Sirtuins as potential targets for metabolic syndrome

Metabolic syndrome threatens health gains made during the past century. Physiological processes degraded by this syndrome are often oppositely affected by calorie restriction, which extends lifespan and prevents disease in rodents. Recent research in the field of ageing has begun to identify important mediators of calorie restriction, offering the hope of new drugs to improve healthspan. Moreover, if metabolic syndrome and calorie restriction are opposite extremes of the same metabolic spectrum, calorie restriction mimetics might provide another therapeutic approach to metabolic syndrome. Sirtuins and other important metabolic pathways that affect calorie restriction may serve as entry points for drugs to treat metabolic syndrome.     

SUR1基因多态性与磺脲类药物疗效的相关性

采用聚合酶链反应-限制性片段长度多态性技术检测了178例2型糖尿病和132例健康对照者磺脲类药物受体1(SURl)基因外显子16-3c／t多态性，并对其中112例糖尿病患者观察了磺脲类降糖药的疗效．与对照组相比，“t”等位基因频率和“tt”基因型(纯合子)在糖尿病组中的分布显著升高，“tt”基因型患者反映其胰岛素分泌功能的Homap指数较其他基因型(tc和cc)组显著降低，糖尿病中33例磺脲药治疗失效组t等位基因频率明显多于79例磺脲药治疗有效组．提示SURl基因变异可能导致2型糖尿病胰岛素分泌功能障碍，SUR1基因外显子16-3c／t多态性与磺脲类降糖药的疗效间存在连锁不平衡．     

GLP-1R agonists therapy for type 2 diabetes

Glucagon-like peptide-1 receptor （GLP-1R） agonists are widely used for treating type 2 diabetes mellitus （T2DM） be- cause of their glucose-lowering and weight-losing effects, and low risk of hypoglycemia. Hence, there is considerable interest in understanding the mechanism underlying the beneficial effects of GLP-I and developing stable and effective GLP-1R agonists. Here, we summarize the presently known mechanism of GLP-I actions, which are mainly through regulating cAMP-PKA signaling pathway; the latest developments in novel clinical GLP-1R agonists are also introduced, which are characterized with multiple properties, such as extended half-life, reduced side-effects, lower production costs and more convenient drug dosing mode. The potential risk of GLP-I-based therapeutics, an often-ignored fact, is also discussed.     

减肥手术治疗2型糖尿病的前景

探讨肥胖手术腹腔镜Roux-en-Y胃旁路手术(LRYGB)、腹腔镜胆胰转流术(LBPD)、腹腔镜可调节胃捆绑术(LAGB)、腹腔镜袖状胃切除术(LSC)、十二指肠空肠旁路术(DJB)治疗2型糖尿病的方法、可能的机制及效果.减重和控制2型糖尿病的效果以LBPD最佳,LAGB效果最差,但仅仅保留末段50～100 cm小肠...     

代谢综合症的运动干预

随着社会的发展和人们生活方式的改变,代谢综合症(MS)从1999年命名至今,发病率逐年升高。MS会并发T2DM、心血管疾病、肥胖等疾病,严重影响人们的生活质量甚至危及生命。MS治疗的基本策略是以改善IR为基础的心血管危险因素的综合防治。包括生活方式干预、饮食控制和运动治疗,无效时考虑药物治疗。运动作为MS的重要干预手段,对MS有着显著的影响,本文就MS与运动之间的关系做一综述。     

Abdominal obesity and metabolic syndrome

Metabolic syndrome is associated with abdominal obesity, blood lipid disorders, inflammation, insulin resistance or full-blown diabetes, and increased risk of developing cardiovascular disease. Proposed criteria for identifying patients with metabolic syndrome have contributed greatly to preventive medicine, but the value of metabolic syndrome as a scientific concept remains controversial. The presence of metabolic syndrome alone cannot predict global cardiovascular disease risk. But abdominal obesity - the most prevalent manifestation of metabolic syndrome - is a marker of 'dysfunctional adipose tissue', and is of central importance in clinical diagnosis. Better risk assessment algorithms are needed to quantify diabetes and cardiovascular disease risk on a global scale.     

