糖尿病全基因组关联研究告诉我们什么？

全基因组关联研究（genome—wide association study,GWAS）是指在全基因组层面上,利用现代基因芯片技术,通过对大样本人群DNA进行高密度遗传标记的分型检测,从而寻找多基因复杂病如糖尿病、肥胖病等的遗传因素的一种研究方法,能够发现与疾病发生、发展相关的基因变异位点.     

单基因糖尿病的研究进展

单基因糖尿病在儿童糖尿病中约占1％～4％,大部分易被误诊为1型或2型糖尿病.目前已发现40余种单基因糖尿病的致病基因,其通过复杂的转录因子网络调控等途径影响胰腺的发育、分化、功能和形态的完整性等.单基因糖尿病的临床表型、遗传方式不尽相同,其确诊依靠基因诊断,基因诊断明确后可以针对性的开展个体化治疗和遗传咨询.     

从青少年起病的成人型糖尿病基因看多基因糖尿病易感性

近年研究表明,单基因糖尿病致病基因的高频多态位点可能影响多基因糖尿病的遗传易感性.这些高频多态本身对基因表达或活性的影响比较微弱甚至并不明显,但可增加个体的糖尿病患病风险.     

口服降糖药在糖尿病防治中的应用策略

糖尿病病人绝大数是2型糖尿病，它是由多基因（遗传）和多因素（环境）共同作用，导致胰岛素分泌缺乏、胰岛素作用减弱或两者兼有共同作用的结果。除个别糖尿病与单基因遗传有密切联系外，大多数糖尿病的易感基因尚无定论，基因治疗仍停留在可望不可及阶段，而针对环境因素对疾病促发作用，采取积极的干预措施可延缓和减少糖尿病前期转为糖尿病，对已诊断的糖尿病，尽早、积极地治疗，包括降糖药的应用，可减少和防止其并发症的发生与发展。     

MODY 13的研究、认识现状及处理

<正>基因与糖代谢间的关系,近些年来所研究提供的信息也越来越多,估计原始的一些看法可能也会有新的变化。比如MODY是针对2型糖尿病的遗传方式而定为单基因性糖尿病的;比如对2型糖尿病遗传方式的研究表明,可能有多个基因参与2型糖尿病的发生,但目前对所涉及的基因的数量和每个基因对发病的贡献大小也不明确~[1](图1)。人们在研究遗传性婴儿高胰岛素血症(Hyperinsulinism of infancy,HI)(也称胰岛母细胞增生症、β细胞成熟障碍综合     

89个糖尿病家系遗传方式的研究

目的 探讨家族性糖尿病的遗传方式.方法 采用家系分析、 Smith无偏差校正法,、多基因分析法对本院4所附属医院以及广东6所县医院糖尿病专科门诊的病例,通过定点病史复习法中发现的89个家族性糖尿病进行了研究.结果 家族性糖尿病主要为常染色体显性遗传,不符合多基因遗传.结论 家族性糖尿病遗传方式的确定对预测后代的发病风险,对糖尿病的预防有一定的临床意义.     

MODY的研究进展

青少年发病的成年型糖尿病 (MODY)是 2型糖尿病中的一种异质性单基因疾病 ,特点是常染色体显性遗传。随着基因定位克隆和候选克隆等技术的发展 ,多个 2型糖尿病的易感性特定缺陷基因及其标记位点已被阐明。讨论了肝细胞核转移因子 (HNF) 4α、葡萄糖激酶 (GCK)、HNF 1α、胰岛素启动因子 (IPF) 1的基因缺陷和有关MODY的发病机制。     

青少年的成人起病型糖尿病(MODY)的研究、认识现状及处理

<正>青少年的成人起病型糖尿病(Maturityonset diabetes of the youm,MODY),已被证实为单基因遗传突变引起的糖尿病,其突变基因具有遗传异质性,属于一种非胰岛素依赖的早发型糖尿病,呈常染色体显性遗传,是单基因糖尿病中常见的一型。MODY数十年前已被人们关注在应用胰岛素以前,早     

