Fetuin-A levels are increased in patients with type 2 diabetes and peripheral arterial disease

OBJECTIVE

Low levels of fetuin-A, a systemic calcification inhibitor, are linked to mortality in patients on dialysis. In contrast, elevated fetuin-A is associated with cardiovascular events in non-renal patients. We investigated fetuin-A in patients with type 2 diabetes and peripheral arterial disease (PAD).

RESEARCH DESIGN AND METHODS

We studied fetuin-A in 76 patients with PAD and normal glucose metabolism (NGM-PAD) and in 129 patients with PAD and type 2 diabetes (type 2 diabetes–PAD). Additionally, 40 patients with diabetes without any complications (type 2 diabetes–non-PAD) were examined.

RESULTS

Type 2 diabetes–PAD subjects (399 ± 155 μg/ml) had significantly higher fetuin-A levels than type 2 diabetes–non-PAD subjects (247 ± 42; P < 0.001). In NGM-PAD subjects (376 ± 144), fetuin-A was significantly higher than in type 2 diabetes–non-PAD subjects (P < 0.001). Type 2 diabetes–PAD patients with mediasclerosis had lower fetuin-A than subjects without (P < 0.03). Regression analysis in type 2 diabetes–PAD subjects revealed that glycated A1C (P < 0.001) and mediasclerosis (P = 0.004) were the strongest predictors of fetuin-A. Multivariate regression revealed that a 1-SD increase in fetuin-A was associated with an odds ratio (OR) of 2.1 (95% CI 1.1–3.3; P < 0.001) for the prevalence of PAD and an OR of 1.4 (1.0–1.7, P = 0.039) for the prevalence of myocardial infarction.

CONCLUSIONS

In contrast to previous findings, fetuin-A was higher in type 2 diabetes–PAD patients than in type 2 diabetes–non-PAD patients. In NGM-PAD patients, fetuin-A was also higher than in type 2 diabetes–non-PAD patients. In type 2 diabetes–PAD patients, fetuin-A was inversely associated with mediasclerosis—the calcification process pathognomonic for diabetic PAD. This association persisted in multivariate regression, which is in line with the calcification inhibition in coronary heart or renal disease.Patients suffering from type 2 diabetes and peripheral artery disease (PAD) (type 2 diabetes–PAD) have a five times higher risk for cardiovascular mortality than patients with one disease alone (1–3). Furthermore, the risk of lower-extremity amputation is higher than in patients without diabetes (3).Fetuin-A, also known as α2-Schmid Heremans glycoprotein (ASHG), is a potent systemic calcification inhibitor (4). Fetuin-A knockout mice develop severe calcification of various organs (4). In a cross-sectional study, low levels of fetuin-A were associated with cardiovascular mortality in patients on dialysis (5). In addition, low fetuin-A has been linked to vascular calcification (6) and flow-limiting aortic stenosis (7).Fetuin-A interacts with the insulin receptor tyrosine kinase and induces insulin resistance in rodents (8,9). Stefan et al. (10) demonstrated in a prospective case-cohort study that elevated fetuin-A is an independent risk factor for developing diabetes. Contrariwise to renal (dialysis) patients, several studies showed that high levels of fetuin-A were associated with atherosclerosis and its manifestations in non-renal patients (11–13). Likewise, high levels of fetuin-A were linked to myocardial infarction and ischemic stroke (12). This possible involvement of fetuin-A in the pathogenesis of cardiovascular disease has been confirmed by a recent trans-European cohort study with 2,520 patients (13). Thus, it seems that high levels of fetuin-A are associated with atherosclerosis and its manifestations in non-renal patients.In contrast to the latter findings, a recent article (14) suggested that fetuin-A levels in a non-dialysis condition are lower in type 2 diabetes–PAD patients (n = 38) than in patients with diabetes alone.However, the role of fetuin-A and its involvement in atherosclerosis seems to be very complex and yet not understood. The situation is even more complex in patients with type 2 diabetes–PAD, who generally suffer from advanced/systemic atherosclerosis (1–3,15). In those high-risk patients, up to 30% show mediasclerosis (2,15). The aim of this study was to investigate fetuin-A levels in patients with type 2 diabetes with or without PAD in comparison with PAD patients with diabetes.     

