环境选择作用对糖尿病易感性的影响

糖尿病是一种遗传基因和环境因素相互作用引起的综合性代谢疾病,目前其发病率不断增长,而且并发症危害性大,严重影响着公共健康。根据对当前发展中国家人群的糖尿病高发病率的数据分析以及大量动物实验研究结果,节俭基因理论认为,长期自然选择引起的"快速消化食物并积累脂肪"这一生存优势是引起2型糖尿病的主要原因。然而,对于宫内发育迟缓胎儿成年后的糖尿病高发现象,节俭表型理论认为,胰岛细胞功能缺陷和外周胰岛素抵抗是机体对不良营养环境的代谢性适应,成年后的肥胖症和糖尿病是机体程序化控制所引起的;而且他们认为,欧洲血统人群的糖尿病易感性相对较低是由于欧洲人长期对高热量食物产生了代谢适应。总之,糖尿病遗传易感基因是决定糖尿病易感性的分子基础,而食物结构和生活方式等环境因素则影响了遗传易感基因的表达调控。因此,深入研究其病因学有助于探寻治疗糖尿病的新药物和新方案。     

慢性代谢性疾病的环境与遗传交互作用以及早期预防

随着我国经济的发展和营养与生活方式的迅速变迁,近年来我国居民肥胖、2型糖尿病等慢性代谢性疾病患病率激增,已成为影响国民健康最主要的威胁。有研究显示:与白种人相比,亚洲人具有较高的2型糖尿病遗传易感性,这可能与"代谢性肥胖"表型和遭遇营养转型中的"致肥胖环境"有关。大量的研究结果表明,此类慢性代谢性疾病是遗传和环境因素交互作用的结果。随着全基因组关联研究开展,目前已发现了20多个肥胖和2型糖尿病易感基因,不仅揭示了不同种族人群在基因结构和效应值方面存在着差异,但同时也发现遗传方面的差异仍无法完全解释东西方人在发病风险方面的不同。膳食、生活方式等环境因素仍被认为是2型糖尿病发病中的重要决定因素。在全基因组关联研究后时代,国际上的研究将更加强调基因—基因、基因—环境、基因—表型之间的交互作用对代谢性疾病的影响和相关的机制。事实上,有研究表明,各种基因多态性、炎性因子和脂肪细胞因子等都可能成为早期诊断的生物标记物,而通过改变膳食和生活方式则是目前国际公认的预防和控制慢性代谢性疾病最有效的方法。然而,我国尤为缺乏在大规模前瞻性流行病学研究中对导致慢性代谢性疾病流行的主要遗传和环境因素,以及基因—环境相互作用对健康的影响方面的系统的研究。而这类研究将为建立适用于中国人群遗传和表型特征的早期诊断生物标记物和有效预防干预策略奠定基础。     

Visfatin 与2 型糖尿病研究新进展

Visfatin是Fukuhara等发现的一种蛋白质细胞因子,由内脏脂肪细胞分泌,受多种因素调节,有烟酰胺磷酸核糖转移酶活性,类胰岛素作用,促炎作用等多种生物学作用。2型糖尿病是一种内分泌代谢性疾病,由多基因遗传因素、环境因素综合作用引起,visfatin与其有密切的关系。Visfatin对于寻找糖尿病新的药物靶点,开发新的疾病生物标志物有非常重要临床意义。     

肠道菌群与代谢综合征研究进展

代谢综合征是导致心脑血管疾病的危险因素之一,被认为是威胁全球人类健康的公共卫生问题。肠道菌群紊乱与肥胖、2型糖尿病及非酒精性脂肪性肝病等代谢性疾病的相关性已被普遍接受,因此肠道菌群调控有望成为治疗代谢综合征的新靶点。本文对肠道菌群与代谢综合征的关系、肠道菌群影响代谢综合征的可能机制以及与肠道菌群相关的调控策略作一综述。     