2型糖尿病易感基因对中国人2型糖尿病遗传易感性影响的系统评价

2型糖尿病（T2DM）是遗传异质性疾病,从遗传模式上讲可分为单基因遗传性糖尿病和多基因遗传性糖尿病。前者往往由一个作用较强的基因突变导致,发病较早,呈现孟德尔遗传模式;后者由多个作用较弱的基因再加上环境因素共同导致疾病的发生。在T2DM中,由于基因诊断技术还不能广泛应用,     

240例糖尿病患者一级亲属调查报告

作者对240例已确诊的糖尿病患者及240例非糖尿病患者进行了一级亲属调查,发现对照者群体糖尿病患病率为0.2％,糖尿病患者一级亲属患病率为2.2％,遗传度为72％,说明糖尿病患者一级亲属的患病率为对照者的11倍,肯定糖尿病与遗传有关。又用胰岛素释放试验对35例NIDDM进行家族调查,发现29例的双亲为正常人;16例家族中新检出14例糖尿病患者及17例可疑糖尿病患者;子代患病率为35.3％;2例家族为父传子;患者以女性为多。这都与孟德尔单基因遗传不符,支持NIDDM为多基因遗传。     

The polymorphisms of UCP2 and UCP3 genes associated with fat metabolism, obesity and diabetes

Uncoupling proteins (UCPs) belong to the family of mitochondrial transporter proteins that may uncouple the transport of protons across the inner mitochondrial membrane from electron transport and the synthesis of ATP from ADP, hence generating heat rather than energy. In mammals, more than five family members have been identified, including UCP1, UCP2, UCP3, UCP4 (or BMCP1/UCP5) and UCP5. The UCPs may play an important role in energy homeostasis and have become prominent in the fields of thermogenesis, obesity, diabetes and free-radical biology and have been considered candidate genes for obesity and insulin resistance. They have been as important potential targets for treatment of aging, degenerative diseases, diabetes and obesity. Recently, a series of studies showed the polymorphisms of UCPs gene association with the fat metabolism, obesity and diabetes. This review summarizes data supporting the roles of UCP2 and UCP3 in energy dissipation, as well as the genetic variety association with fat metabolism, obesity and diabetes in humans.     

Lifestyle and genetics in obesity and type 2 diabetes

Obesity and type 2 diabetes mellitus are multifactorial health threats caused by a complex interplay between genetic predisposition and the environment with dramatically increasing worldwide prevalence. The role of heritability in their etiology is well recognized, however, the numerous attempts made in order certain genetic variants determining individual susceptibility to be identified have had limited success, until recently. At present the advancements in human genetics and the utilization of the genome-wide association approach have led to the identification of over 20 genetic loci associated with, respectively obesity and type 2 diabetes. Most of the genes identified to date, however, have modest effect on disease risk suggesting that both diseases are unlikely to develop without the individual being exposed to obesity- and/or type 2 diabetes-promoting environment. Indeed, unhealthy lifestyle, characterized by physical inactivity and food overconsumption is an unequivocally established risk factor for obesity and type 2 diabetes. Numerous epidemiological studies and randomized controlled trials, on the other hand, have demonstrated that lifestyle modification is effective in obesity and type 2 diabetes prevention. Furthermore, gene-lifestyle interaction studies suggest that genetic susceptibility to obesity and type 2 diabetes may be partially or totally kept under control by healthy lifestyle or lifestyle modification and that lifestyle determines whether an individual is likely to develop the disease. Inherited factors, however, seem to influence individual response to a lifestyle intervention program and even the motivation for lifestyle change. Personalized interventions according to genotype may be, therefore, considered in the future. By then lifestyle modification targeting dietary change and increased physical activity may be recommended for successful obesity and type 2 diabetes prevention irrespectively of genetic susceptibility.     

