Low human paraoxonase predicts cardiovascular events in Japanese patients with type 2 diabetes

Human serum paraoxonase (PON1) is associated with HDL and inhibits oxidative modification of LDL. PON1 enzymatic activity has been shown to decrease in diabetic patients; however, the effect of PON1 status on long-term outcome has not been reported. In this study, we examined the association between baseline PON1 status and the development of cardiovascular disease (CVD) during 10 years of follow-up in 88 type 2 diabetic patients whose enzymatic activities, concentrations, and genetic polymorphisms of PON1 had been determined. A total of 20 CVD events were recorded during the follow-up period. Using Kaplan–Meier survival curves, we found a significantly increased incidence of CVD in patients with a lower concentration or paraoxonase activity of PON1 than each median value (log-rank 7.460; P < 0.01, and log-rank 4.187; P < 0.05, respectively). By Cox regression analysis, both concentration and paraoxonase activity were significantly associated with the development of CVD, even after correction for gender, age, and preexisting CVD (P < 0.05). Low concentration and enzymatic activity of PON1 may be an independent predictor of cardiovascular events in diabetic patients.     

Carotid intima-media thickness progression predicts cardiovascular events in Japanese patients with type 2 diabetes

Aims

The aim of this retrospective study was to investigate the relationship between progression of carotid intima-media thickness (cIMT) and cardiovascular events in Japanese patients with type 2 diabetes mellitus (T2DM) and free of history of cardiovascular events.

Methods

Patients with T2DM (n = 342) without history of cardiovascular events whose cIMT was assessed more than twice by ultrasonography were recruited and followed up for cardiovascular events.

Results

During a mean follow-up of 7.6 years, 56 (16.4%) cardiovascular events (27 coronary events and 29 cerebrovascular events) were recorded. Multivariate analysis with the Cox proportional hazard model identified cIMT progression as a significant determinant of cardiovascular events, with a hazard ratio (HR) of 2.24 (95% confidence interval; CI, 1.25–4.03, P < 0.01), in addition to baseline cIMT. The Kaplan–Meier curves also showed significantly higher event rate in patients with high cIMT progression compared with those with low cIMT progression (log-rank χ² = 6.65; P < 0.01). Furthermore, the combination of high baseline cIMT and high cIMT progression was a significant predictor of cardiovascular events.

Conclusion

Our findings suggest that cIMT progression, in addition to baseline cIMT, is a predictor of cardiovascular events in patients with T2DM without history of cardiovascular events, and that the combination of cIMT progression and baseline cIMT has a strong predictive power for such events.     

Pulse pressure predicts cardiovascular risk in patients with type 2 diabetes mellitus

BACKGROUND: Pulse pressure (PP), a marker of arterial stiffness, is a better predictor of coronary heart disease (CHD) risk than systolic blood pressure (SBP) or diastolic blood pressure (DBP) in older adults. Whether this is also true in subjects with type 2 diabetes, who are at increased risk for cardiovascular disease, is unknown. METHODS: Data on 2911 type 2 diabetic subjects relating to blood pressure (BP), other risk factors, and cardiovascular events were abstracted from The Cardiff Diabetes Database. Logistic regression was used to assess the relationship among BP components and the risk of CHD, cerebrovascular (CVD), and peripheral vascular (PVD) events after correction for age, gender, cholesterol, and smoking status. RESULTS: In the 4-year follow-up period there were 574 CHD, 168 CVD, and 157 PVD events. Both PP and SBP, but not DBP, were positively associated with the risk of all event types. However, PP emerged as the best predictor of CHD events, and SBP as the best predictor of CVD and PVD events. Total and HDL-cholesterol were the most important variables associated with PP after age. CONCLUSIONS: In summary, PP is a better predictor of CHD events than SBP in persons with type 2 diabetes, but the converse is true for CVD and PVD.     