Elevated serum levels of S-adenosylhomocysteine, but not homocysteine, are associated with cardiovascular disease in stage 5 chronic kidney disease patients

OBJECTIVE: The putative role of sulfur amino acids such as homocysteine (tHcy) as cardiovascular risk factors is controversial in chronic kidney disease (CKD). Although, S-adenosylhomocysteine (SAH) levels have been linked to CVD in non-renal populations, such relationship has not been evaluated in CKD. DESIGN: Serum concentrations of S-adenosylmethionine (SAM), SAH and total homocysteine (tHcy) were determined by HPLC in 124 CKD stage 5 patients (GFR range 1-11 m/min) and 47 control subjects, and related to renal function, presence of CVD, inflammation and protein-energy wasting (PEW). RESULTS: The levels of SAM and SAH were higher in CKD patients than in controls. Both SAM (rho=-0.19; P<0.05) and SAH (rho=-0.37, P<0.001) were inversely related to GFR. The concentrations of SAH were significantly higher (P<0.001) in patients with CVD than in non-CVD patients, (683 (201-3057) vs 485 (259-2620) nmol/L; median (range)) as opposed to tHcy levels, which were lower in CVD patients. While SAH was not associated with the presence of inflammation or PEW, it was a significant contributor (OR; 4.9 (CI 1.8-12.8), P<0.001) to CVD in a multinomial logistic regression model (pseudo r(2)=0.31). CONCLUSION: Concentrations of serum SAH and SAM in CKD stage 5 patients are associated with renal function, but not with inflammation or PEW. Among the investigated sulfur amino acids, only SAH was independently associated with the presence of clinical signs of CVD. These findings suggest that while tHcy might be influenced by a number of confounding uremic factors, SAH levels may better reflect the putative increased cardiovascular risk of sulfur amino acid alterations in CKD patients.     

Vitreous and serum levels of transthyretin (TTR) in high myopia patients are correlated with ocular pathologies

PurposeTo detect serum and vitreous transthyretin (TTR) in high myopia patients and to evaluate potential associations between TTR and clinical parameters and ocular pathologies, including different ocular pathologies.Design and methodsSerum samples from 16 high myopia patients and 4 controls were analyzed by LTQ-MASS. Serum samples from 116 high myopia patients and 86 healthy controls were tested by Western blots and ELISA. Eight healthy and 40 pathologic vitreous samples were analyzed by ELISA. And corresponding serum samples were also analyzed by ELISA.ResultsSignificant increased TTR serum levels were detected in high myopia patients compared to healthy controls. The high levels of serum TTR were associated with ocular pathologies, long axial length, and low visual acuity. TTR in high myopia patients with macular hole and macular detachment was upregulated in both vitreous and the corresponding serum samples. TTR levels in serum samples of high myopia patients with long axial lengths were higher than in the vitreous.ConclusionsSerum TTR may be a biomarker for high myopia patients with ocular pathologies.     

Polychlorinated biphenyl serum levels in pregnant subjects with diabetes

OBJECTIVE--Polychlorinated biphenyls (PCBs) are persistent pollutants that are ubiquitous in the food chain; detectable amounts are in the blood of nearly everyone. Their effect on humans at background levels of exposure is an area of active investigation. Increased blood levels of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin), a PCB-like compound, have recently been reported among subjects with diabetes, suggesting that PCB levels could be similarly elevated. To test this hypothesis, we examined a group of pregnant women whose serum PCB levels had been measured and whose diabetes status had been previously recorded. RESEARCH DESIGN AND METHODS--Using stored serum from a large birth cohort study, we conducted a cross-sectional study of 2,245 pregnant women, of whom 44 had diabetes (primarily type 1) and 2,201 were control subjects. RESULTS--The adjusted mean serum level of PCBs among the subjects with diabetes was 30% higher than in the control subjects (P = 0.0002), and the relationship of PCB level to adjusted odds of diabetes was linear. CONCLUSIONS--The possibility exists that PCBs and diabetes are causality related; alternatively, the pharmacokinetics of PCBs could be altered among patients with diabetes. At any event, if the association is replicated in other studies, increased serum levels of PCBs in subjects with diabetes or their offspring may put them at increased risk of PCB-induced changes in thyroid metabolism or neurodevelopment.     

