These findings suggest that abnormal glucose tolerance, which is a predisposing factor for diabetes mellitus, does not appear to be a risk indicator for periodontal disease. On the other hand, impaired lipid metabolism does seem to be a risk indicator for periodontitis.

Objective. Human urate transporter 1 (hURAT1) is a member of the organic anion transporter family (SLC22A12) that mainly regulates tubular urate reabsorption. Loss-of-function mutations result in idiopathic hypouricemia. The present case-control study was designed to analyze whether hURAT1 might also be a candidate gene for hyperuricemia with primary reduced renal urate excretion.Methods. DNA samples from 389 individuals with reduced fractional excretion of uric acid (FEUA) (<6.5%) and from 263 controls (FEUA >6.5%) were sequenced. Genotype frequencies between groups were compared by Cochran-Armitage trend test.Results. Significantly different genotype distributions could be demonstrated for the ؊788 T>A (promoter; P ‫؍‬ 0.014), the C258T (exon 1; P ‫؍‬ 0.006), and the C426T (exon 2; P ‫؍‬ 0.0002) polymorphisms, but not for the T1309C (exon 8) and the ؉18 C>T (intron 9) polymorphisms. The strongest association with reduced FEUA was observed for the C426T polymorphism, with odds ratios (ORs) of 1.59 and 2.54 (P ‫؍‬ 0.0002) for the CT and TT genotypes, respectively. Adjusted values for FEUA in the C426T genotype, were significantly reduced decreasing to 7.3%, 6.7%, and 6.3% in individuals with the CC, CT, and TT genotypes, respectively (P ‫؍‬ 0.004). Haplotypes were constructed from the ؊788 T>A, C258T, and C426T polymorphisms. Individuals carrying at least 1 ACT haplotype (n ‫؍‬ 349) had a significantly higher risk for reduced FEUA than individuals without any ACT haplotype (n ‫؍‬ 303) (OR 1.39, P ‫؍‬ 0.041).Conclusion. These results indicate that polymorphisms in the N-terminus of the hURAT1 gene were significantly associated with reduced renal uric acid excretion. The main regulating factor seems to be located close to the C426T polymorphism or is in strong linkage disequilibrium.In Germany, as in most Western countries, the prevalence of hyperuricemia is ϳ30% in men and 3% in women (1). Of these individuals, ϳ10% develop gout. The familial nature of hyperuricemia and gout has long been recognized. Among family members of patients with gout, the prevalence of asymptomatic hyperuricemia ranges from 25% to 27% (2,3). In a study of twins, Emmerson et al (4) observed that monozygotic twins had more similar values of urate clearance and fractional excretion of uric acid (FEUA) than did dizygotic twins. The heritability of the renal urate clearance was estimated as ϳ60%, whereas the heritability of the fractional urate excretion was found to be 87% (4). In Ͼ90% of patients with primary gout, reduced renal uric acid clearance causes hyperuricemia.Glomerular filtration and bidirectional urate transport, including both tubular secretion and reabsorption, are the essential physiologic processes in renal handling of uric acid (5). Under normal conditions, uric acid is freely filtered at the kidney glomerulus and almost completely reabsorbed from urine in the proximal tubule. According to the "four-component model" of urate excretion (6), net urate excretion is determined by tubular urate secretion and postsecretory urate ...

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 51:3102-3106, 2002

We prospectively evaluated whether an effective 12-month uric acid-lowering therapy (ULT) with the available xanthine oxidase (XO) inhibitors allopurinol and febuxostat in patients with chronic tophaceous gout has an impact on oxidative stress and/or vascular function. Patients with chronic tophaceous gout who did not receive active ULT were included. After clinical evaluation, serum uric acid levels (SUA) and markers of oxidative stress were measured, and carotid-femoral pulse wave velocity (cfPWV) was assessed. Patients were then treated with allopurinol (n = 9) or with febuxostat (n = 8) to target a SUA level ≤ 360 μmol/L. After 1 year treatment, the SUA levels, markers of oxidative stress and the cfPWV were measured again. Baseline characteristics of both groups showed no significant differences except a higher prevalence of moderate impairment of renal function (estimated glomerular filtration rate <60 ml/min) in the febuxostat group. Uric acid lowering with either inhibitors of XO resulted in almost equally effective reduction in SUA levels. The both treatment groups did not differ in their baseline cfPWV (allopurinol group: 14.1 ± 3.4 m/s, febuxostat group: 13.7 ± 2.7 m/s, p = 0.80). However, after 1 year of therapy, we observed a significant cfPWV increase in the allopurinol group (16.8 ± 4.3 m/s, p = 0.001 as compared to baseline), but not in the febuxostat patients (13.3 ± 2.3 m/s, p = 0.55). Both febuxostat and allopurinol effectively lower SUA levels in patients with severe gout. However, we observed that febuxostat also appeared to be beneficial in preventing further arterial stiffening. Since cardiovascular events are an important issue in treating patients with gout, this unexpected finding may have important implications and should be further investigated in randomized controlled trials.