Apolipoprotein E genotype predicts cardiovascular endpoints in dialysis patients with type 2 diabetes mellitus

ObjectiveCardiovascular disease (CVD) is the leading cause of death in patients with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Lipid metabolism is influenced by environmental and genetic factors. Among the latter, the apolipoprotein E (apoE) genotype is known to be associated with CVD risk and thus may affect cardiovascular outcome.Methods and resultsBased on the German Diabetes and Dialysis Study evaluating 1255 T2DM patients on haemodialysis (HD) (median follow-up 4 years), the impact of the apoE genotype (available for 1177 patients) on pre-specified, centrally adjudicated endpoints was investigated: all-cause mortality (n = 558), combined cardiovascular events (CVE: cardiac death, MI, stroke; n = 442), and cardiac death (n = 218). Patients with at least one ?4 allele (?4+) showed a 30% increased risk for CVE (HR 1.299, 95%CI 1.045–1.615, p = 0.018) and a 36% increased risk for cardiac death (HR 1.362, 95%CI 1.002–1.852, p = 0.048) compared to patients with no ?4 allele. Consistently, addition of ?4+ to a multivariate ROC model for risk prediction of CVE including atorvastatin treatment, history of cardiovascular disease, dialysis and lipoprotein parameters, hsCRP, and NT-pro-BNP increased the area under the curve from 0.666 (95%CI 0.634–0.698) to 0.671 (95%CI 0.639–0.702), p = 0.013.ConclusionsThe presence of the ?4 allele increases the risk for CVE and cardiac death in patients with T2DM and ESRD. Whether treatment strategies guided by apoE genotype will improve outcome needs to be evaluated in the future.     

Circulating intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin in patients with type 2 diabetes mellitus

Serum levels of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin in patients with type 2 diabetes mellitus (n = 64) and control subjects (n = 40) were studied. Serum ICAM-1 concentrations in diabetic patients were significantly higher than those of control subjects (378.2 +/- 70.0 versus 220.4 +/- 31.8 ng/ml, P < 0.01). By multiple regression analysis, hemoglobin A1c was independently associated with serum ICAM-1 concentration in patients with diabetes. The serum VCAM-1 concentration of diabetic patients with macroangiopathy was higher than those of patients without macroangiopathy and of control subjects (806.9 + 276.5 versus 639.0 +/- 146.0 (P < 0.01), and 652.1 +/- 146.9 ng/ml (P < 0.01), respectively). There was no difference in serum E-selectin concentration between diabetic patients with or without macroangiopathy and normal control subjects. These results suggest that adhesion molecules may contribute to the development of atherosclerosis in the diabetic state.     

2型糖尿病的分子病因学研究

目的探讨多个糖尿病易感基因在2型糖尿病发病中的作用及其与环境因素的关系.方法采用聚合酶链反应（PCR）技术,结合短串联重复序列（STR）多态性标记方法,对山东地区汉族107例2型糖尿病患者和105例正常对照者的GCK基因、NIDDM1（D2S140）基因及小肠脂肪酸结合蛋白（FABP2）基因的多态性进行分析.结果GCK等位基因A5及D2S140等位基因B2与2型糖尿病呈正相关（P＜0.01）;GCK等位基因A1、A3及D2S140等位基因B6与2型糖尿病呈负相关（P＜0.01）;FABP2各等位基因频率在两组分布未见显著性差异.2型糖尿病的发病与等位基因A5及B2、年龄、甘油三酯、载脂蛋白B及脂蛋白（a）呈显著正相关;与等位基因A3及B6呈显著负相关.结论GCK基因、NIDDM1（D2S140）基因多态性与山东地区汉族2型糖尿病具有相关性,是2型糖尿病发病的危险因素.     

Inflammation and insulin resistance are independently related to all-cause of death and cardiovascular events in Japanese patients with type 2 diabetes mellitus

