and the mesenteric and common iliac arteries in 123 consecutive autopsy cases (90 males and 33 females, aged 18-93 years). The severity of atherosclerosis in the arteries was evaluated, and the percentage of stenosis was measured. The intimal thickness in the internal elastic lamina (IEL) of the coeliac (CA), superior mesenteric (SMA) and inferior mesenteric (IMA) arteries were measured by light-microscopy. The LL homozygous men had more atherosclerotic plaques and complicated lesions in the common iliac arteries (56.8%) than the M allele carriers (28.3%, P=0.007). In logistic regression analysis, age (P<0.001) and the PON M/L55 genotype (P=0.015) were associated significantly with the severity of atherosclerosis in the common iliac arteries independent of smoking status, R/Q192 genotype, hypertension, diabetes mellitus, BMI and sex. The mean intima of the IMA was significantly thicker (P=0.035) and the number of stenotic lesions in SMAs significantly higher (P=0.008) in the LL homozygous men than M allele carriers. In turn, the R/Q192 genotype was not statistically significantly associated with plaque type, intimal thickness in the IEL or with the number of stenotic lesions. This study demonstrates that PON L55 homozygosity is an independent risk factor for autopsy-verified atherosclerosis in Finns.
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PMID:Paraoxonase producing PON1 gene M/L55 polymorphism is related to autopsy-verified artery-wall atherosclerosis. 1147 29

In vivo supplementation studies of the antioxidant alpha-tocopherol in human Type II diabetes have used surrogate, rather than direct, markers of oxidative damage/antioxidant protection and have used higher doses of alpha-tocopherol than used in coronary secondary prevention trials. We tested the hypothesis that oral alpha-tocopherol in a dosage regimen used in secondary prevention trials would reduce directly observed oxidatively induced single-strand breaks in lymphocyte DNA in Type II diabetes. We studied 40 people with Type II diabetes and 30 controls in a randomized, double-blind, placebo-controlled trial of 400 i.u. of oral alpha-tocopherol daily for 8 weeks. Lymphocyte DNA single-strand breaks and low-density lipoprotein (LDL) particle size and oxidizability were measured at baseline, after 8 weeks, and after 4 weeks washout. Polymorphisms in the gene for the antioxidant enzyme paraoxonase-1 gene (position 192) were measured. The diabetics had increased DNA oxidative susceptibility (P=0.008), without increased LDL oxidative susceptibility. There was a direct relationship between DNA oxidative susceptibility and baseline plasma alpha-tocopherol in the diabetes group alone (r=0.421, r(2)=0.177 and P=0.023), but DNA and LDL oxidative susceptibility were not influenced by alpha-tocopherol supplementation in either group in this regimen. Paraoxonase-1 gene polymorphisms did not contribute to LDL or DNA oxidative susceptibility or response to alpha-tocopherol. Increased DNA oxidative susceptibility, therefore, can occur in Type II diabetes without increased LDL oxidative susceptibility, but alpha-tocopherol supplementation in this regimen has no influence on DNA or LDL oxidative susceptibility in Type II diabetes or controls. Polymorphisms in the paraoxonase gene (position 192) are not associated with differences in oxidative susceptibility or responses to alpha-tocopherol.
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PMID:Increased DNA oxidative susceptibility without increased plasma LDL oxidizability in Type II diabetes: effects of alpha-tocopherol supplementation. 1152 40