A genome-wide association study identifies novel risk loci for type 2 diabetes

Type 2 diabetes mellitus results from the interaction of environmental factors with a combination of genetic variants, most of which were hitherto unknown. A systematic search for these variants was recently made possible by the development of high-density arrays that permit the genotyping of hundreds of thousands of polymorphisms. We tested 392,935 single-nucleotide polymorphisms in a French case-control cohort. Markers with the most significant difference in genotype frequencies between cases of type 2 diabetes and controls were fast-tracked for testing in a second cohort. This identified four loci containing variants that confer type 2 diabetes risk, in addition to confirming the known association with the TCF7L2 gene. These loci include a non-synonymous polymorphism in the zinc transporter SLC30A8, which is expressed exclusively in insulin-producing beta-cells, and two linkage disequilibrium blocks that contain genes potentially involved in beta-cell development or function (IDE-KIF11-HHEX and EXT2-ALX4). These associations explain a substantial portion of disease risk and constitute proof of principle for the genome-wide approach to the elucidation of complex genetic traits.     

Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes

Calorie restriction extends lifespan and produces a metabolic profile desirable for treating diseases of ageing such as type 2 diabetes. SIRT1, an NAD+-dependent deacetylase, is a principal modulator of pathways downstream of calorie restriction that produce beneficial effects on glucose homeostasis and insulin sensitivity. Resveratrol, a polyphenolic SIRT1 activator, mimics the anti-ageing effects of calorie restriction in lower organisms and in mice fed a high-fat diet ameliorates insulin resistance, increases mitochondrial content, and prolongs survival. Here we describe the identification and characterization of small molecule activators of SIRT1 that are structurally unrelated to, and 1,000-fold more potent than, resveratrol. These compounds bind to the SIRT1 enzyme-peptide substrate complex at an allosteric site amino-terminal to the catalytic domain and lower the Michaelis constant for acetylated substrates. In diet-induced obese and genetically obese mice, these compounds improve insulin sensitivity, lower plasma glucose, and increase mitochondrial capacity. In Zucker fa/fa rats, hyperinsulinaemic-euglycaemic clamp studies demonstrate that SIRT1 activators improve whole-body glucose homeostasis and insulin sensitivity in adipose tissue, skeletal muscle and liver. Thus, SIRT1 activation is a promising new therapeutic approach for treating diseases of ageing such as type 2 diabetes.     

Investigation and identification of breath acetone as a potential biomarker for type 2 diabetes diagnosis

Acetone is regarded as a promising biomarker for the noninvasive diagnosis and monitoring of diabetes.We collected breath acetone from 25 type 2 diabetics(T2D)and 44 healthy subjects using aluminum foil bags(3 L),and the samples were analyzed by gas chromatography–mass spectrometry.T2D patients had significantly higher acetone levels(mean=2.167 ppmv(1 ppmv=1 lL/L),standard error(SE)=0.231)than healthy volunteers(mean=0.488 ppmv,SE=0.025;P\0.0001).The receiver operating characteristics curve showed that the optimum diagnostic cutoff value for exhaled acetone was 0.891 ppmv(area under the curve 0.999,sensitivity 100%,and specificity 97.7%)in T2D patients relative to healthy subjects.Thus,breath acetone could be a useful marker for the high accuracy diagnosis and monitoring of diabetes.In addition,the ratios of the mean acetone concentration in ambient air relative to that in the total exhaled air and in the net exhaled air were 1:18 and 1:17,respectively.The post-breakfast acetone concentrations(mean=0.437 ppmv,SE=0.035)were slightly lower than the pre-breakfast levels(mean=0.553 ppmv,SE=0.047;P[0.05).Thus,the increased acetone concentrations in T2D patients are affected strongly by physiological factors related to the disease,rather than the ambient air and diet.     

网球运动对2型糖尿病血液流变性影响的研究

观察网球运动对2型糖尿病患者血液流变性的影响,初步探讨其可能的作用机制．将60名2型糖尿病患者随机分为运动组和对照组,其中,运动组进行4个月的网球运动锻炼．分别检测对照组和运动组实验前和实验4个月后次日、安静空腹状态下血液流变学指标,以及血糖和血脂指标．结果显示,各检测指标与对照组相比均有显著性差异,网球运动有助于2型糖尿病患者血液流变学、血糖和血脂指标的改善．本实验提示,网球运动对2型糖尿病患性病情有较好的辅助治疗作用,有利于糖尿病患者病情的康复．     

Identification of susceptibility genes loci associated with type 2 diabetes

In this study, we selected 10 susceptible SNPs loci to investigate their contribution to susceptibility to type 2 diabetes in Han Chinese among Hubei population. We genotyped SNPs rs5219, rs1801282, rs1470579, rs1111875, rs1081661, rs7754840, rs4506565, rs13266634, rs4402960, and rs5643981 by using the method of polymerase chain reaction-ligase detection reaction (PCR-LDR). In a case-control study, we have genotyped the 10 candidate susceptibility SNP loci, and here, we reported that the SNP rs5219 in KCNJ1...     

