血浆促酰化蛋白水平与儿童青少年肥胖和代谢综合征的关联性分析

目的探讨儿童青少年血浆促酰化蛋白（ASP）水平与肥胖及代谢综合征（MS）的关系。方法以2004年北京市儿童青少年代谢综合征（BCAMS）调查总样本中1 603名6~18岁儿童青少年为研究对象。采用中国肥胖问题工作组推荐的标准诊断超重和肥胖。符合下述5项指标中的3项及以上者诊断为MS：①腹型肥胖（腰围≥P90）;②高血压（≥P90）;③高密度脂蛋白胆固醇≤1.03 mmol·L-1;④三酰甘油≥1.24 mmol·L-1;⑤高空腹血糖（≥5.60 mmol·L-1)。采用ELISA法检测血浆ASP水平,免疫透射比浊法检测补体3（C3）水平。采用方差分析比较超重、肥胖及MS儿童青少年的血浆ASP水平,多因素Logistic回归分析血浆ASP水平与超重、肥胖及MS的关系。结果1 603名研究对象中男性873名（54.5%）、女性730名（45.5％）;超重和肥胖者分别为291名（18.2%）和709名（44.2%）;MS为376名（23.4%）。正常体重、超重和肥胖组MS检出率分别为2.2%(13/603名)、15.5%(45/291名)和44.9%(318/709名)。正常体重组血浆ASP水平男性低于女性,差异有统计学意义（t=2.527,P<0.05）。正常体重、超重和肥胖组血浆ASP的几何均值（P25~P75）,男性分别为37.52(22.36~64.58)、57.88(34.10~95.11)和60.63(35.30~109.72) nmol·L-1;女性分别为44.16(27.27~74.72)、60.25(35.68~113.15)和66.68(44.56~113.97) nmol·L-1,均呈逐渐升高趋势（男性：F=34.329,P<0.001;女性：F=22.246,P<0.001）。C3水平仅在肥胖女性中升高（P<0.01）。血浆ASP水平随MS组分聚集的数目增加而升高（男性：F=16.422,P<0.001;女性：F=9.661,P<0.001）,与高血压、腹型肥胖和高空腹血糖的关系尤为密切。血浆ASP水平升高与儿童青少年超重、肥胖和MS的患病风险密切相关,相对于最低5分位值,位于最高5分位值的ASP水平与超重、肥胖和MS关系的OR值(95%CI)分别为3.90(2.38~6.39)、6.05(4.06~9.01)和2.89(1.93~4.33)。结论超重、肥胖和MS儿童青少年血浆ASP水平明显升高,血浆ASP水平可能对儿童青少年超重、肥胖和MS的发生具有较好的预测价值。     

促酰化蛋白诱导前脂肪细胞分化过程中DGAT、LPL、adipsin mRNA表达

目的观察促酰化蛋白（acylation stimulating protein，ASP）诱导3T3-L1前脂肪细胞的分化过程中。脂肪特异性的功能酶脂蛋白脂酶（LPI。）、二酰基甘油转酰酶（DGAT）以及脂肪细胞特异性功能蛋白adipsin表达的时序性和强度。方法以3T3-L1前脂肪细胞为实验对象，用ASP代替经典激素鸡尾酒诱导刺激中的胰岛素。诱导3T3-L1前脂肪细胞分化，分别在诱导分化1、2、4、6、8d收获细胞，采用RT—PCR法检测分化过程中LPL、DGAT和adipsin的mRNA表达情况。结果在ASP诱导3T3-L1前脂肪细胞分化过程中。LPL、DGAT、adipsinmRNA表达逐渐升高。其中LPL mRNA表达最早，在分化1d时就有低水平的表达。分化2d时出现DGAT mRNA的表达，并随着脂肪细胞的进一步分化成熟，LPL和DGAT mRNA表达水平逐步升高，持续到分化终末期；adipsin mRNA表达出现最晚，在分化4d时才有表达，随后其表达水平急剧升高，持续到分化终末期。结论ASP诱导3T3-L1前脂肪细胞分化过程中。按照一定的时序性依次诱导脂肪特异性的功能酶LPL、DGAT和功能蛋白adipsin的mRNA表达，是脂肪细胞生物学功能成熟的重要物质基础，同时也是ASP诱导前脂肪细胞分化的分子机制之一。     