Insulin resistance (IR)/hyperinsulinemia and low-grade inflammation (high-sensitivity C-reactive protein [hs-CRP]) can predict cardiovascular disease. However, because IR and inflammation (IF) have not been evaluated simultaneously, it is not known whether IR and IF are independently related to cardiovascular disease. Furthermore, the combined effect of IR and IF on the prediction of cardiovascular disease is presently unknown. Thus, we measured insulin sensitivity (K index of the insulin tolerance test; KITT) and hs-CRP in 350 Japanese patients with type 2 diabetes, and followed them for 1-7 years (mean, 4.5 years). During the follow-up, 33 patients died and 53 patients developed non-fatal coronary artery disease or stroke (endpoint). Age, systolic blood pressure, current smoking, past history of cardiovascular disease, KITT, and hs-CRP independently and significantly correlated with endpoint. One-S.D. difference was associated with a significant increase of relative risk in KITT (1.45; 95% CI 1.09-1.91) and hs-CRP (1.30; 1.04-1.67). When patients were subdivided to tertile, the relative risk in the highest tertile of KITT was 1.76 (95% CI 1.01-3.11) and hs-CRP was 2.00 (1.03-3.85) compared with the patients with lowest tertile. The relative risk in the highest tertile of both KITT and hs-CRP was 5.32 (1.18-24.0) compared with the lowest tertile of both values. In conclusion, low-grade IF and IR are independently related to all-cause of death and cardiovascular disease in Japanese patients with type 2 diabetes. Coexistence of low-grade IF and IR amplify this effect.     

抗氧化剂对老年2型糖尿病糖负荷后粘附分子表达的影响

目的 探索不同剂量的大豆异黄酮(isoflavones，IFs)和维生素C(VC)、维生素E(VE)混合干预物对老年2型糖尿病(2—DM)病人糖负荷后血液中粘附分子(adhesion motecules AMs)表达的影响。方法 随机将115例已确诊的老年2—DM病人分为空白(B组)、低剂量(C组)、中间剂量(D组)和高剂量(E组)的大豆异黄酮和VC、VE混合干预物组，与正常人对照(A组)比较，观察各组糖负荷(OGTT)前、后AMs的表达。结果 OGTT中，A组、B组和C组血液中可溶性细胞粘附分子-1(sICAM—1)、E—选择素(E—selectin)都显著增高，而D组、E组无这种现象，两组间无显著差异。结论 高血糖可产生过氧化应激而引起血液中AMs的过度表达。由150 mg IFs和500 mg VC、400IU VE组成的混合干预物(每日顿服剂量)，可作为2—DM人群以防治动脉粥样硬化(atherosclerosis，AS)等并发症为目的的推荐摄入量。     

Asymmetric dimethylarginine as a risk factor for cardiovascular disease in Japanese patients with type 2 diabetes mellitus

Aims Although asymmetric dimethylarginine (ADMA) is known to be involved in the developing process of cardiovascular diseases (CVD), little is known about the effects of ADMA on atherosclerosis in Asian patients with diabetes , who have the racial feature of lower body mass index (BMI) and decreased capacity of insulin secretion and sensitivity. Methods We employed 55 Japanese patients with type 2 diabetes mellitus (mean age, 64·2 years; 56% men) in a 6‐month‐longitudinal study and 450 patients (mean age, 62·7 years; 56% men) in a cross‐sectional study and examined the association of serum ADMA with atherosclerosis parameters [intima‐media thickness (IMT) and brachial‐ankle pulse wave velocity (baPWV)] as well as with the presence of CVD. Results In the longitudinal study, multiple regression analysis showed that basal serum ADMA level had a significantly positive association with changes in IMT (β = 0·35, P = 0·03) independently of age, duration of diabetes, BMI, blood pressure, low‐density lipoprotein and high‐density lipoprotein (LDL and HDL) cholesterol, HbA_1c, and renal function. In the cross‐sectional study, the serum ADMA level was significantly and positively associated with the presence of CVD (odds ratio = 7·22, 95% confidence interval 1·29–40·40, P = 0·02, by logistic analysis) and with baPWV (β = 0·14, P < 0·01, by multiple regression analysis). In contrast, serum symmetric dimethylarginine level, a structural isomer of ADMA, was associated neither with parameters for atherosclerosis nor with the presence of CVD in both studies. Conclusions Serum ADMA is a predictor of atherosclerosis and associated with the presence of CVD in Japanese patients with type 2 diabetes mellitus.     

