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)

Human serum paraoxonase is physically associated with HDL and has been implicated in the detoxification of organophosphates and possibly in the prevention of LDL lipid peroxidation. We investigated the serum activity and concentration of paraoxonase in 78 patients with type 1 diabetes mellitus, 92 with type 2 diabetes, and 82 nondiabetic control subjects. Paraoxonase activity was generally lower in diabetics than in control subjects. This decrease was unrelated to differences in paraoxonase phenotype distribution or its serum concentration. Rather, the difference in paraoxonase activity was explained by its specific activity, which was lower in diabetics, indicating either the presence of a circulating inhibitor or disturbance of the interaction of paraoxonase with HDL affecting its activity. Paraoxonase specific activity was lowest in patients with peripheral neuropathy, suggesting an association of paraoxonase with neuropathy. In control subjects but not patients with diabetes, paraoxonase correlated with HDL cholesterol and apolipoprotein A-1. Our results indicate that the low paraoxonase activity in diabetes is due to decreased specific activity. In other studies low serum paraoxonase activity has been associated with increased susceptibility to atherosclerosis, and the present results also suggest an association with peripheral neuropathy, which could be due to reduced capacity to detoxify lipid peroxides in diabetes.
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PMID:Serum paraoxonase activity, concentration, and phenotype distribution in diabetes mellitus and its relationship to serum lipids and lipoproteins. 758 60

We investigated the association of paraoxonase (PON) gene polymorphism with both the occurrence of coronary heart disease (CHD) and the severity of coronary artery stenosis in Japanese subjects. PON is a protein associated with plasma HDL. It has been hypothesized an A/B (Gln 192-->Arg) polymorphism of PON may be involved in the pathogenesis of CHD, especially among subjects with non-insulin-dependent diabetes mellitus (NIDDM). The polymorphism was determined in 134 patients with myocardial infarction (MI) or angina pectoris, and in 252 healthy subjects as controls. The frequencies of the AA, AB, and BB genotypes in the patients were 15, 50 and 35%, respectively, and these frequencies did not differ from those in control subjects (14, 49, and 37%). The relative risk of CHD was not found to be associated with these genotypes. These data also were similar among selected subgroups (patients with MIs, those with a low-risk lipoprotein profile for CHD, and those with NIDDM). Neither the number of affected vessels nor Gensini's scores differed among the genotype groups. Our case-control study in Japanese subjects did not show that the PON A/B polymorphism is associated with a risk of CHD.
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PMID:Paraoxonase gene polymorphism in Japanese subjects with coronary heart disease. 896 Sep 46

Epidemiological, population and familial studies have revealed the multifactorial aspect of diabetes mellitus. Several mutations implicated in the pathogenesis of diabetes have been described over the last decade. These mutations are localised within genes associated with glucose metabolism, providing a molecular basis for the heterogeneity in the clinical presentation of diabetes mellitus. However, chronic hyperglycaemia associated with other vascular risk factors can only partly explain the incidence of micro and macrovascular complications. Familial studies have revealed the presence of a familial susceptibility for some vascular complications as nephropathy and coronary heart disease. In addition, these two vascular complications of diabetes mellitus are frequently associated in the same individual. This familial susceptibility could not be exclusively explained by environmental factors. Consequently the quest for susceptibility genes of vascular complications appears as a logical approach. The study of genes associated with an increased cardiovascular risk like the renin angiotensin system, the hemostasis cascade or the lipoproteins, may constitute the first step in this new research avenue. Moreover, glycation and oxidation pathways seem to play a role in the development of vascular complications. For example, the paraoxonase genes are good candidates for an increased vascular risk. This enzyme is entirely bound to HDL-cholesterol and could explain its anti-oxidant capacity. The natural substrate of this enzyme is unknown but there is some evidence suggesting that it may participate in the oxidated phospholipids degradation. Functional studies of paraoxonase with other exogenous substrates have revealed different phenotypes associated with different catalytic activities. In addition, varying enzymatic activities seem to be associated with different polymorphisms of the paraoxonase gene recently described (at position 192 and 55 of the paraoxonase gene), and these two polymorphisms have been recently studied in relation with coronary heart disease in non insulin dependent diabetic patients. The two polymorphisms were associated with coronary heart disease. But these initial results still await confirmation in different populations. Such studies will likely open the way to novel approach of vascular complications in diabetes mellitus.
Diabetes Metab 1997 Mar
PMID:Diabetes mellitus and the late complications: influence of the genetic factors. 910 85