Genetic susceptibility to type 2 diabetes and obesity: from genome-wide association studies to rare variants and beyond

During the past 7 years, genome-wide association studies have shed light on the contribution of common genomic variants to the genetic architecture of type 2 diabetes, obesity and related intermediate phenotypes. The discoveries have firmly established more than 175 genomic loci associated with these phenotypes. Despite the tight correlation between type 2 diabetes and obesity, these conditions do not appear to share a common genetic background, since they have few genetic risk loci in common. The recent genetic discoveries do however highlight specific details of the interplay between the pathogenesis of type 2 diabetes, insulin resistance and obesity. The focus is currently shifting towards investigations of data from targeted array-based genotyping and exome and genome sequencing to study the individual and combined effect of low-frequency and rare variants in metabolic disease. Here we review recent progress as regards the concepts, methodologies and derived outcomes of studies of the genetics of type 2 diabetes and obesity, and discuss avenues to be investigated in the future within this research field.     

A strategy to search for common obesity and type 2 diabetes genes.

Worldwide, the incidence of type 2 diabetes is rising rapidly, mainly because of the increase in the incidence of obesity, which is an important risk factor for this condition. Both obesity and type 2 diabetes are complex genetic traits but they also share some nongenetic risk factors. Hence, it is tempting to speculate that the susceptibility to type 2 diabetes and obesity might also partly be due to shared genes. By comparing all of the published genome scans for type 2 diabetes and obesity, five overlapping chromosomal regions for both diseases (encompassing 612 candidate genes) have been identified. By analysing these five susceptibility loci for type 2 diabetes and obesity, using six freely available bioinformatics tools for disease gene identification, 27 functional candidate genes have been pinpointed that are involved in eating behaviour, metabolism and inflammation. These genes might reveal a molecular link between the two disorders.     

Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity

Until recently, progress in identification of the genetic variants influencing predisposition to common forms of diabetes and obesity has been slow, a sharp contrast to the large number of genes implicated in rare monogenic forms of both conditions. Recent advances have transformed the situation, however, enabling researchers to undertake well-powered scans able to detect association signals across the entire genome. For type 2 diabetes, the six high-density genome-wide association studies so far performed have extended the number of loci harboring common variants implicated in diabetes susceptibility into double figures. One of these loci, mapping to the fat mass and obesity associated gene (FTO), influences diabetes risk through a primary effect on fat mass, making this the first common variant known to influence weight and individual risk of obesity. These findings offer two main avenues for clinical translation. First, the identification of new pathways involved in disease predisposition-for example, those influencing zinc transport and pancreatic islet regeneration in the case of type 2 diabetes-offers opportunities for development of novel therapeutic and preventative approaches. Second, with continuing efforts to identify additional genetic variants, it may become possible to use patterns of predisposition to tailor individual management of these conditions.     

蛋白酪氨酸磷酸酶1B基因1484插入G变异与中国人肥胖相关

目的 确定蛋白酪氨酸磷酸酶1B（PTPIB）基因1484插入G（insG）变异是否与中国人肥胖相关。方法 选取上海地区中国人305例，用PCR／SacⅡ酶解法检测1484insG突变，突变的样本全部进行DNA序列分析。结果 正常对照组、单纯性肥胖、肥胖合并2型糖尿病组各发现8例、10例、16例PTP1B1484insG突变，正常对照组的1484insG突变率与单纯肥胖组、肥胖总组比较差异无统计学意义。但正常对照组与肥胖合并2型糖尿病组比较差异有统计学意义（P〈0．05），单纯肥胖组与肥胖合并2型糖尿病组比较差异无统计学意义（P〉0．05）。结论 PTP1B基因1484insG突变与中国人肥胖伴2型糖尿病有相关性，可能是中国肥胖人群发生2型糖尿病的遗传因素之一。     