Characteristics of sleep-disordered breathing in Japanese patients with type 2 diabetes mellitus

Sleep-disordered breathing (SDB), especially sleep apnea-hypopnea syndrome, is often observed in patients with type 2 diabetes mellitus; but there are only a few studies on SDB in Japanese diabetic subjects. We investigated the prevalence of SDB in diabetic patients; associations between severity of sleep apnea (SA) and clinical factors, visceral fat, and adiponectin; and associations between type of SA and clinical factors. In the present study, 40 Japanese diabetic patients underwent overnight cardiorespiratory monitoring, and night and morning measurements of serum adiponectin concentrations. Sleep apnea was detected in Japanese diabetic patients at a high prevalence (77.5%). The following variables were associated with SDB: age, body mass index, estimated visceral fat area, and nocturnal reduction in serum adiponectin concentrations. The prevalence of central sleep apnea (CSA, ≥5/h) was 32.3% among diabetic SDB patients. Diabetic SDB patients with CSA had higher hemoglobin, increased intima-media thickness, and higher plasma brain natriuretic peptide levels than those without CSA (<5/h). In conclusion, our study demonstrated a high prevalence of SDB in Japanese diabetic patients, which correlated with visceral fat area and adiponectin. A high frequency of CSA was noted in diabetic SDB patients, together with high hemoglobin, high brain natriuretic peptide, and increased intima-media thickness. The present results of prevalence of SDB may be relevant to the higher incidence of cardiovascular disease in diabetic patients, which need to be clarified in future studies.     

Prevalence of adrenal masses in Japanese patients with type 2 diabetes mellitus

Background

The Metabolic syndrome (MetS) is a cardiovascular risk factor of public health significance and of recent has become a topical issue. The prevalence of diabetes mellitus (DM) is on the increase and with this scenario, a possible increase in burden of DM which may be largely attributed to cardiovascular complications is expected. The objective of this report is to determine the prevalence of the MetS and compare gender characteristics in subjects with type 2 DM.

Methods

Subjects with type 2 DM were recruited from an urban hospital for the study. Clinical data was obtained by interviewing the patients and referring to their Case folders. The anthropometric indices and blood pressure measurements were documented. Laboratory parameters analysed for included total cholesterol, high density and low density cholesterol, triglyceride and glycosylated haemoglobin. Statistical analysis included usage of Student's t test and chi square.

Results

963 patients with type 2 DM aged between 35-85 years were recruited for the study. The main outcome measures included the prevalence of the metabolic syndrome and the gender differences of its components. The prevalence of the metabolic syndrome was 86%. The frequency of occurrence of the MetS was similar for men (83%) and women (86%) and increased with age in both sexes. The prevalence of MetS increased from 11% among participants aged 20 through 29 years to 89% in participants aged 70 through 79. In our patients with DM, the commonest occurring and least detected MetS defining parameters are central obesity and elevated triglyceride levels respectively. The components of the MetS that differed significantly in both sexes was HDL-C. The combination of the components of the MetS were comparable in both genders and 5.8% of the subjects with the MetS had all components of the MetS.

Conclusion

The prevalence of the MetS in type 2DM is high in both genders and increases with age thus posing a potential high cardiovascular risk in this group of patients. The modifiable risk factors for the MetS should be a focus point in the management of subjects with type 2 DM,     

Effects of long-term fenofibrate therapy on cardiovascular events in people with type 2 diabetes mellitus

Conclusions The authors of the FIELD study conclude that the result of this large and scientifically rigorous study provides information to help guide clinicians on the future use of fenofibrate in patients with type 2 diabetes. They state the “results are likely to be of particular importance among patients without previous cardiovascular disease where both the prevention of non-fatal macrovascular events and microvascular complications are judged important.” I do not believe the results of the FIELD trial support an expanded role of fenofibrate therapy for patients with diabetes. To suggest we use fenofibrate as primary prevention in diabetic patients because a post hoc analysis of the FIELD study demonstrated no benefit in patients with known heart disease and modest benefit in patients without known heart disease is scientifically invalid and biologically implausible. To suggest we use fenofibrate to reduce microvascular disease will require a clinical trial designed to look at those specific endpoints. At present, there is no evidence to suggest that therapy with fenofibrate is superior to generic gemfibrozil. The clinical utility of fenofibrate in patients with more severe hypertriglyceridemia or in combination with statin therapy will remain to be demonstrated in a well-designed clinical trial.     

