A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants

Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.     

Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels

New strategies for prevention and treatment of type 2 diabetes (T2D) require improved insight into disease etiology. We analyzed 386,731 common single-nucleotide polymorphisms (SNPs) in 1464 patients with T2D and 1467 matched controls, each characterized for measures of glucose metabolism, lipids, obesity, and blood pressure. With collaborators (FUSION and WTCCC/UKT2D), we identified and confirmed three loci associated with T2D-in a noncoding region near CDKN2A and CDKN2B, in an intron of IGF2BP2, and an intron of CDKAL1-and replicated associations near HHEX and in SLC30A8 found by a recent whole-genome association study. We identified and confirmed association of a SNP in an intron of glucokinase regulatory protein (GCKR) with serum triglycerides. The discovery of associated variants in unsuspected genes and outside coding regions illustrates the ability of genome-wide association studies to provide potentially important clues to the pathogenesis of common diseases.     

A common variant on chromosome 9p21 affects the risk of myocardial infarction

The global endemic of cardiovascular diseases calls for improved risk assessment and treatment. Here, we describe an association between myocardial infarction (MI) and a common sequence variant on chromosome 9p21. This study included a total of 4587 cases and 12,767 controls. The identified variant, adjacent to the tumor suppressor genes CDKN2A and CDKN2B, was associated with the disease with high significance. Approximately 21% of individuals in the population are homozygous for this variant, and their estimated risk of suffering myocardial infarction is 1.64 times as great as that of noncarriers. The corresponding risk is 2.02 times as great for early-onset cases. The population attributable risk is 21% for MI in general and 31% for early-onset cases.     

2型糖尿病合并高血压患者血清脂联素和内脏脂肪素水平的变化

目的:了解2型糖尿病合并高血压患者血清脂联素和内脏脂肪素的变化,探讨脂联素和内脏脂肪素与2型糖尿病合并高血压的相关性.方法:选取高血压患者40例,2型糖尿病患者38例,2型糖尿病合并高血压患者40例,健康对照者40例作为研究对象,测定其血清脂联素和内脏脂肪素水平,同时测定血压、血糖、血脂和体质量指数等指标,并分析以上指标与脂联素和内脏脂肪素的关系.结果:单纯2型糖尿病组和单纯高血压组内脏脂肪素水平明显高于正常对照组,分别为(18.26±1.22)ng/mL,(17.31±1.26)ng/mL和(13.32±1.31)ng/mL(p<0.05);2型糖尿病合并高血压组(24.99±1.36)ng/mL又明显高于单纯2型糖尿病组和单纯高血压组.2型糖尿病组和高血压组脂联素水平明显低于正常对照组,分别为(8.75±1.29)μg/mL,(9.71±1.28)μg/mL和(12.67±1.48)μg/mL(p<0.05);2型糖尿病合并高血压组(5.73±1.23)μg/mL又明显低于单纯2型糖尿病组和单纯高血压组.2型糖尿病组和高血压组的脂联素和内脏脂肪素水平差异不具有统计学意义(p>0.05).相关分析显示2型糖...     

A common allele on chromosome 9 associated with coronary heart disease

Coronary heart disease (CHD) is a major cause of death in Western countries. We used genome-wide association scanning to identify a 58-kilobase interval on chromosome 9p21 that was consistently associated with CHD in six independent samples (more than 23,000 participants) from four Caucasian populations. This interval, which is located near the CDKN2A and CDKN2B genes, contains no annotated genes and is not associated with established CHD risk factors such as plasma lipoproteins, hypertension, or diabetes. Homozygotes for the risk allele make up 20 to 25% of Caucasians and have a approximately 30 to 40% increased risk of CHD.     

The mutational landscape of head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously known HNSCC genes (TP53, CDKN2A, PTEN, PIK3CA, and HRAS), our analysis revealed many genes not previously implicated in this malignancy. At least 30% of cases harbored mutations in genes that regulate squamous differentiation (for example, NOTCH1, IRF6, and TP63), implicating its dysregulation as a major driver of HNSCC carcinogenesis. More generally, the results indicate the ability of large-scale sequencing to reveal fundamental tumorigenic mechanisms.     