Paraoxonase (PON) is structurally associated with the high-density lipoprotein fraction of serum, suggesting a role for this enzyme in lipoprotein metabolism. In Chinese Singaporeans, triglycerides (TG) had significant positive correlation with PON but high-density lipoprotein cholesterol (HDL-C) did not. Our paper investigates the influence of PON on serum lipids under controlling confounding factors in Taiwanese. Blood samples and questionnaires were collected from 476 Taiwanese with no participant excluded for any reason. Cases were examined for biochemistry, PON, TG, cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and HDL-C. PON phenotypes were determined by Hardy-Weinberg equilibrium. We compared median differences in PON, TG, TC, HDL-C and LDL-C between genders by means of the Wilcoxon Rank Sums test. Relationships among PON, TG, TC, HDL-C and LDL-C were represented by Pearson's correlation. A rank multiple regression analysis was also used to analyze the association between PON, TG, TC, HDL-C and LDL-C adjusted for age, gender and diabetes mellitus, since no uremia, acute myocardial infarction or peripheral neuropathy was present in our cases. Median TG and LDL-C were higher in males than in females, but median HDL-C was higher in females. For women and the total group, TC and HDL-C showed a significant positive correlation with PON. Only HDL-C showed a positive correlation with PON adjusted for age, gender and diabetes mellitus. PON is influenced by many confounding factors. Only after adjusting for the confounding factors in this study, HDL-C is positively correlated to PON like the structural relationship.
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PMID:Relationship of paraoxonase and serum lipids in Taiwan. 1214 27

Paraoxonase (PON1) is an antioxidant enzyme closely associated with high-density lipoproteins. Low PON1 has been shown in oxidative stress-associated processes such as dyslipidemia, diabetes mellitus, advancing age, and smoking. Indeed, oxidative stress is related to the degree of insulin resistance, a key component of the metabolic syndrome. Therefore, the possible relationship between PON1 activity and the metabolic syndrome was investigated. From 1364 randomly recruited subjects, 285 were found to have the metabolic syndrome, according to the guidelines published by the National Cholesterol Education Program, Adult Treatment Panel III. PON1 activity, lipid peroxides, and PON1 codon 192 genotypes, which strongly modulate PON1 activity, were determined. Serum PON1 activity levels were found to be significantly lower, and lipid peroxide concentrations significantly higher, in subjects with the metabolic syndrome compared with unaffected subjects (P = 0.033 and < 0.001, respectively). Study subjects showed a significant decreasing trend in PON1 activity levels and a significant increasing trend in lipid peroxide concentrations, with the increase in the number of metabolic disturbances. No differences in the prevalence of PON1 codon 192 genotypes were found among the categories of metabolic abnormalities. In conclusion, a greater degree of severity of the metabolic syndrome is associated with a progressively worse antioxidant/oxidant balance, which is consistent with increased oxidative stress and lower antioxidant PON1 enzymatic capacity.
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PMID:Antioxidant paraoxonase 1 activity in the metabolic syndrome. 1460 83

The high incidence of atherosclerosis in women after menopause is associated with a risk pattern including an increase in low density lipoprotein (LDL), even though high density lipoprotein (HDL) cholesterol levels tend to be maintained or slightly decreased. Since estrogens are considered potent antioxidants, an increase in lipid peroxidation and formation of reactive oxygen species would be expected after menopause. If HDL becomes oxidized, the ability to protect LDL against oxidation may be impaired. In postmenopausal women there are scarce reports concerning HDL oxidability and no data about its antioxidant activity. We studied copper-induced oxidation and conjugated dienes formation in HDL isolated from 58 women, 30 postmenopausal (PMW) and 28 premenopausal (PreMW). None presented diabetes or cardiovascular disease and none was receiving hormonal, hypolipidemic or antioxidant therapy either. In order to evaluate the effect of HDL on LDL oxidation we isolated LDL and HDL from the same subject and assessed copper-induced LDL oxidation in the presence of HDL, followed by thiobarbituric acid-reactive substances determination. Relationships with HDL chemical composition, alpha-tocopherol content, cholesteryl ester transfer protein (CETP) and paraoxonase activity (PON) were investigated. HDL chemical composition in PMW exhibited triglyceride enrichment when compared to PreMW (p <0.05). alpha-Tocopherol content and CETP activity were similar in both groups. However, CETP activity correlated positively with HDL triglyceride and negatively with HDL cholesterol percentage (r=0.44, p <0.01 and r=-0.32, p <0.05, respectively). Paraoxonase activity did not show differences between PMW and PreMW. When evaluating HDL oxidability, PMW revealed a shorter lag time in comparison to PreMW, even after adjustment for age, p <0.05. Moreover, when the effect of HDL on LDL oxidation was evaluated, HDL from PMW showed a reduction in its ability to inhibit LDL oxidation, compared to PreMW (p <0.05). In addition, the extent of inhibition of LDL oxidation by HDL was positively correlated with HDL resistance to oxidation (r=0.27, p <0.05). After women classification by paraoxonase phenotype, HDL ability to protect LDL against oxidation remained reduced only in PMW belonging to the PON QR phenotype, in comparison to PreMW QR. These results suggest that HDL from PMW exhibits impairment in its antioxidant ability, which is associated to a decreased HDL resistance to oxidation. In turn, this was related to triglyceride enrichment of HDL particles. All these alterations were independent from HDL cholesterol plasma levels.
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PMID:Impaired high density lipoprotein antioxidant activity in healthy postmenopausal women. 1548 85