Plasma biguanide levels are correlated with metabolic effects in diabetic patients

Metabolic abnormalities occur in biguanide-treated diabetic patients. We investigated the relationship between plasma metformin and phenformin concentrations and metabolic effects. Drug levels were measured in 37 type II diabetic patients by HPLC. The method was sensitive, specific, and linear over a wide range of drug concentrations. Metformin and phenformin values ranged from 236 to 718 ng/ml and from 28 to 114 ng/ml, respectively. The plasma metformin level was correlated with triglycerides (r = -0.55; P less than 0.05) but not with drug dosage, plasma glucose, HbA1, creatinine, creatinine clearance, lactate, pyruvate, lipid, and clinical parameters. Plasma phenformin concentrations correlated with lactate (r = 0.49; P less than 0.05) and HbA1 (r = 0.50; P less than 0.05) but not with drug dosage, parameters of diabetes control, creatinine, creatinine clearance, pyruvate, and clinical parameters. The clinical usefulness of this HPLC method, the evidence that the increase of lactate is related to the circulating phenformin levels, and the demonstration that the metformin effect on triglyceride metabolism is correlated to plasma drug levels are the positive findings of this work.     

Serum levels of interleukin-6 and tumour-necrosis-factor-alpha are not correlated to disease activity in patients with rheumatoid arthritis after treatment with low-dose methotrexate

Abstract. Cytokines are major mediators of inflammatory responses in rheumatoid arthritis. Some of them have been shown to correlate with the disease activity and thus are proposed to be used for monitoring patients. Therefore the effects of a low-dose therapy with methotrexate on serum concentrations of interleukin-6 (IL-6) and tumour-necrosis-factor-alpha (TNF-α) were examined in eight patients with seropositive rheumatoid arthritis. Serum levels of IL-6 and TNF-α were significantly elevated in patients compared to healthy controls. Before the onset of MTX treatment IL-6 concentrations were correlated to the c-reactive protein ( P < 0·05) but the correlation was abolished after treatment. For TNF-α no correlations neither before nor after treatment were observed. Both cytokines remained substantially elevated after MTX treatment despite a clear reduction in disease activity. Thus we suggest that one of the effects of MTX might be the inhibition of some of the actions of IL-6 and TNF-α.     

Pediatric reference values for serum magnesium levels in Iranian subjects

Abstract

Magnesium (Mg), an essential element, plays important roles in many physiological functions. Mg deficiency is associated with insulin resistance, cardiovascular disease, and disorders of the nervous system. The aim of this study was to determine reference values for serum Mg concentration in pediatrics. Serum Mg level was measured by flame atomic absorption spectrophotometry in 306 subjects (141 boys and 165 girls), aged 3–19 years, selected from among participants of the Tehran Lipid and Glucose Study. The International Federation of Clinical Chemistry guidelines (IFCC) and the robust method were used for determining reference values for sample sizes greater or less than 120 subjects respectively. The 95% reference values for serum Mg concentrations were 0.76–1.0, 0.75–1.0, and 0.76–0.99 mmol/L in boys, girls, and the all subjects respectively. According to the reference values obtained in this study, the prevalences of hypo- and hypermagnesemia, were 5.9% and 5.6% respectively. In conclusion, the current study presents pediatric reference values for serum Mg levels derived from a randomly selected healthy population, values which could be instrumental in detecting serum Mg abnormalities.     

