UMLS:C0011860 - FACTA Search

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Query: UMLS:C0011860 (type 2 diabetes)
57,723 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

Human serum paraoxonase (PON1) is located on high density lipoprotein and has been implicated in the detoxification of organophosphates and possibly in the prevention of low density lipoprotein lipid peroxidation. PON1 has two genetic polymorphisms both due to amino acid substitution, one involving glutamine (A genotype) and arginine (B genotype) at position 192 and the other leucine (L genotype) and methionine (M genotype) at position 55. We investigated the effect of these polymorphisms on serum PON1 activity and concentration in 252 non-insulin dependent diabetes mellitus (NIDDM) individuals and 282 non-diabetic controls. Serum PON1 activity in the controls (214.6 nmol/min per ml (26.3-620.8)) was significantly higher than in NIDDM (158.7 nmol/min per ml (3.6-550.5) (P < 0.001) as was serum PON1 concentration (89.1 microg/ml (16.8-527.4)) compared to 76.7 microg/ml (3.6-443.8) (P < 0.01). In the control population MM homozygotes had significantly lower serum PON1 activity regardless of the 192 polymorphism whereas in NIDDM both LM and MM genotypes had lower serum PON1 activity than LL homozygotes only when the 192 AA genotype was present. Serum PON1 concentration was lower in NIDDM with AA/LM, AA/LL, AB/LL and AB/MM genotypes than in controls. Differences in PON1 activity were the major cause of differences in specific activity between genotypes. Neither the PON1 55 or 192 polymorphisms consistently influenced the serum lipid or lipoprotein concentrations in either population. Low serum PON1 activity in NIDDM may be related to an increased tendency to lipid peroxidation and may also increase susceptibility to toxicity from organophosphate exposure. Our findings thus raise the possibility that PON1 may be of importance in both the genetic and acquired predisposition to premature atherosclerosis and neuropathy in diabetes.
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PMID:Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus. 971 41

The effect of heparin-induced extracorporal lipid precipitation (HELP) on the activities of paraoxonase (EC 3.1.8.1) and arylesterase (EC 3.1.1.2) was studied in serum of a patient with hyperlipoproteinaemia (A) and of a patient with non-insulin dependent diabetes mellitus and hyperlipoproteinaemia (B). The enzyme activities were measured spectrophotometrically (Tris-HCl buffer, pH 7.4, 37 degrees C) with paraoxon and phenylacetate as substrates of paraoxonase and arylesterase, respectively. Both patients underwent HELP applications once a week over a period of 7 weeks. Over that period no overall change was observed either in enzyme activities or in the lipid and protein content of the sera. However, each HELP session caused an immediate decrease of EDTA-insensitive arylesterase activity (on average 56% in A and 42% in B), while EDTA-sensitive arylesterase remained almost unaltered. Paraoxonase remained unchanged in A, but decreased in B (approximately 60%). Of the atherogenic lipoprotein parameters, the most pronounced decrease was found in VLDL-cholesterol and in triglycerides (on average 45% in A and 32% in B), while the anti-atherogenic HDL-cholesterol decreased < 10%. Possible implications of the effect of HELP on the enzyme activities studied remain to be explained.
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PMID:Paraoxonase and arylesterase activities in the serum of two hyperlipoproteinaemic patients after repeated extracorporal lipid precipitation. 1042 77

Human serum paraoxonase (PON1) is associated with high-density lipoprotein (HDL) and inhibits the oxidation of low-density lipoprotein (LDL) in vitro, suggesting that PON1 protects against atherosclerosis. We detected 3 polymorphisms of the PON1 gene and investigated PON1 enzyme activities as paraoxonase (PON), arylesterase (ARYL) and diazoxonase (DIAZ), and serum PON1 concentration in 106 patients with type 2 diabetes and 161 control subjects. All 3 enzyme activities and specific activities of PON1 in diabetic patients were significantly lower than those in controls, while there was no difference in serum PON1 concentration between the patient and control groups. The specific activities of PON, ARYL, and DIAZ in patients were 6.82 +/- 3.14 nmol x min(-1) x U(-1) (mean +/- SD, U; unit for serum PON1 concentration), 4.77 +/- 0.17 micromol x min(-1) x U(-1), and 193 +/- 92 nmol x min(-1) x U(-1), respectively, whereas those in controls were 9.33 +/- 3.92 nmol x min(-1) x U(-1), 5.36 +/- 0.14 micromol x min(-1) x U(-1), and 242 +/- 103 nmol x min(-1) x U(-1), respectively. There was no significant difference in the allelic frequencies of -108C/T, 55L/M, or 192Q/R between the patient and control groups. When each enzyme activity was compared between the patient and control groups in each genotype subgroup, all activities were lower in the patient group. The PON and ARYL activities were lower in patients with retinopathy or nephropathy than in those without such complications, and the ARYL activity was also lower in patients with neuropathy. In conclusion, all specific enzyme activities of PON1 were lower in patients with type 2 diabetes independent of the -108C/T, 55L/M, or 192Q/R polymorphism, and this impaired PON1 function may be involved in development of diabetic microangiopathy.
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PMID:Serum arylesterase/diazoxonase activity and genetic polymorphisms in patients with type 2 diabetes. 1109 1

The paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) in the blood and is low in patients with type 2 diabetes. Hormone-replacement therapy (HRT) can increase HDL cholesterol levels, but its effect on serum PON1 arylesterase activity is uncertain. The aim of the present study was to determine the effect of 6 months' HRT with conjugated equine estrogen and medroxyprogesterone acetate on serum PON1 arylesterase activity in postmenopausal women with type 2 diabetes. Serum PON1 activity was measured immediately before and at the end of the second arm of a randomized, placebo-controlled, crossover with washout study originally designed to test the effect of HRT on plasma lipids in diabetic postmenopausal women. Baseline serum PON1 arylesterase activity was significantly (P <.001) lower in the postmenopausal diabetic women (149 +/- 38 micromol/mL/min; n = 47) than values in healthy postmenopausal women (173 +/- 32 micromol/mL/min; n = 51). Serum PON1 activity increased (10%) significantly (P =.009) in diabetic women treated with HRT compared with placebo. A significant (P =.02) interaction between baseline PON1 activity and treatment indicated a greater increase in PON1 activity during HRT in women with lower baseline activities. At baseline, serum PON1 arylesterase activity was correlated significantly with plasma HDL cholesterol levels in diabetic women (r = 0.333, P =.01, n = 47), and the increase in serum PON1 activity was correlated significantly with the change in plasma HDL cholesterol during HRT (r = 0.659, P =.0001, n = 28). These data suggest that serum PON1 activity is abnormally low in postmenopausal women with type 2 diabetes and increases during HRT, particularly in women with lower baseline levels and in those who show a concomitant increase in HDL cholesterol.
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PMID:Hormone-replacement therapy increases serum paraoxonase arylesterase activity in diabetic postmenopausal women. 1123 Jul 85

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.
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PMID:HDL oxidability and its protective effect against LDL oxidation in Type 2 diabetic patients. 1134 63

Human serum paraoxonase (PON) is an antioxidative enzyme, which circulates on high-density lipoproteins and appears to use oxidized phospholipids as physiological substrates. PON M/L55 substitution changes the ability of PON to prevent lipid oxidation. Urinary 8-iso-PGF(2alpha) (one of F2 -isoprostanes) may represent a non-invasive in vivo index of free radical generation and we propose that PON might influence the biosynthesis of 8-iso-PGF(2alpha) in the vasculature. We studied the urinary excretion of 8-iso-PGF(2alpha) and related it to PON M/L55 genotypes in patients with type 2 diabetes mellitus (n = 55) and non-diabetic control subjects (n = 55). Urinary 8-iso-PGF(2alpha) was determined by competitive ELISA and the PON genotype by a PCR based restriction enzyme digestion method. LL homozygotes were compared to M-allele carriers (ML heterozygotes and MM homozygotes). The urinary excretion of 8-iso-PGF(2alpha) among non-diabetic non-smoking LL homozygotes was 3995.5 +/- 3352.8 ng/24-hour and among M-allele carriers 1689.8 +/- 1051.3 ng/24-hour (p = 0.017, ANCOVA; gender, hypertension, total cholesterol, triglycerides and LDL cholesterol as covariates). The excretion of 8-iso-PGF(2alpha), was increased in type 2 diabetes mellitus compared to non-diabetic control subjects. PON may thus protect against oxidative stress by destroying some biologically active lipids. Excretion of 8-iso-PGF(2alpha) is increased in type 2 diabetes, which may reflect oxidant injury.
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PMID:Lipid peroxidation is increased in paraoxonase L55 homozygotes compared with M-allele carriers. 1137 31

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.
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PMID:In vivo evidence for increased oxidation of circulating LDL in impaired glucose tolerance. 1235 54

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.
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PMID:Relationships between polymorphisms of the human serum paraoxonase gene and insulin sensitivity in Japanese patients with type 2 diabetes. 1270 15

The oxidative modification of low-density lipoprotein (LDL) plays a central role in the initiation and acceleration of atherosclerosis. Human serum paraoxonase (PON1) is associated with high-density lipoprotein (HDL) and has been shown to reduce the susceptibility of LDL to lipid peroxidation. We investigated whether circulating oxidized LDL (Ox-LDL) levels were associated with diabetic vascular complications, and whether the enzymatic activity and gene polymorphisms of PON1 influenced Ox-LDL concentrations in vivo. There was no difference in the plasma Ox-LDL concentrations between diabetic patients with and without macrovascular diseases. However, Ox-LDL concentrations corrected by LDL-cholesterol (OxLDL/LDL-C) or apolipoprotein B (apoB) concentrations (Ox-LDL/apoB), which probably reflect the proportion of oxidatively modified LDL to total LDL particles, were significantly higher in patients with macrovascular diseases than in those without. In addition, patients with peripheral neuropathy had a significantly higher Ox-LDL/apoB ratio than patients without this complication. The genotype TT of -108C/T polymorphism in the promoter region of the PON1 gene, which is associated with decreased PON1 expression, showed a significantly higher Ox-LDL/apoB ratio than genotypes TC or CC (TT: 0.60 +/- 0.15, CT + CC: 0.55 +/- 0.11, P =.02). Stepwise multiple regression analysis for Ox-LDL concentration revealed that the -108C/T polymorphism, subsequently to apoB concentration, was identified as a significant contributor. In summary, the Ox-LDL/apoB ratio was associated with macrovascular disease and peripheral neuropathy in Japanese patients with type 2 diabetes. Increased Ox-LDL/apoB may result, at least partly, from reduced serum antioxidant capacity in the diabetic state, including the attenuation of PON1 action. Increased Ox-LDL/apoB could be a significant marker for susceptibility to vascular complications in diabetic patients.
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PMID:Correlation of plasma oxidized low-density lipoprotein levels to vascular complications and human serum paraoxonase in patients with type 2 diabetes. 1501 40

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