以LPAR3为中心的2型糖尿病相关基因功能富集及蛋白互作分析

本研究目的是查找与2型糖尿病相关的潜在基因及其参与的生物过程、信号通路和蛋白互作网络。利用GEO数据库中GSE20966数据集,采用GENE-E平台,筛选出与LPAR3共表达的基因,结合生物信息学工具GOC、DAVID、COREMINE、Gene Mania对共表达基因进行基因功能富集分析、文本挖掘及蛋白互作分析。我们筛选出LPAR3在2型糖尿病患者胰腺β细胞中表达值显著低于正常对照组,其共表达基因603个,主要涉及代谢过程、信号调控等生物过程和Hippo信号通路。共表达相关系数高的8个基因与2型糖尿病相关,且均与肿瘤相关,涉及代谢过程、信号转导、发病机理、细胞增殖、细胞粘附等生物过程。LPAR3与20个已报道的2型糖尿病基因存在互作关系。本研究发现LPAR3及其共表达基因可能与2型糖尿病相关,并可能增加患者罹患各系统肿瘤的风险。     

Cell Metab:改善睡眠的保健品可能增加糖尿病患病风险

正近日,来自瑞典隆德大学糖尿病中心的研究人员在国际学术期刊Cell Metabolism上发表了一项最新研究进展,他们发现胰岛细胞中褪黑素信号增强会降低胰岛素分泌,可能导致高血糖症并增加2型糖尿病患病风险。目前2型糖尿病逐渐成为一种全球性公共健康问题,其流行趋势越来越严重。全基因组关联性分析已经发现了超过100个与糖尿病有关的变异基因,其中包括一个比较常见的变异基因--MTNR1B(褪黑素受体1b)。MTNR1B能够增加细胞对褪黑素的敏感性,但该基因在胰岛细胞中     

ATP敏感性钾通道与2型糖尿病

ATP敏感性钾通道（KATP）是调节葡萄糖代谢平衡的关键因子。KATP通道的遗传变异可改变β-细胞电活性、葡萄糖代谢平衡,增加2型糖尿病易感性,因此,编码该通道的基因可作为2型糖尿病的易感标记。Kir6．2的E23K多态性在高加索人群中与2型糖尿病易感性增加和肥胖相关。E23K多态性在高加索人群中较常见,提示其可能具有进化优势。     

烟酰胺合成酶基因在植物铁胁迫应答反应中的功能

铁离子在植物的生理生化代谢中具有重要的功能.缺铁和铁过量都会对植物造成伤害,因此,维持植物铁离子的动态平衡具有很重要的作用.烟酰胺合成酶基因(NAS)与植物铁离子的吸收转运关系非常密切,但在机理Ⅰ型和机理Ⅱ型植物中,NAS基因的作用机理和表达模式却不同.在双子叶和非禾本科单子叶植物中,烟酰胺(NA)的主要功能是铁离子的储藏和运输,NAS基因的表达不受缺铁胁迫诱导.而在禾本科植物中,NAS基因的表达受缺铁胁迫诱导,并且与铁元素的吸收关系密切.     

HNFlα的蛋白质复合体

肝细胞核因子1A（hepatocyte nuclear factor1A,HNFlα）是肝脏富集转录因子家族成员之一,调控多种肝脏特异基因的表达,参与维系肝脏的正常表型与功能。HNFlα与多种蛋白质相互作用,以复合体的形式发挥转录调节功能。复合体组成的动态变化在调控基因组织特异性表达、维持内环境稳定、修复组织损伤以及药物代谢中发挥了重要的作用。HNFlα的突变型改变了其在体内的相互作用网络,致使靶基因转录失调,诱发青少年发病型成人糖尿病（MODY3）。     

microRNAs对脂肪细胞分化相关因子的作用及预测

microRNAs是一类调节靶基因的转录后翻译的小型非编码单链RNA,研究已发现microRNAs在癌症、心血管疾病及糖尿病中显示极为重要的生物学功能。糖尿病目前已成为威胁人类健康的最主要疾病,尤其是II型糖尿病的发病机制成为研究热点。脂肪细胞分化异常是导致II型糖尿病以及胰岛素抵抗的主要因素。进一步阐明microRNAs对脂肪细胞分化过程的作用机制,可能为糖尿病治疗找到新的靶点。本综述将从microRNAs与脂肪细胞分化基因、核激素受体以及相关信号通路相互作用三方面阐述和预测microRNAs对脂肪细胞分化的潜在作用。     