Atherosclerotic risk is increased in diabetes partly because of increased plasma levels of the oxidized low-density lipoprotein and homocysteine, 2 independent and important cardiovascular disease (CVD) risk factors. Paraoxonase (PON) is a multifunctional antioxidant enzyme component of high-density lipoprotein (HDL), which can protect against low-density lipoprotein (LDL) oxidation. It also exhibits homocysteine thiolactonase (HCTL) activity that detoxifies homocysteine thiolactone, which can damage proteins by homocysteinylation of the lysine residues, thus leading to atherosclerosis. We conducted a cross-sectional study to correlate PON-1, HCTL activities, and the lag time of LDL oxidation in 15 healthy control subjects and in 55 subjects with type 2 diabetes mellitus with different degrees of CVD. Compared with healthy controls and diabetic subjects without evidence of overt CVD, we not only found 47% (P < .005) decrease in PON-1 activity, but also for the first time, 30% (P = .019) decrease in HCTL activity in subjects with a prior coronary artery bypass surgery. There was corresponding decreased effectiveness of HDLs from diabetic groups (with and without CVD) in protecting against LDL oxidation. Moreover, the PON-1 activity was significantly inversely correlated to the extent of intracoronary lesions determined at catheterization (ie, a high Gensini score). These decreases in PON-1 and HCTL activity were not due to any bias in preferential distribution of low-activity QQ homozygotes in the diabetic groups compared with the control group because QQ allele was equally distributed in all the experimental groups, whereas RR allele tended to increase in the diabetic subjects with coronary artery bypass surgery compared with the other groups. Therefore, clinical intervention to restore the impaired antiatherogenic activities of HDL should be considered an important goal in the treatment of persons with diabetes.
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PMID:Inverse correlation of serum paraoxonase and homocysteine thiolactonase activities and antioxidant capacity of high-density lipoprotein with the severity of cardiovascular disease in persons with type 2 diabetes mellitus. 1691 39

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

Increased coronary artery disease (CAD) risk is well established in diabetes mellitus (DM). Paraoxonase (PON) enzyme is known to have protective effects on lipid peroxidation. This study aimed to investigate the changes in PON activity levels with duration of DM as well as the role of PON activity in progression of CAD. Eighty-four consecutive diabetic patients (mean age 58 years, 46 men) who underwent coronary angiography for diagnostic purposes were examined. Before the angiography, fasting venous blood samples were taken for PON enzyme activity, thiobarbituric acid reactive substances (TBARS), and routine biochemical parameters. Severity and extent of coronary atherosclerosis were scored numerically using the Gensini scoring system. The population was divided into three groups according to Gensini score: Group 1, mild CAD; Group 2, moderate CAD; Group 3, severe CAD. Group 1 had higher PON levels and shorter DM duration than those of Group 3. Gensini score was significantly correlated with, PON activity (r = -0.361) and apo-AI (r = -0.375). TBARS (r = -0.290) and the duration of DM (r = -0.336) also showed a significant correlation with PON activity levels. Also, multivariate linear regression and Pearson correlation analyses showed that PON activity (P = 0.04), apo-AI levels (P = 0.01), and the duration of DM (P = 0.003) were significantly associated with Gensini score. Paraoxonase activity decreases parallel to DM duration. The lack of protective effect of PON enzyme on lipid peroxidation may be a factor in acceleration of CAD in DM.
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PMID:The role of paraoxonase (PON) enzyme in the extent and severity of the coronary artery disease in type-2 diabetic patients. 1753 19