Soluble adhesion molecules and C-reactive protein in the progression of silent cerebral infarction in patients with type 2 diabetes mellitus

The purpose of this study was to investigate the association between the progression of silent cerebral infarction (SCI) and levels of soluble adhesion molecules and high-sensitivity C-reactive protein (hs-CRP) in type 2 diabetic patients. One hundred twenty middle-aged and elderly diabetic patients without histories of vascular events were followed up for a period of 3 years. We measured levels of soluble intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule 1, E-selectin, and hs-CRP and assessed brain ischemic lesions by magnetic resonance imaging at baseline and 3 years later. Silent cerebral infarction was observed in 13% of the patients at baseline, and these patients were significantly older and had significantly higher blood pressure than those without SCI. Thirty-two patients had newly diagnosed SCI after 3 years. There were no significant differences in factors such as age, blood pressure, and diabetic control between patients without SCI and those in whom it was newly diagnosed. However, only sICAM-1 levels, but not the other soluble adhesion molecules or hs-CRP, were associated with the progression of SCI, and this relationship remains after adjustment for risk factors. On the other hand, higher levels of sICAM-1 and hs-CRP at baseline were observed in 7 patients who were excluded from the present study because of the onset of symptomatic cerebral infarction during follow-up. Our present study suggests that sICAM-1 levels may be a potential marker for SCI, which may lead to future stroke and vascular dementia, and that this marker could be useful in monitoring disease progression and as a surrogate marker in treatment studies.     

Soluble tumor necrosis factor receptor 2 is independently associated with pulse wave velocity in nonobese Japanese patients with type 2 diabetes mellitus

The aim of the present study was to investigate the factors contributing to pulse wave velocity (PWV) in patients with type 2 diabetes mellitus. We focused on tumor necrosis factor (TNF) including soluble TNF receptors (sTNF-R1, sTNF-R2) in this study because TNF seems to be associated with the progression of atherosclerosis and because the relationships between PWV and TNF were not yet examined in type 2 diabetic patients. Univariate regression analyses showed that PWV was positively correlated with age (r=0.492, P<.001), diabetes duration (r=0.251, P=.021), systolic (r=.595, P<.001) and diastolic (r=0.248, P=.022) blood pressure, antihypertensive medication (r=0.268, P=.013), and the concentrations of sTNF-R1 (r=0.354, P=.001) and sTNF-R2 (r=0.415, P<.001). Although there was a positive correlation between TNF-alpha and sTNF-R1 (r=0.382, P<.001) or sTNF-R2 (r=0.394, P<.001), TNF-alpha was not associated with PWV. Other variables including gender were not associated with PWV. Multiple regression analyses showed that PWV was independently predicted by the level of age (F=15.1), systolic blood pressure (F=31.6), and sTNF-R2 (F=5.2), which explained 49.2% of the variability of PWV. From these results, it can be concluded that serum soluble TNF receptor is an important independent factor associated with aortic PWV in type 2 diabetic patients.     

低血糖对青年2型糖尿病患者心血管事件的影响

目的：探讨低血糖对青年2型糖尿病患者心血管事件的影响。方法：采用回顾性研究方法,2014年8月到2016年6月选择在我院内分泌科诊治的青年2型糖尿病患者360例,收集所有患者的病历资料与血压样本检测结果,记录低血糖发生情况与调查相关因素,随访心血管事件发生情况。结果：360例患者中发生低血糖20例,发生5.6%。根据2型糖尿病患者是否发生低血糖分为低血糖组(n=20)与对照组(n=340),两组的HDL-C、HbA1c、LDL-C、TG、TC值等对比无明显差异(P>0.05),不过低血糖组的SCr、CRP、CK值等都明显高于对照组(P<0.05)。通过采用Logistic回归分析发现,引起低血糖的主要因素为CRP、病程、CK以及年龄。所有患者随访6个月,低血糖组的不稳定性心绞痛、心力衰竭、靶血管血运重建、猝死等心血管事件发生率为40.0%,明显高于对照组的3.8%(P<0.05)。结论：青年2型糖尿病患者存在低血糖状况,主要发病因素包括年龄、病程、CRP、CK等,可导致心血管事件的增加,在临床上要积极进行预防性控制。