2型糖尿病患者膳食现状调查及营养治疗研究

为了解2型糖尿病患者膳食摄入现况,评价其膳食质量;同时对2型糖尿病患者进行营养治疗,观察治疗效果。应用3天膳食回顾法对在首都医科大学附属北京同仁医院住院的86例2型糖尿病患者进行膳食现况调查,对调查结果进行营养学分析评价;由营养师根据患者的具体情况提供个性化的糖尿病饮食,并且分别测定营养治疗前后患者的相关血糖指标。结果表明,2型糖尿病患者水果类和鱼虾类摄入量偏低,奶类、蔬菜类、禽畜肉类、蛋类、油脂类摄入量偏高,能量来源分配比例不合理,脂肪摄入过高,碳水化合物摄入过低;采用营养治疗措施以后,患者空腹血糖和餐后2 h血糖比干预前有所降低,且饮食结构趋于合理。由此可见,目前2型糖尿病患者膳食结构不合理,经过营养治疗可以更好的控制患者住院期间的血糖,显著减少不良临床结局显的出现;建议对2型糖尿病患者加强营养教育,促进营养干预。     

中等强度有氧运动对2型糖尿病患者胰岛素抵抗相关因素的影响

探讨中等强度有氧运动对2型糖尿病患者胰岛素抵抗相关因素的影响。选取海南医学院附属医院内分泌科自2011年2月至2014年3月确诊的2型糖尿病（T2DM）患者86例,随机分成两组。观察组46例,其中男25例,女21例;对照组40例,其中男23例,女17例。对照组继续按照糖尿病的一般治疗进行教育与自我检测血糖,同时按照医院治疗方案进行口服药物或胰岛素注射等基础治疗。观察组除上述治疗外,按照美国糖尿病学会（ADA）与美国运动医学学会（ACSM）于2010年颁布的《2型糖尿病运动指南》中的推荐,制定针对个体的不同中等强度运动方案。两组患者在实验前及12个月后晨起空腹状态测定BMI、体脂率、FPG、HbA1c、FINS、HOMA-IR。研究显示长期中等强度有氧运动对2型糖尿病患者BMI、体脂率、FPG、HbA1c、FINS、HOMA-IR等指标有显著影响。     

缬沙坦联用吲达帕胺缓释片对2型糖尿病伴高血压左心室肥厚及舒张功能的影响

目的观察缬沙坦联用吲达帕胺缓释片对2型糖尿病伴高血压左心室肥厚及舒张功能的影响。方法2型糖尿病伴高血压左心室肥厚及舒张功能不全患者120例,随机分为对照组和观察组,每组各60例。对照组服用缬沙坦80mg,每日1次;观察组服用缬沙坦80mg及吲达帕胺缓释片1.5mg,每日1次。所有病例观察20周,主要观察药物降压疗效、对左心室肥厚及左心室舒张功能的影响。结果缬沙坦和吲达帕胺缓释片联用比单用缬沙坦的降压效果更好。疗程结束后,观察组的舒张末期室间隔厚度及舒张末期左心室后壁厚度的改善程度明显优于对照组(P<0.01)。结论缬沙坦与吲达帕胺缓释片联用能有效的降低2型糖尿病伴高血压左心室肥厚及舒张功能不全患者的血压、逆转左心室肥厚及改善左心室的舒张功能。     

Allosteric activators of glucokinase: potential role in diabetes therapy

Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic beta cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.     

Mitochondrial dysfunction in the elderly: possible role in insulin resistance

Insulin resistance is a major factor in the pathogenesis of type 2 diabetes in the elderly. To investigate how insulin resistance arises, we studied healthy, lean, elderly and young participants matched for lean body mass and fat mass. Elderly study participants were markedly insulin-resistant as compared with young controls, and this resistance was attributable to reduced insulin-stimulated muscle glucose metabolism. These changes were associated with increased fat accumulation in muscle and liver tissue assessed by 1H nuclear magnetic resonance (NMR) spectroscopy, and with a approximately 40% reduction in mitochondrial oxidative and phosphorylation activity, as assessed by in vivo 13C/31P NMR spectroscopy. These data support the hypothesis that an age-associated decline in mitochondrial function contributes to insulin resistance in the elderly.     

Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkbeta

We show that high doses of salicylates reverse hyperglycemia, hyperinsulinemia, and dyslipidemia in obese rodents by sensitizing insulin signaling. Activation or overexpression of the IkappaB kinase beta (IKKbeta) attenuated insulin signaling in cultured cells, whereas IKKbeta inhibition reversed insulin resistance. Thus, IKKbeta, rather than the cyclooxygenases, appears to be the relevant molecular target. Heterozygous deletion (Ikkbeta+/-) protected against the development of insulin resistance during high-fat feeding and in obese Lep(ob/ob) mice. These findings implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type 2 diabetes mellitus and identify the IKKbeta pathway as a target for insulin sensitization.     

脑疝后脑梗死的危险因素分析

目的探讨脑疝后脑梗死发生的危险因素。方法脑疝患者109例,其中发生脑梗死18例,收集这些患者的临床和影像学资料,分析脑疝后脑梗死发生的危险因素。结果糖尿病史、外伤所致脑疝及脑疝时大脑脚池、环池受压明显者脑疝后脑梗死发生率高于阴性患者(P<0.01或0.05)。结论糖尿病史、外伤所致脑疝及脑疝时大脑脚池、环池受压明显是脑疝后脑梗死的危险因素。     

梅花 PmAP2基因的克隆及表达1）

为了解析梅花（Prunus mume Sieb．et Zucc．）花器官发育的分子调控机理,采用RT－PCR的方法从梅花‘三轮玉蝶’中克隆了APETALE2的同源基因PmAP2,并采用荧光定量PCR对PmAP 2的表达模式进行了分析。序列分析表明,PmAP2基因CDS区域全长1647 bp,编码548个氨基酸,含有两个保守的AP2结构域,属于AP2／ERF基因家族。多序列比对和系统进化结果显示,该基因与桃、苹果AP2基因相似性较高,分别为96％和82％。PmAP2在梅花营养器官、四轮花器官和果实中均有表达,花瓣中的表达量最高;台阁花型梅花花中PmAP2表达量最高,重瓣品种次之,单瓣品种表达量最低。 PmAP2的差异表达可能与梅花的花型进化有关。     

A family with severe insulin resistance and diabetes due to a mutation in AKT2

Inherited defects in signaling pathways downstream of the insulin receptor have long been suggested to contribute to human type 2 diabetes mellitus. Here we describe a mutation in the gene encoding the protein kinase AKT2/PKBbeta in a family that shows autosomal dominant inheritance of severe insulin resistance and diabetes mellitus. Expression of the mutant kinase in cultured cells disrupted insulin signaling to metabolic end points and inhibited the function of coexpressed, wild-type AKT. These findings demonstrate the central importance of AKT signaling to insulin sensitivity in humans.     

社区综合干预对Ⅱ型糖尿病患者自我管理和疗效的影响

目的：评价Ⅱ型糖尿病患者通过社区综合干预疗法后对其自我管理能力和治疗效果的影响.方法将100例Ⅱ型糖尿病患者随机分为观察组和对照组,每组各50例,两组患者原治疗方案不变,观察组在维持原治疗方案的基础上进行为期10个月的社区综合干预.分别于干预前后进行糖尿病相关知识问卷调查及自我管理能力的测试,并检测空腹血糖和糖化血红蛋白等.结果综合干预10个月后,观察组有关糖尿病知识掌握情况、自我管理能力大大提高,与对照组比较差异具有统计学意义（P〈0.05）.观察组空腹血糖（FBG）、餐后2 h血糖（PBG）、糖化血红蛋白（HbAlc）干预前后比较差异具有统计学意义（P〈0.05）.结论社区综合干预可有效提高Ⅱ型糖尿病患者的糖尿病知识水平和自我管理能力,患者FBG,PBG,HbAlc控制较好,可提高Ⅱ型糖尿病患者的治疗效果.     