Paraoxonase (PON1) is a high-density lipoprotein (HDL)-associated enzyme that protects low-density lipoprotein (LDL) and HDL from peroxidation. In this study, PON1 activities were determined in patients with erectile dysfunction (ED) to investigate the relationship between ED and atherosclerosis. Forty patients, who had been diagnosed with ED by the medical and sexual anamnesis and routine laboratory tests, were included in the study. Thirty healthy, sexually active, married and age-matched men were selected as the control group. The patients and controls who underwent surgical or medical treatment in 1-week time and had a systemic disease such as malignancy, liver and renal insufficiency, and active infection and who smoked cigarettes were excluded. PON1 activities were measured spectrophotometrically. Unpaired samples t-test, correlation analyses and multiple linear regression analyses were used for statistical analyses. The results are given as mean+/-standard deviation of mean. The mean ages of the patient and the control groups were 31.05+/-6.90 (range 22-51) and 29.40+/-6.26 (range 19-46), respectively (P=0.307). Serum PON1 levels of the patient and the control groups were found to be 119.05+/-62.11 and 185.04+/-55.64, respectively. The difference between the groups was quite significant (P=0.001). Epidemiological and experimental studies indicate that PON1 activation was lower in individuals who had a tendency to develop atherosclerosis due to comorbidities such as diabetes, familial hypercholesterolemia and kidney disease. In this study, PON1 activity level was found to be significantly lower in ED patients than in control group. The decrease of PON1 activity may have a role in the ethiopathogenesis of ED, and the atherosclerosis development may be faster in the patients due to decreased activity of PON1, which is an antiatherogenic enzyme.
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PMID:Paraoxonase activity in patients with erectile dysfunction. 1778 55

The present study was designed to investigate the relationship between the serum levels of oxidant-antioxidant system (malondialdehyde (MDA) level, Paraoxonase (PON1) activity, nitric oxide (NO) level and superoxide dismutase (SOD) activity) and thyroid hormone status in hypothyroidism pre and posttreatment. The study group comprised 33 patients with primary hypothyroidism. 18 of these patients were reevaluated after euthyroid state i.e. at least 6 months of thyroxine replacement. The patients were compared with 26 normal healthy controls. Serum MDA level, PON1 activity, NO level and SOD activity were measured according to an enzymatic spectrophotometric method. MDA levels were found higher in patients with hypothyroidism before the treatment than the controls. MDA levels were also found to be decreased after the treatment in patients with hypothyroidism. However MDA were found still higher than the controls after the treatment. PON1 activity was found to be lower in patients pretreatment when compared to posttreatment hypothyroidism and controls. Posttreatment of hypothyroidism mean PON1 activity significantly increased compared to pretreatment level but it was still significantly lower than control level. NO level was higher in pretreatment hypothyroidism when compared to controls. SOD activity was not found different in patients before treatment when compared to controls. SOD activity was significantly higher in after treatment when compared to both pretreatment and control levels. In conclusion, increased ROS levels in hypothyroidism may result in a pro-oxidation environment, which in turn could result in decreased antioxidant PON1 activity, increased MDA and NO levels. As a result, lipid peroxidation may have a role in the pathogenesis of the atherosclerosis in hypothyroidism.
Exp Clin Endocrinol Diabetes 2007 Sep
PMID:Oxidative stress and enzymatic antioxidant status in patients with hypothyroidism before and after treatment. 1785 36


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