We have examined the effects of mildly oxidized LDL and atherosclerosis on the levels of two proteins associated with HDL; apolipoprotein J (apoJ), and paraoxonase (PON). On an atherogenic diet, PON activity decreased by 52%, and apoJ levels increased 2.8-fold in fatty streak susceptible mice, C57BL/6J (BL/6), but not in fatty streak resistant mice, C3H/HeJ (C3H). Plasma PON activity was also significantly decreased, and apoJ levels were markedly increased in apolipoprotein E knockout mice on the chow diet, resulting in a 9.2-fold increase in the apoJ/PON ratio as compared to controls. Furthermore, a dramatic increase in the apoJ/PON ratio (over 100-fold) was observed in LDL receptor knockout mice when they were fed a 0.15%-cholesterol-enriched diet. Injection of mildly oxidized LDL (but not native LDL) into BL/6 mice (but not in C3H mice) on a chow diet resulted in a 59% decrease in PON activity (P < 0.01) and a 3.6-fold increase in apoJ levels (P < 0.01). When an acute phase reaction was induced in rabbits, or the rabbits were placed on an atherogenic diet, hepatic mRNA for apoJ was increased by 2.7-fold and 2.8-fold, respectively. Treatment of HepG2 cells in culture with mildly oxidized LDL (but not native LDL) resulted in reduced mRNA levels for PON (3.0-fold decrease) and increased mRNA levels for apoJ (2.0-fold increase). In normolipidemic patients with angiographically documented coronary artery disease who did not have diabetes and were not on lipid-lowering medication (n = 14), the total cholesterol/HDL cholesterol ratio was 3.1+/-0.9 as compared to 2.9+/-0.4 in the controls (n = 19). This difference was not statistically significant. In contrast, the apoJ/PON ratio was 3.0+/-0.4 in the patients compared to 0.72+/-0.2 in the controls (P < 0.009). In a subset of these normolipidemic patients (n = 5), the PON activity was low (48+/-6.6 versus 98+/-17 U/ml for controls; P < 0.009), despite similar normal HDL levels, and the HDL from these patients failed to protect against LDL oxidation in co-cultures of human artery wall cells. We conclude that: (a) mildly oxidized LDL can induce an increased apoJ/PON ratio, and (b) the apoJ/PON ratio may prove to be a better predictor of atherosclerosis than the total cholesterol/HDL cholesterol ratio.
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PMID:Mildly oxidized LDL induces an increased apolipoprotein J/paraoxonase ratio. 910 46

Serum paraoxonase/arylesterase (PONA) is associated with high-density lipoprotein and may prevent oxidation of low-density lipoprotein by hydrolyzing lipid peroxides. A recent report suggested an association of glutamine (A type)/arginine (B type) polymorphism at position 192 of PONA gene with coronary heart disease (CHD) among Caucasian patients with noninsulin-dependent diabetes mellitus (NIDDM). However, conflicting results have also been reported. To investigate the significance of this polymorphism in the pathogenesis of CHD, we performed an association study of this polymorphism with CHD in Japanese NIDDM patients. We genotyped 164 patients with NIDDM, 42 with CHD, and 122 without CHD. Other known risk factors for CHD were matched between the 2 groups. AB+BB isoforms were detected in 41 of 42 diabetic patients with CHD. The proportion of B allele carriers (AB+BB) was significantly higher than that of AA carriers among diabetic patients with CHD compared with those without CHD (chi 2 = 7.68, P = 0.003). Multivariate logistic regression analyses showed a markedly increased odds ratio (OR: 8.823, CI, 1.13-68.7) in B allele carriers, while ORs of other risk factors remained between 1.01 and 1.92. Carriers of the B allele of the Gln192Arg polymorphism in the PONA gene proved to be at increased risk for developing CHD in Japanese NIDDM patients. This association was independent of other known risk factors for CHD, suggesting an important role of the paraoxonase B isoform in the pathogenesis of CHD.
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PMID:Paraoxonase polymorphism (Gln192-Arg) is associated with coronary heart disease in Japanese noninsulin-dependent diabetes mellitus. 921 3

The human serum paraoxonase (PON) in one of the enzymes showing pharmacogenetic polymorphism. According to our present knowledge the enzyme inhibits the lipidperoxydation and through its effect on the lipid metabolism or another pathogenetic mechanism may take part in the pathogenesis of diabetes mellitus and ishaemic heart disease.
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PMID:[Polymorphism and clinical significance of human paraoxonase enzyme]. 930 97