Three recessive loci required for insulin-dependent diabetes in nonobese diabetic mice

A polygenic basis for susceptibility to insulin-dependent diabetes in nonobese diabetic (NOD) mice has been established by outcross to a related inbred strain, nonobese normal (NON). Analysis of first and second backcross progeny has shown that at least three recessive genes are required for development of overt diabetes. One, Idd-1s, is tightly linked to the H-2K locus on chromosome 17; another, Idd-2s, is localized proximal to the Thy-1/Alp-1 cluster on chromosome 9. Segregation of a third, Idd-3s, could be shown in a second backcross. Neither Idd-1s nor Idd-2s could individually be identified as the locus controlling insulitis; leukocytic infiltrates in pancreas were common in most asymptomatic BC1 mice. Both F1 and BC1 mice exhibited the unusually high percentage of splenic T lymphocytes characteristic of NOD, suggesting dominant inheritance of this trait. The polygenic control of diabetogenesis in NOD mice, in which a recessive gene linked to the major histocompatibility complex is but one of several controlling loci, suggests that similar polygenic interactions underlie this type of diabetes in humans.     

乙型肝炎肝硬化患者血清IL-18、IL-18结合蛋白a亚群水平的检测及临床意义

目的探讨乙型肝炎肝硬化患者血清白细胞介素18（IL-18）和白细胞介素18结合蛋白（IL-18BP）的水平变化及其与病情的关系。方法用ELISA法检测75例乙型肝炎肝硬化患者（Child—PughA级、Child—PughB级、Child-PughC级各25例）和25例正常对照血清IL-18、IL-18BPa亚群（IL-18BPa）水平。结果乙型肝炎肝硬化患者血清IL-18、IL-18BPa水平均明显高于正常对照（P〈0．01）,并且Child—PughA、B、C三级IL-18、IL-18BPa的水平依次递增,各级间差异有统计学意义（P〈0．01或0．05）。结论检测血清IL-18、IL-18BP水平有助于判断乙型肝炎肝硬化病情的严重程度,IL-18BP可能不足以中和IL-18。     

mtDNA A3243G 点突变小鼠模型的建立及其致病机制探讨

    利用显微注射线粒体技术建立转人线粒体小鼠模型,研究外源突变mtDNA在不同组织的分布及遗传规律,探讨mtDNA A3243G点突变对线粒体功能的影响.从健康成人及2型糖尿病患者(携带mtDNA 3243A-G突变)血液标本中分离有活性的线粒体,将其显微注射至小鼠受精卵,胚胎移植,产出仔鼠后利用分子生物学方法检测人mtDNA及mtDNA A3243G点突变.获得嵌合体小鼠后,对其空腹血糖和全血乳酸进行测定,并使用荧光法和比色法分析A3243G点突变小鼠重要脏器组织细胞活性氧生成量(ROS)、线粒体复合酶Ⅰ和Ⅳ活力及线粒体ATP合成活力的变化.研究结果显示:在1只雌性(转健康人线粒体)和2只雄性小鼠(转患者线粒体)中检测到人mtDNA,其中2只雄性小鼠携带mtDNA 3243A-G突变;将嵌和体雌鼠与野生型C57BL/6J 雄鼠交配后,在1只后代仔鼠中检测到人mtDNA;人mtDNA仅在嵌合小鼠的部分组织中表达.在含有mtDNA A3243G突变的组织中发现,线粒体复合酶Ⅰ、Ⅳ活力降低,ATP合成速率下降,ROS水平升高,说明A3243G点突变能损伤线粒体正常功能从而导致疾病的发生.综上所述,本研究利用显微注射法成功建立了嵌和小鼠,引入了致病性的点突变,为线粒体疾病的研究提供了良好的思路.