Genetic advances of type 2 diabetes in Chinese populations

In recent decades, the prevalence of type 2 diabetes in China has increased significantly, underscoring the importance of investigating the etiological mechanisms, including genetic determinants, of the disease in Chinese populations. Numerous loci conferring susceptibility to type 2 diabetes (T2D) have been identified worldwide, with most having been identified in European populations. In terms of ethnic heterogeneity in pathogenesis as well as disease predisposition, it is imperative to explore the specific genetic architecture of T2D in Han Chinese. Replication studies of European-derived susceptibility loci have been performed, validating 11 of 32 loci in Chinese populations. Genetic investigations into heritable traits related to glucose metabolism are expected to provide new insights into the pathogenesis of T2D, and such studies have already inferred some new susceptibility loci. Other than replication studies of European-derived loci, efforts have been made to identify specific susceptibility loci in Chinese populations using methods such as genome-wide association studies. These efforts have identified additional new loci for the disease. Genetic studies can facilitate the prediction of risk for T2D and also promote individualized anti-diabetic treatment. Despite many advances in the field of risk prediction and pharmacogenetics, the pace of clinical application of these findings is rather slow. As a result, more studies into the practical utility of these findings remain necessary.     

Adenylate cyclase 3: a new target for anti‐obesity drug development

Obesity has become epidemic worldwide, and abdominal obesity has a negative impact on health. Current treatment options on obesity, however, still remain limited. It is then of importance to find a new target for anti‐obesity drug development based upon recent molecular studies in obesity. Adenylate cyclase 3 (ADCY3) is the third member of adenylyl cyclase family and catalyses the synthesis of cAMP from ATP. Genetic studies with candidate gene and genome‐wide association study approaches have demonstrated that ADCY3 genetic polymorphisms are associated with obesity in European and Chinese populations. Epigenetic studies have indicated that increased DNA methylation levels in the ADCY3 gene are involved in the pathogenesis of obesity. Furthermore, biological analyses with animal models have implicated that ADCY3 dysfunction resulted in increased body weight and fat mass, while reduction of body weight is partially explained by ADCY3 activation. In this review, we describe genomic and biological features of ADCY3, summarize genetic and epigenetic association studies of the ADCY3 gene with obesity and discuss dysfunction and activation of ADCY3. Based upon all data, we suggest that ADCY3 is a new target for anti‐obesity drug development. Further investigation on the effectiveness of ADCY3 activator and its delivery approach to treat abdominal obesity has been taken into our consideration.     

The emerging pattern of the genetic contribution to human obesity

It has been a little more than 5 years since the publication of the first genome scans focused on obesity-related phenotypes in humans. While the number of scans reported has grown steadily during this time, the results from many of these studies have been modest at best. However, there are a handful of studies that have now reported highly significant findings, and even more important perhaps is the fact that several of these findings have now been replicated as well. Currently there is strong statistical support for approximately half a dozen quantitative trait loci (QTLs) influencing obesity-related phenotypes across a number of populations and ethnic groups. While some of these signals localize near genes that might have been considered a priori as candidate genes for obesity, several others offer evidence for previously unsuspected genes. As a result, there is an intriguing pattern of genetic contribution to obesity that has begun to emerge and which promises to greatly increase our understanding of the relationship between obesity and other chronic diseases such as coronary heart disease and type 2 diabetes.     

You are what you eat,or are you? The challenges of translating high-fat-fed rodents to human obesity and diabetes

Obesity and type 2 diabetes mellitus (T2DM) are rapidly growing worldwide epidemics with major health consequences. Various human-based studies have confirmed that both genetic and environmental factors (particularly high-caloric diets and sedentary lifestyle) greatly contribute to human T2DM. Interactions between obesity, insulin resistance and β-cell dysfunction result in human T2DM, but the mechanisms regulating the interplay among these impairments remain unclear. Rodent models of high-fat diet (HFD)-induced obesity have been used widely to study human obesity and T2DM. With >9000 publications on PubMed over the past decade alone, many aspects of rodent T2DM have been elucidated; however, correlation to human obesity/diabetes remains poor. This review investigates the reasons for this translational discrepancy by critically evaluating rodent HFD models. Dietary modification in rodents appears to have limited translatable benefit for understanding and treating human obesity and diabetes due—at least in part—to divergent dietary compositions, species/strain and gender variability, inconsistent disease penetrance, severity and duration and lack of resemblance to human obesogenic pathophysiology. Therefore future research efforts dedicated to acquiring translationally relevant data—specifically human data, rather than findings based on rodent studies—would accelerate our understanding of disease mechanisms and development of therapeutics for human obesity/T2DM.