Cross talks between the vascular and immune system play a critical role in vascular diseases, in particular in atherosclerosis. The osteoclast-associated receptor (OSCAR) is a regulator of osteoclast differentiation and dendritic cell maturation. Whether OSCAR plays a role in vascular biology and has an impact on atherogenic processes provoked by proinflammatory stimuli is yet unknown. We identified OSCAR on the surface of human primary endothelial cells. Stimulation of endothelial cells with oxidized low-density lipoprotein (oxLDL) caused a time- and dose-dependent induction of OSCAR, which was lectin-like oxidized LDL receptor 1 and Ca(2+) dependent. OSCAR was transcriptionally regulated by oxLDL as shown by OSCAR promoter analysis. Specific inhibition of the nuclear factor of activated T cells (NFAT) pathway prevented the oxLDL-mediated increase of endothelial OSCAR expression. As assessed by EMSA, oxLDL induced binding of NFATc1 to the OSCAR promoter. Notably, in vivo-modified LDL from patients with diabetes mellitus stimulated OSCAR mRNA expression in human endothelial cells. Furthermore, apolipoprotein E knockout mice fed a high-fat diet showed an enhanced aortic OSCAR expression associated with increased expression of NFATc1. In summary, OSCAR is expressed in vascular endothelial cells and is regulated by oxLDL involving NFATc1. Our data suggest that OSCAR, originally described in bone as immunological mediator and regulator of osteoclast differentiation, may be involved in cell activation and inflammation during atherosclerosis.

Chemiluminescence is a widely used tool to detect extracellular generation of reactive oxygen species (ROS). In the present study we tested four different chemilumigenic substrates (CLS)--luminol, isoluminol, lucigenin and pholasin-to detect extracellular CL in different cell types: polymorphonuclear leukocytes (PMN); DMSO-differentiated HL-60 cells; murine macrophages (RAW 264.7); and TNF alpha-stimulated human endothelial cells (HUVEC). Extracellular ROS production was calculated by subtracting intracellular CL response in the presence of superoxide dismutase and catalase from the overall CL response in the absence of enzymes. CL varied considerably in dependence on the CLS and the stimulus used to evoke ROS generation. Luminol (oxidized LDL and zymosan stimulation) and isoluminol (FMLP and PMA stimulation) were the most effective CLS for PMN. Using 5 micromol/L lucigenin as CLS, small but consistent CL responses could be obtained in macrophages stimulated with PMA, zymosan or oxidized LDL. FMLP-stimulated extracellular CL in H-60 cells, HUVEC and macrophages was detected with the greatest sensitivity by pholasin. Our results demonstrate that none of the investigated CLS consistently yielded the highest CL quantum, either in different cell types with one stimulating agent or by different stimulating agents in one cell type. To get the highest CL quantum in experimental studies, we recommend optimizing the CLS depending on the cell type and the ROS-generating stimulus used.

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.

Diabetic dyslipidemia is characterized by increased circulatory very-low-density lipoprotein (VLDL) levels. Aldosterone, apart from its role in fluid and electrolyte homeostasis, has also been implicated in insulin resistance and myocardial fibrosis. The impact of VLDL as a potential risk factor for aldosterone-mediated cardiovascular injury in diabetes mellitus, however, remains to be investigated. We have therefore studied native and modified VLDL-mediated steroidogenesis and its underlying molecular mechanisms in human adrenocortical carcinoma cells, NCI H295R. Native VLDL (natVLDL), isolated from healthy volunteers, was subjected to in vitro modification with glucose (200 mmol/l) or sodium hypochlorite (1.5 mmol/l) for preparation of glycoxidized and oxidized VLDL, respectively. VLDL treatment induced steroidogenesis in both a concentration- and time-dependent manner. Native and glycoxidized VLDL (50 μg/ml) were almost two-fold more potent in adrenocortical aldosterone release than angiotensin II (100 nmol/l). These forms of VLDL significantly augmented transcriptional regulation of aldosterone synthase (Cyp11B2), partially through scavenger receptor class B type I, as evident from the effect of BLT-1. In contrast to glycoxidized VLDL, oxidized VLDL significantly attenuated the stimulatory effect of natVLDL on adrenocortical hormone synthesis. Moreover, treatment with specific pharmacological inhibitors (H89, U0126, AG490) provided supporting evidence that VLDL, irrespective of modification, presumably recruited PKA, ERK1/2 and Jak-2 for steroid hormone release through modulation of Cyp11B2 mRNA level. In conclusion, this study demonstrates a novel insight into intracellular mechanism of VLDL-mediated aldosterone synthesis through transcriptional regulation of steroidogenic acute regulatory protein (StAR) and Cyp11B2 expression in human adrenocortical carcinoma cell line.