老年血液透析患者血清hs-CRP、Fetuin-A水平与心脏瓣膜钙化和血管钙化的关系

目的研究老年维持性血液透析(MHD)患者心脏瓣膜钙化(CVC)和血管钙化(VC)发生情况并分析血清超敏C反应蛋白(hs-CRP)和Fetuin-A水平诊断价值和与钙化程度的相关性。方法选取2016年2月至2019年3月于本院接受治疗的老年MHD患者104例进行横断面研究,采用心脏彩超和腹部侧位X线检查CVC和VC发生情况并评估严重程度,同时检测患者血清hs-CRP和Fetuin-A水平,作受试者工作特征曲线(ROC)并计算曲线下面积(AUC)分析二者对CVC和VC诊断价值,然后分别研究hs-CRP和Fetuin-A与CVC和VC钙化程度的相关性。结果 104例老年MHD患者经心脏彩超确诊为CVC者47例(45.19%),合并CVC的患者血清hs-CRP水平高于非CVC患者,血清Fetuin-A水平低于非CVC患者,差异均有统计学意义(P<0.05);104例患者AACS评分为0~21分,平均(5.73±1.32)分,其中发生VC者41例(39.42%),合并VC的患者血清hs-CRP水平高于非VC患者,血清Fetuin-A水平低于非VC患者,差异具有统计学意义(P<0.05);老年MHD患者血清hs-CRP、Fetuin-A水平及两者联合诊断CVC的AUC分别为0.847、0.715和0.874,诊断VC的AUC分别为0.895、0.840和0.951;血清hs-CRP水平与CVC严重程度和AACS评分均呈明显正相关性(P<0.05),Fetuin-A水平与二者均呈明显负相关性(P<0.05)。结论老年MHD患者常合并CVC或VC,其中hs-CRP和Fetuin-A可能在钙化发生和进展过程中发挥重要作用,且对CVC或VC诊断和严重程度评估均具有良好参考价值。     

Low serum 25-hydroxyvitamin D levels are associated with perennial allergic rhinitis but not disease severity

BackgroundVitamin D deficiency plays an essential role in allergic rhinitis(AR), but the role of vitamin D deficiency in perennial allergic rhinitis (pAR) remains unclear. Therefore, our study explored 25(OH)D levels in patients with pAR and healthy individuals in a single center in China for three years.MethodsA total of 655 patients with pAR and 682 healthy controls were enrolled in this study from 2015 to 2017. Patients'' clinical history and symptoms were recorded. sIgE tests were performed using the allergen detection system (UniCAP), and the ADVIA centaur XP system (SIEMENS) was used to measure serum 25(OH)D levels.ResultsSerum 25(OH)D levels were significantly different between the pAR group and control group over the three‐year study period(all P < .05). Specifically, 25(OH)D levels were decreased in the pAR groups over three years. Serum25(OH)D deficiency, insufficiency, and sufficiency were noted in 66.9% ~71.9%, 22.5% ~29.4%, and 2.5%~5.6%, respectively, of patients in the pAR group and 53.2%~60.7%, 31.4%~36.6%, and 7.9% ~11.4%, respectively, of participants in the control group. We did not identify significant associations between serum 25(OH)D levels and clinical characteristics of patients with pAR over the three‐year period (all P > .05) after adjusting for sex, age, duration of disease, total nasal symptom score (TNSS), sIgE levels, number of positive allergens, and family history.ConclusionpAR patients exhibited lower serum 25(OH)D levels compared with healthy people with a high prevalence of 25(OH)D deficiency or insufficiency. We did not identify a significant correlation between 25(OH)D and pAR associated factors.     

Free 1,25-dihydroxyvitamin D levels in serum from normal subjects, pregnant subjects, and subjects with liver disease