Type 2 diabetes in childhood: the American perspective

The incidence of type 2 diabetes mellitus is steadily escalating throughout the world in people from a wide range of ethnic groups and all social and economic levels. Type 2 diabetes is no longer a disease only of adults: parallel with the global epidemic of type 2 diabetes in adults, an 'emerging epidemic' of type 2 diabetes has been observed in youth over the last decade. Research and clinical experience in adults have established that insulin resistance is a major risk factor for type 2 diabetes. However, insulin resistance alone is not sufficient to cause diabetes, which will develop only when insulin secretion by the beta-cells fails. This review discusses the recent emergence of type 2 diabetes in children and adolescents, its risk factors, pathophysiologic mechanisms and treatment modalities.     

The Risk of Type 2 Diabetes in Men Is Synergistically Affected by Parental History of Diabetes and Overweight

Interactions between genetic- and lifestyle factors may be of specific importance for the development of type 2 diabetes. Only a few earlier studies have evaluated interaction effects for the combination of family history of diabetes and presence of risk factors related to lifestyle. We explored whether 60-year-old men and women from Stockholm with a parental history of diabetes are more susceptible than their counterparts without a parental history of diabetes to the negative influence from physical inactivity, overweight or smoking regarding risk of developing type 2 diabetes. The study comprised 4232 participants of which 205 men and 113 women had diabetes (the vast majority type 2 diabetes considering the age of study participants) and 224 men and 115 women had prediabetes (fasting glucose 6.1–6.9 mmol/l). Prevalence odds ratios (OR) with 95% confidence intervals (95% CI) were calculated using logistic regression. Biologic interaction was analyzed using a Synergy index (S) score. The crude OR for type 2 diabetes associated with a parental history of diabetes was 2.4 (95% CI 1.7–3.5) in men and 1.4 (95% CI 0.9–2.3) in women. Adjustments for overweight, physical inactivity and current smoking had minimal effects on the association observed in men whereas in women it attenuated results. In men, but not in women, a significant interaction effect that synergistically increases the risk of developing type 2 diabetes was observed for the combination of BMI>30 and a parental history of diabetes, S 2.4 (95% CI 1.1–5.1). No signs of interactions were noted for a parental history of diabetes combined with physical inactivity and smoking, respectively. In conclusion, obesity in combination with presence of a parental history of diabetes may be particularly hazardous in men as these two factors were observed to synergistically increase the risk of developing type 2 diabetes in men.     

Mouse models of type 1 and type 2 diabetes derived from the same closed colony: genetic susceptibility shared between two types of diabetes

Except for rare subtypes of diabetes, both type 1 and type 2 diabetes are multifactorial diseases in which genetic factors consisting of multiple susceptibility genes and environmental factors contribute to the disease development. Due to complex interaction among multiple susceptibility genes and between genetic and environmental factors, genetic analysis of multifactorial diseases is difficult in humans. Inbred animal models, in which the genetic background is homogeneous and environmental factors can be controlled, are therefore valuable in genetic dissection of multifactorial diseases. We are fortunate to have excellent animal models for both type 1 and type 2 diabetes--the nonobese diabetic (NOD) mouse and the Nagoya-Shibata-Yasuda (NSY) mouse, respectively. Congenic mapping of susceptibility genes for type 1 diabetes in the NOD mouse has revealed that susceptibility initially mapped as a single locus often consists of multiple components on the same chromosome, indicating the importance of congenic mapping in defining genes responsible for polygenic diseases. The NSY mouse is an inbred animal model of type 2 diabetes established from Jcl:ICR, from which the NOD mouse was also derived. We have recently mapped three major loci contributing to type 2 diabetes in the NSY mouse. Interestingly, support intervals where type 2 diabetes susceptibility genes were mapped in the NSY mouse overlapped the regions where type 1 diabetes susceptibility genes have been mapped in the NOD mouse. Although additional evidence is needed, it may be possible that some of the genes predisposing to diabetes are derived from a common ancestor contained in the original closed colony, contributing to type 1 diabetes in the NOD mouse and type 2 diabetes in the NSY mouse. Such genes, if they exist, will provide valuable information on etiological pathways common to both forms of diabetes, for the establishment of effective methods for prediction, prevention, and intervention in both type 1 and type 2 diabetes.     