Defining the genetic determinants of NIDDM requires evidence from several complementary approaches, including both linkage and association analyses using both discrete phenotypes and intermediate quantitative traits. We tested for association between common genomic variation in three genes that map to chromosome 7q21-q22 and quantitative traits related to NIDDM in a sample of Oji-Cree. We found that a common genomic variation in codon 148 (alanine or glycine) of the paraoxonase-2 gene (PON2) demonstrated a significant association with a variation in fasting plasma glucose (P < 0.0001). Furthermore, we found a significant association between a variation in fasting plasma glucose and the interaction term comprised of a PON2 codon 148 genetic variation and the presence of noninsulin-dependent diabetes mellitus (NIDDM; P < 0.0001). We then analyzed subjects according to PON2 genotype and NIDDM status. In subjects with NIDDM, the PON2 codon 148 G/G homozygotes had significantly higher mean fasting plasma glucose than subjects with the other two genotypes (P < 0.0001). However, in non-NIDDM subjects, there was no difference in mean fasting plasma glucose among any of the genotypes. There was no association of the PON2 genotype with NIDDM itself, with impaired glucose tolerance, or with other quantitative traits related to NIDDM in this sample. These findings suggest that 1) the PON2 G148 gene variant worsens glycemia in subjects with NIDDM; 2) defining the physiological role of the PON2 gene product would be worthwhile; and 3) genetic factors can modify the severity of clinical phenotypes in subjects with NIDDM.
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PMID:Paraoxonase-2 gene (PON2) G148 variant associated with elevated fasting plasma glucose in noninsulin-dependent diabetes mellitus. 932 71

We investigated the serum paraoxonase (PON) activity and genotype distribution in 139 patients with non-insulin-dependent diabetes mellitus and in 240 control subjects in a Japanese population. There were no significant differences in PON genotype frequencies between the diabetic and control subjects, but the PON activity was significantly less in diabetic subjects (p<0.01). PON activity was significantly related to levels of total cholesterol and high density lipoprotein (HDL) cholesterol in the control subjects, but not in the diabetic subjects. In diabetic subjects with the genotype AA, the mean maximum intimal-medial thickness (IMT) of the carotid artery was significantly greater than in subjects with genotype AB or BB. PON may play an important role in the development of atherosclerosis associated with diabetes mellitus.
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PMID:Serum paraoxonase activity and genotype distribution in Japanese patients with diabetes mellitus. 971 83

Paraoxonase is an esterase that hydrolyzes organophosphate compounds. The enzyme is associated with HDL and could protect LDL against peroxidation, which suggests a possible involvement of paraoxonase in the antiatherogenic properties of HDL. Paraoxonase activity has been shown to be low in patients with myocardial infarction, diabetes mellitus, or familial hypercholesterolemia. Because cardiovascular disease is the main cause of death in chronic renal failure, serum paraoxonase activity was measured by spectrophotometry using three synthetic substrates (phenyl acetate, paraoxon, and 4-nitrophenyl acetate) in 305 patients with kidney disease, including 47 patients with non-end-stage chronic renal failure, 104 patients treated with hemodialysis, 22 patients treated with peritoneal dialysis, and 132 renal transplant patients. Patients were compared with two groups of aged-matched control subjects (total number = 195). Especially with 4-nitrophenyl acetate, paraoxonase activity was lower in patients with some degree of renal insufficiency (chronic renal failure [P < 0.05], chronic hemodialysis [P < 10(-4)], chronic peritoneal dialysis [P < 10(-4)]) than in control subjects. In transplant patients, paraoxonase activity was not found to be different from that in control subjects. The decrease of paraoxonase activity and thus the reduction of its antiatherogenic properties in renal failure could be an essential factor of premature vascular aging, especially when dialysis is used. Renal transplantation seems to restore paraoxonase activity.
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PMID:Decrease of serum paraoxonase activity in chronic renal failure. 980 94

The human serum HDL-linked paraoxonase enzyme limits the LDL peroxidation by preventing transformation of LDL into biologically active atherogenic particles. Paraoxonase serum activity varies among individuals due to an Gln/Arg polymorphism with low (A phenotype) and high activity (B phenotype). The present study correlates the paraoxonase enzyme activity and the paraoxonase gene polymorphism among 200 Indians with or without coronary artery disease (CAD). We analyzed the PON enzyme activity and have identified A and B phenotypes by Alwl restriction mapping. In 120 CAD patients, the genotypes A and B constituted 75 and 25%, where as in 80 control subjects, the genotypes A and B constituted 25 and 17%, respectively. The frequency of AB genotype is higher in CAD subjects with or without diabetes, than in controls. Arg allele frequency was higher (0.45) in CAD subjects than in controls (0.17). The conventional risk factors and the family history of CAD did not affect the genotype frequency distribution among Indians. In conclusion, paraoxonase polymorphism may have been involved in the predisposition to CAD through a mechanism other than lipid oxidation.
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PMID:Paraoxonase gene polymorphism and coronary artery disease in Indian subjects. 982 30


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