2型糖尿病患者血浆脂联素水平及其影响因素

目的 了解2型糖尿病患者血浆脂联素水平与体重指数(BMI)、血浆胰岛素水平、游离脂肪酸(FFA)及血脂的相关性。方法 根据BMI水平将51名2型糖尿病患者分为肥胖2型糖尿病组(BMI≥25kg/m2)、正常体重2型糖尿病组,将28名正常体重非糖尿病者设为对照组。以ELISA法测定脂联素和FFA,化学发光法测定空腹胰岛素(FINS),同时测定空腹血糖(FPG)、餐后2 h血糖(2HPG)、甘油三酯(TG)、总胆固醇(TC)、高密度脂蛋白胆固醇(HDL-C),计算低密度脂蛋白胆固醇(LDL-C)和胰岛素抵抗指数(HOMA-IR)。结果 肥胖2型糖尿病组脂联素水平显著低于非肥胖2型糖尿病组和对照组(P<0.05),后两组脂联素水平无差异。单因素相关分析显示脂联素与BMI及TG负相关,相关系数分别为-0.3459(P<0.01)和-0.3603(P<0.01),与FFA等无相关性。包括年龄、BMI、HDL-C、LDL-C、TG、TC、FPG、FINS、FFA和HOMA-IR的多因素回归分析显示,BMI和TG对脂联素的影响相当。结论 不同BMI个体的脂联素水平具有差异,在正常BMI范围内的2型糖尿病患者与非糖尿病者血浆脂联素水平差异无显著性。胰岛素抵抗程度对脂联素无明显影响。TG和BMI是一组很好的评估脂联素水平和作用的指标。     

Increased plasma acylation-stimulating protein in pediatric proteinuric renal disease

Hyperlipidemia has been well recognized as a striking feature of nephrotic syndrome and other renal diseases. However, the underlying pathophysiological mechanisms still have not yet been elucidated. In this study, we evaluated acylation-stimulating protein (ASP) and complement component 3 (C3) in children (n = 48) with various forms of proteinuric renal disease [nephrotic syndrome, acute poststreptococcal infection glomerulonephritis (APSGN), and lupus nephritis (LN)] in comparison with age- and gender-matched controls (n = 279). In children with proteinuric renal disease, various aberrations in plasma lipids were noted, including increased triglyceride, cholesterol, and low-density lipoprotein cholesterol (LDL-C) (all p < 0.0001). Whereas C3 was not altered in children with nephrotic syndrome (1.05 ± 0.05 g/L vs. 1.29 ± 0.04 controls), the decrease was pronounced in children with LN and APSGN (0.42 ± 0.11, p < 0.05 and 0.30 ± 0.06, p < 0.001, respectively). Plasma C3 correlated positively with lipid parameters [triglyceride, cholesterol, LDL-C, apolipoprotein B (apoB), high-density lipoprotein cholesterol (HDL-C) and apoA1] and inversely with total protein, blood urea nitrogen, and creatinine. By contrast, plasma ASP was significantly elevated in all proteinuric renal diseases (101.4 ± 7.1 nmol/L nephrotic syndrome, 90.9 ± 14.1 LN, and 81.8 ± 7.2 APSGN vs. 44.3 ± 1.5 controls, p < 0.05 to p < 0.001), and this increase was correlated with changes in lipid parameters (triglycerides and apoA1). In summary, these results demonstrate alterations in C3 and ASP that may contribute to or compensate for dyslipidemia.     

Abnormal adipokines associated with various types of obesity in Chinese children and adolescents

Objective To explore the role of adipokines including insulin, resistin, leptin, adiponectin, acylation stimulating protein (ASP) and complement C3 (C3) in various types of obesity (peripheral obesity, abdominal obesity and mixed obesity) in Chinese children and adolescents, and their relationships with body size and pubertal development. Methods Children and adolescents (n=3 508) aged 6 to 18 years, with 1 788 boys and 1 720 girls were assessed for body mass index, waist circumference, pubertal development...     

Lifestyle behaviours and components of energy balance as independent predictors of ghrelin and adiponectin in young non-obese women