Familial Aggregation between the 14th and 21st Century and Type 2 Diabetes Risk in an Isolated Dutch Population

IntroductionThe development of type 2 diabetes results from an interaction of hereditary factors and environmental factors. This study aimed to investigate the contribution of interrelatedness to the risk of developing type 2 diabetes in an isolated Dutch population.ResultsPatients with type 2 diabetes were more interrelated, expressed by a higher KC compared to controls (7.2 vs. 5.2, p=0.001). First, second and third degree relatives had an increased risk of developing type 2 diabetes. Second degree relatives had a similar risk,1.7 (1.5-2.0) as third degree relatives,1.8 (1.5-2.2). Spouses of patients with diabetes had a 3.4 (2.7-4.4) higher risk of developing type 2 diabetes.ConclusionsInterrelatedness was higher among inhabitants with type 2 diabetes compared to controls. This differences extended beyond the nuclear family, thereby supporting the hypothesis that interrelatedness contributed to the development of type 2 diabetes on Urk. However, the size of this effect was small and the patterns of risk in first, second and third degree relatives suggested that factors other than interrelatedness were the main contributors to the development of type 2 diabetes on Urk.     

Prevention of type 2 diabetes: the strategic approach for implementation

A growing need exists to deliver effective and affordable prevention programs and to take urgent action to address the major public health challenge that diabetes represents. Achieving prevention of type 2 diabetes requires moving through a series of steps from basic science discovery to widespread distribution of effective interventions. Understanding the cellular level influences on diabetes prevention will help target particular interventions to those who may be most responsive. Several randomized controlled trials conducted throughout the world have demonstrated that type 2 diabetes can be prevented or delayed. Subsequent real-world translation studies have provided important information necessary to reduce cost and increase access. Ultimately achieving a population impact in diabetes prevention requires widespread distribution of effective interventions, which is supported by policies that help achieve sustainability and reach. The use of a global stakeholder network can help to share experiences and build on partner knowledge gained.     

GM3 and diabetes

We demonstrated the molecular pathogenesis of type 2 diabetes and insulin resistance focusing on the interaction between insulin receptor and GM3 ganglioside in adipocytes and propose a working hypothesis “metabolic disorders, such as type 2 diabetes, are membrane microdomain disorders caused by aberrant expression of gangliosides”. It is expected that the development of novel diagnosis of metabolic syndrome by identifying the specific ganglioside species and a therapeutic strategy “membrane microdomain ortho-signaling therapy”.     

Endothelial dysfunction and diabetes: roles of hyperglycemia,impaired insulin signaling and obesity