Large-scale prediction and testing of drug activity on side-effect targets

Discovering the unintended 'off-targets' that predict adverse drug reactions is daunting by empirical methods alone. Drugs can act on several protein targets, some of which can be unrelated by conventional molecular metrics, and hundreds of proteins have been implicated in side effects. Here we use a computational strategy to predict the activity of 656 marketed drugs on 73 unintended 'side-effect' targets. Approximately half of the predictions were confirmed, either from proprietary databases unknown to the method or by new experimental assays. Affinities for these new off-targets ranged from 1 nM to 30 μM. To explore relevance, we developed an association metric to prioritize those new off-targets that explained side effects better than any known target of a given drug, creating a drug-target-adverse drug reaction network. Among these new associations was the prediction that the abdominal pain side effect of the synthetic oestrogen chlorotrianisene was mediated through its newly discovered inhibition of the enzyme cyclooxygenase-1. The clinical relevance of this inhibition was borne out in whole human blood platelet aggregation assays. This approach may have wide application to de-risking toxicological liabilities in drug discovery.     

代谢综合征的流行病学调查与分析

目的：了解20岁以上成年人代谢综合征的发生率;对比分析其相关的危险因素及保护因素。方法：(1)通过1026名20岁以上成人体检,应用修订的代谢综合征的美国诊断标准,凡具备以下5项标准中3项及3项以上,即①体质指数(BMI)≥24,②甘油三酯ρ(TG)≥150mg／dL,③高密度脂蛋白胆固醇ρ(HDL—C)男＜40mg／dL、ρ(HDL—C)女＜50mg／dL,④空腹血糖ρ(FBC)≥110mg／dL,⑤收缩期血压(SBP)≥130mmHg或舒张期血压(DBP)≥85mmHg或SBP／DBP≥130mmHg／85mmHg(1mmHg＝0．133kPa),诊断为代谢综合征,共检出136名为病例组。(2)从既往无高血压、糖尿病、冠心病及血脂异常史,且本次筛检未纳入代谢综合征的人群中,抽取与病例组性别、年龄相当的136名进行配对调查分析,计算其相关因素的χ^2值、P值、机会比(OR)值,以及机会比值的95％可信限(OR 95％CI)。结果：(1)从1026名中共检出代谢综合征136名,其发生率为13．26％;(2)调查分析发现摄入过量和长时间处于坐位而又缺乏运动两项可能为代谢综合征的危险因素;而运动可能是代谢综合征的保护因素。结论：(1)本次广东地区部分人群筛查20岁以上成人代谢综合征的发生率为13．26％,虽较美国人为低,但中年组为17．48％,老年组高达29．27％,必须引起重视;(2)坚持终身运动和合理膳食可能是预防代谢综合征的切实可行、经济、有效的措施。     

乒乓球运动对2型糖尿病患者糖化血红蛋白影响的研究

随机选取50名2型糖尿病患者,分为运动组和对照组,观察乒乓球运动对其糖化血红蛋白的影响.运动组进行4个月的乒乓球运动.检测实验前后安静空腹状态下糖化血红蛋白以及常规血糖和血脂指标.乒乓球锻炼有助于2型糖尿病患者糖化血红蛋白、血糖和血脂指标的改善(分别P<0.05和P<0.01).乒乓球运动锻炼对2型糖尿病患者有较好的辅助治疗作用,是有效的康复手段.     

基于网络药理学探究黄酮对2型糖尿病的作用机制

应用网络药理学的方法探究了已分离得到的6个黄酮与2型糖尿病相互作用的机制.通过相关数据库的筛选与预测,获得了化合物与疾病的靶基因,进一步得到了两者的交集基因;通过Cytoscape 3.8.0软件构建了这些化合物与2型糖尿病相关的PPI网络与成分-疾病-靶点网络图;通过R语言半编程程序对交集基因进行生物功能富集和通路富...     

Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes

In obesity and type 2 diabetes, expression of the GLUT4 glucose transporter is decreased selectively in adipocytes. Adipose-specific Glut4 (also known as Slc2a4) knockout (adipose-Glut4(-/-)) mice show insulin resistance secondarily in muscle and liver. Here we show, using DNA arrays, that expression of retinol binding protein-4 (RBP4) is elevated in adipose tissue of adipose-Glut4(-/-) mice. We show that serum RBP4 levels are elevated in insulin-resistant mice and humans with obesity and type 2 diabetes. RBP4 levels are normalized by rosiglitazone, an insulin-sensitizing drug. Transgenic overexpression of human RBP4 or injection of recombinant RBP4 in normal mice causes insulin resistance. Conversely, genetic deletion of Rbp4 enhances insulin sensitivity. Fenretinide, a synthetic retinoid that increases urinary excretion of RBP4, normalizes serum RBP4 levels and improves insulin resistance and glucose intolerance in mice with obesity induced by a high-fat diet. Increasing serum RBP4 induces hepatic expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and impairs insulin signalling in muscle. Thus, RBP4 is an adipocyte-derived 'signal' that may contribute to the pathogenesis of type 2 diabetes. Lowering RBP4 could be a new strategy for treating type 2 diabetes.     

2型糖尿病患者IRS-2基因型对运动易感性差异的研究

研究西安市汉族人群中2型糖尿病患者IRS-2基因密码子1057g／a多态性与运动易感性间的相关性．PCR—RFLP的方法检测IRS-2基因密码子1057g／a多态性后,随机分3组：gg、ga和aa基因型组,经12周的太极拳运动锻炼后发现,aa基因型组对运动的易感性最高,反映糖尿病情改善的主要指标均发生了良好的改变．发现西安市汉族人群中不同2型糖尿病患者IRS-2基因型对运动的易感性存在着明显差异,aa基因型组患者的运动易感性高于其他基因型．     

Genetic analysis of autoimmune type 1 diabetes mellitus in mice.

Two genes, Idd-3 and Idd-4, that influence the onset of autoimmune type 1 diabetes in the nonobese diabetic mouse have been located on chromosomes 3 and 11, outside the chromosome 17 major histocompatibility complex. A genetic map of the mouse genome, analysed using the polymerase chain reaction, has been assembled specifically for the study. On the basis of comparative maps of the mouse and human genomes, the homologue of Idd-3 may reside on human chromosomes 1 or 4 and Idd-4 on chromosome 17.     

血糖控制良好的2型糖尿病患者血清VEGF—A及其受体VEGFR1和VEGFR2含量检测

研究目的：探讨血糖控制良好的2型糖尿病患者血管内皮生长因子-A（VEGF—A）及其受体VEGFR1和VEGFR2含量及其临床意义。研究方法：本文以31例血糖得到良好控制且没有明显大血管或微血管病变的2型糖尿病患者作为研究对象（实验组）,30位健康志愿者为对照组,同期检测患者及健康志愿者的空腹血糖、血脂、糖化血红蛋白水平,及血清VEGF—A、VEGFR1和VEGFR2含量,并加以比较和统计学分析。重要结论：研究结果表明,血糖控制良好的2型糖尿病患者血清中的VEGF-A及其受体VEGFR1和VEGFR2的含量和健康志愿者基本一致,两者无统计学意义,这可能显示血糖水平的合理控制能延缓血管并发症的产生。同时,2型糖尿病患者的血清VEGFR2含量和高密度脂蛋白胆固醇水平之间存在负相关,而血清VEGF-A、VEGFR2含量和甘油三脂水平之间存在正相关,这也表明糖尿病患者的血脂紊乱可能参与了血管生成的调节。     

2型糖尿病并发尿路感染36例分析

目的探讨2型糖尿病并发尿路感染的有效诊断及治疗方法.方法采用回顾性分析的方法,对36例2型糖尿病合并尿路感染的患者进行分析.结果结合临床表现、尿十一项和尿培养确诊者36例,经控制血糖和抗感染治疗后均痊愈.结论控制血糖,适当选择敏感抗生素是控制糖尿病并发尿路感染的关键.