We measured the free concentration of 1,25-dihydroxyvitamin D (1,25[OH]2D) using centrifugal ultrafiltration, and the level of vitamin D-binding protein (DBP) in 24 normal subjects, 17 pregnant subjects, and 25 alcoholic subjects with liver disease. Our objective was to determine whether the increase in total 1,25(OH)2D levels in pregnant women and the reduction in total 1,25(OH)2D levels in subjects with liver disease reflected a true difference in free 1,25(OH)2D levels or whether such differences were due solely to the variations in DBP levels (and thus, the amount of 1,25[OH]2D bound) in these groups. In subjects with liver disease the mean total 1,25(OH)2D concentration (22.6 +/- 12.5 pg/ml) and the mean DBP concentration (188 +/- 105 micrograms/dl) were nearly half the normal values (41.5 +/- 11.5 pg/ml and 404 +/- 124 micrograms/dl, respectively, P less than 0.001), whereas the mean free 1,25(OH)2D level was similar to normal values (209 +/- 91 fg/ml and 174 +/- 46 fg/ml, respectively). In contrast, in pregnant subjects the mean total 1,25(OH)2D level (82 +/- 21 pg/ml) and mean DBP level (576 +/- 128 micrograms/dl) were significantly higher than normal (P less than 0.001). Although the mean percent free 1,25(OH)2D level in pregnant subjects was below normal (0.359 +/- 0.07% vs. 0.424 +/- 0.07%, P less than 0.001), the mean free 1,25(OH)2D level was 69% higher than normal (294 +/- 98 fg/ml vs. 174 +/- 46 fg/ml, P less than 0.001). When data from all three groups were combined, there was a linear correlation between total 1,25(OH)2D and DBP levels but not between DBP and percent free 1,25(OH)2D levels; the increased DBP levels in the pregnant subjects were associated with less of an effect on percent free 1,25(OH)2D than were the reduced DBP levels in the subjects with liver disease. Our data suggest that (a) free 1,25(OH)2D levels appear to be well maintained even in subjects with liver disease and reduced DBP levels, (b) free 1,25(OH)2D levels are increased during pregnancy despite the increase in DBP levels, and (c) free 1,25(OH)2D levels cannot be inferred accurately from measurements of total 1,25(OH)2D and DBP levels alone in subjects with various physiologic and pathophysiologic conditions.     

Folic acid does not improve endothelial function in healthy hyperhomocysteinaemic subjects

Folic acid supplementation lowers total plasma homocysteine (tHcy) and improves endothelial function in individuals with coronary artery disease (CAD) and in those with additional CAD risk factors. In the present study, we assessed whether endothelial function is impaired in healthy subjects with hyperhomocysteinaemia but without other CAD risk factors and whether folic acid supplementation improves endothelial function in these subjects. Flow-mediated dilatation (FMD) of the brachial artery was performed on 26 healthy subjects, age 49 +/- 2 years (mean +/- S.E.M.), with high tHcy (15.6 +/- 1.5 micromol/l) and 16 healthy age-matched subjects with low tHcy (7.9 +/- 0.6 micromol/l; P < 0.001). Subjects with high tHcy were then randomized to receive 5 mg/day of folic acid or placebo for 8 weeks in a double-blind cross-over trial with a 4-week washout. FMD was not associated with tHcy and was not different between high and low tHcy groups (7.0 +/- 0.6% compared with 6.6 +/- 1.2%, P = 0.76). Treatment with folic acid decreased tHcy by 34% in hyperhomocysteinaemic subjects ( P = 0.02 compared with placebo), but had no effect on FMD (+ 0.5 +/- 0.6% compared with -0.7 +/- 0.5%; P = 0.17 compared with placebo). In healthy subjects with hyperhomocysteinaemia, but without additional cardiovascular risk, endothelial function is unimpaired and folic acid supplementation has no additional effect.     

The DSL analog free testosterone assay: serum levels are not related to sex hormone-binding globulin in normative data throughout childhood and adolescence

In this study we tested the performance of easy-to-use and rapid, commercially available immunoassays to measure free testosterone (fT) and sex hormone-binding globulin (SHBG). We asked whether fT and SHBG serum levels are age-dependent and whether or not there is a gender dependence of fT and SHBG in this age group. Finally, by measuring fT and SHBG in sera of a cohort of healthy children and adolescents using commercially available immunoassays, we established normative data for fT and SHBG in this age group: in boys fT levels increased significantly (r=0.83, p<0.0001) from 0.63 pmol/l (median) in the age group below 5 years to 56.9 pmol/l in the age group 16-20 years. In girls fT levels also increased with age (r=0.66, p<0.0001): from 0.72 pmol/l (median) in the age group below 5 years to 3.34 pmol/l in the age group 16-20 years. In contrast, SHBG serum concentrations significantly decreased with age in boys (r=-0.62, p<0.0001) but remained constant in girls (r=0.04, n.s.). Importantly, fT values were independent of SHBG levels as determined by our methods. In conclusion, fT can be measured in an acceptable quality using the DSL analog tracer-based immunoassay and normative data are now available. In addition, SHBG levels in healthy children and adolescents are also given and may permit for studies of pathophysiologic states in this age group.