Endothelial dysfunction comprises a number of functional alterations in the vascular endothelium that are associated with diabetes and cardiovascular disease, including changes in vasoregulation, enhanced generation of reactive oxygen intermediates, inflammatory activation, and altered barrier function. Hyperglycemia is a characteristic feature of type 1 and type 2 diabetes and plays a pivotal role in diabetes-associated microvascular complications. Although hyperglycemia also contributes to the occurrence and progression of macrovascular disease (the major cause of death in type 2 diabetes), other factors such as dyslipidemia, hyperinsulinemia, and adipose-tissue-derived factors play a more dominant role. A mutual interaction between these factors and endothelial dysfunction occurs during the progression of the disease. We pay special attention to the possible involvement of endoplasmic reticulum stress (ER stress) and the role of obesity and adipose-derived adipokines as contributors to endothelial dysfunction in type 2 diabetes. The close interaction of adipocytes of perivascular adipose tissue with arteries and arterioles facilitates the exposure of their endothelial cells to adipokines, particularly if inflammation activates the adipose tissue and thus affects vasoregulation and capillary recruitment in skeletal muscle. Hence, an initial dysfunction of endothelial cells underlies metabolic and vascular alterations that contribute to the development of type 2 diabetes. E.C. Eringa is supported by the Dutch Diabetes Foundation (grant 2003.00.030), the Dutch Kidney foundation (grant C03.2046), and the Dutch organization for scientific research (grant 916.76.179). V.W.M. van Hinsbergh is supported by the European Vascular Genomics Network (grant LSHM-CT-2003–503254).     

Worldwide Distribution of Type II Diabetes-Associated TCF7L2 SNPs: Evidence for Stratification in Europe

Type II diabetes is a multifactorial disease with a complex etiology. Numerous genes have been implicated in disease pathogenesis. In particular, SNPs at the TCF7L2 locus have consistently shown strong associations with type II diabetes. This study characterizes the global distribution of type II diabetes-associated TCF7L2 SNPs utilizing HapMap, HGDP-CEPH, and Alfred databases and the literature. High frequencies of rs7903146(T), rs12255372(T), and rs7901695(C) SNPs are observed in Africa, Europe, and the Middle East, but they are reduced and almost absent in Southeast Asian and Native American populations. In contrast, rs11196218(A) has the highest frequency in Eurasia but is reduced in sub-Saharan African and Native American populations. Regional variations in rs7903146(T) follow a gradient of decreasing frequency from southern into northeastern Europe. These findings demonstrate extensive global and regional variations in the frequencies of TCF7L2 SNPs, which may contribute to differences in the incidence of type II diabetes worldwide.     

Morphometric Changes in Lateral Ventricles of Patients with Recent-Onset Type 2 Diabetes Mellitus

It is becoming increasingly evident that type 2 diabetes mellitus can have effects on global and regional brain morphology. Ventricular enlargement reflecting cerebral atrophy has been reported particularly in elderly type 2 diabetes patients. However, little is known about its timing through the disease course and morphological variability. Using the combined volumetric and advanced three-dimensional morphological approach, we identified differences in size and shape of the lateral ventricles between recent-onset type 2 diabetes patients and healthy individuals. High-resolution T1-weighted images were obtained from 23 type 2 diabetes patients whose illness duration was less than 1 year and 23 carefully matched healthy individuals. By volume measurement, we found enlarged lateral and third ventricles in type 2 diabetes patients, relative to healthy individuals (F _1,41 = 7.96, P = 0.007; F _1,41 = 11.16, P = 0.002, respectively). Morphological analysis revealed that the expansion of lateral ventricles in the diabetic brain was prominent in the bilateral frontal horns. The current findings suggest that atrophic changes particularly of the anterior frontal lobe can occur as early as the first year after the clinical diagnosis of type 2 diabetes mellitus.     

A systems genetics approach identifies genes and pathways for type 2 diabetes in human islets

Close to 50 genetic loci have been associated with type 2 diabetes (T2D), but they explain only 15% of the heritability. In an attempt to identify additional T2D genes, we analyzed global gene expression in human islets from 63 donors. Using 48 genes located near T2D risk variants, we identified gene coexpression and protein-protein interaction networks that were strongly associated with islet insulin secretion and HbA(1c). We integrated our data to form a rank list of putative T2D genes, of which CHL1, LRFN2, RASGRP1, and PPM1K were validated in INS-1 cells to influence insulin secretion, whereas GPR120 affected apoptosis in islets. Expression variation of the top 20 genes explained 24% of the variance in HbA(1c) with no claim of the direction. The data present a global map of genes associated with islet dysfunction and demonstrate the value of systems genetics for the identification of genes potentially involved in T2D.