AIM: Dysregulation of the normal levels of ghrelin, leptin and adiponectin in young non-obese subjects could promote food intake, diabetes and cardiovascular disease in later stages of life. Little information is available on how plasmatic concentrations of these hormones may be influenced by eating habits and/or components of energy balance in a young population, which if known, could facilitate their voluntary regulation. METHODS: In this cross-sectional study we examined the predictors of fasting plasma ghrelin, adiponectin and leptin in a population of well-characterized young non-obese women (N = 63). Energy intake was assessed by 24-hour dietary recall, resting metabolic rate (RMR) by indirect calorimetry, physical activity energy expenditure (PAEE) by tri-axial accelerometer, physical fitness by VO(2 peak), and eating behaviors by self administrated questionnaire. RESULTS: Lower RMR and higher HDL-cholesterol were independent predictors of higher plasma ghrelin explaining 17.6% of its variation even after correcting for BMI. Higher total or central fat mass was the only predictor of higher plasma leptin, and no other variable added any power to the prediction equation. Finally, higher energy intake and waist circumference and lower PAEE predicted lower plasma adiponectin in young non-obese women, explaining 43% of the variation in its concentrations even after correcting for total or central fat mass. CONCLUSION: Components of the energy balance (ie: energy intake and/or expenditure) influence adiponectin and ghrelin circulating levels. That is, higher energy intake and lower physical activity independently predict lower adiponectin concentrations, whereas lower resting metabolic rate independently predicts higher ghrelin levels in young non-obese women. Prospective studies are needed to examine whether circulating concentrations of ghrelin and adiponectin can be voluntarily regulated by lifestyle interventions.     

The risk and cost-effective individual patient management: The challenge of a new generation of clinical trials

Summary The percentage reduction of risk demonstrated in several recent trials is quite remarkable. For example 1 out of 5, and even as many as 1 out of 3, fatal cardiovascular events can be prevented by some treatments. Further efforts aimed at producing a substantially greater percentage reduction of risk than demonstrated so far with thrombolytic agents in acute MI, aspirin in patients discharged from the hospital with a diagnosis of unstable angina, or statins in the secondary and primary prevention of ischemic heart disease would be quite difficult to achieve and would require greater patient compliance and more powerful drugs, possibly with greater side effects and costs. The growing size of trials with very broad inclusion criteria may seem logical to trialists, who reason that the broader the inclusion criteria, the easier it is to recruit very large numbers of patients in a short space of time and the more widely applicable the results of the study. The pharmaceutical industry also prefers broad inclusion criteria, which imply wider indications for use of their products. However, very large trials with broad inclusion criteria raise two grounds for concern for practicing physicians and for the economics of health care. The first is the fact that the larger the number of patients that have to be included in a trial in order to prove a statistically significant benefit, the greater the uncertainty about the reasons why the beneficial effects of the treatment cannot be detected in a smaller trial. Secondly, this method of assessment is rapidly increasing the number of treatments that produce a statistically significant improvement in prognosis within the same broad group of patients. A large percentage reduction in mortality that reaches statistical significance only in very large trials suggests either a relatively low rate of preventable deaths in all individuals in the group or considerable heterogeneity in the patients enrolled, only a few of whom benefit from the treatment. This alternative is of considerable practical importance, first because a large heterogeneity of patients implies a dilution effect of those susceptible to the benefits of treatment by those who are not susceptible and are treated unnecessarily; and second, because uniformly low rates of potentially preventable death raise such issues as prolongation of life expectancy, surrogate endpoints, and the effects of treatment on the quality of life. Only a new generation of clinical trials that include only homogenous groups of potential responders can produce both results more readily applicable to personalized patient care in clinical practice (which is a desirable target for the practicing physician) and a large reduction in the number of events per patient treated (which is a desirable target for the economics of health care).     

Elevated sensitivity to diet-induced obesity and insulin resistance in mice lacking 4E-BP1 and 4E-BP2

The most common pathology associated with obesity is insulin resistance, which results in the onset of type 2 diabetes mellitus. Several studies have implicated the mammalian target of rapamycin (mTOR) signaling pathway in obesity. Eukaryotic translation initiation factor 4E-binding (eIF4E-binding) proteins (4E-BPs), which repress translation by binding to eIF4E, are downstream effectors of mTOR. We report that the combined disruption of 4E-BP1 and 4E-BP2 in mice increased their sensitivity to diet-induced obesity. Increased adiposity was explained at least in part by accelerated adipogenesis driven by increased expression of CCAAT/enhancer-binding protein delta (C/EBPdelta), C/EBPalpha, and PPARgamma coupled with reduced energy expenditure, reduced lipolysis, and greater fatty acid reesterification in the adipose tissue of 4E-BP1 and 4E-BP2 double KO mice. Increased insulin resistance in 4E-BP1 and 4E-BP2 double KO mice was associated with increased ribosomal protein S6 kinase (S6K) activity and impairment of Akt signaling in muscle, liver, and adipose tissue. These data clearly demonstrate the role of 4E-BPs as a metabolic brake in the development of obesity and reinforce the idea that deregulated mTOR signaling is associated with the development of the metabolic syndrome.