宫内生长受限引起成年人代谢综合征的表观遗传机制研究进展

胎儿宫内生长受限是指胎儿出生体质量低于同胎龄平均体质量的第10百分位数。宫内生长受限与成年后代谢综合征的发生密切相关,宫内环境不良引起的表观遗传改变很可能是成年后发生胰岛素抵抗的重要原因。该文从表观遗传修饰及其重点DNA的甲基化,宫内生长受限与DNA甲基化,宫内生长受限致关键启动子的表观遗传标记改变及可能的干预措施介绍...     

宫内发育迟缓发生胰岛素抵抗的机制

"慢性疾病胎儿起源学说"假说、"节俭表型假说"、"营养程序化"、"代谢程序化" 概念指出了早期营养与远期健康的关系问题,流行病学调查也已证实宫内发育迟缓与胰岛素抵抗密切相关,但宫内发育迟缓发生胰岛素抵抗的具体机制目前尚未明确.遗传信息的调控可能会不同程度改变胎儿组织器官的结构和功能,在基因水平上,胰十二指肠同源盒基因、Munc13-1、过氧化物酶体增殖物激活受体基因、胰岛素受体底物基因、线粒体DNA、ghrelin mRNA等的表达情况都对宫内发育迟缓发生胰岛素抵抗有影响.     

低出生体重与胰岛素抵抗

近年来,越来越多的证据显示低出生体重与成年期的胰岛素抵抗综合征的发生密切相关,其发生机制尚不清楚,可能的发生机制如下:(1)宫内不良环境影响关键阶段胎儿的发育,影响胎儿组织的生长和分化,使胰岛β细胞数量减少和功能减低;(2)宫内不良环境的刺激导致持续的下丘脑-垂体-肾上腺轴活动增强,此外,还可选择性地抑制胎盘11β-羟甾类脱氢酶的功能,导致内源性糖皮质激素过多进入胎儿体内;(3)可能存在某种基因基础,导致胎儿宫内发育迟缓及成年期的胰岛素抵抗,由基因决定的胰岛素抵抗减弱了胰岛素介导的胎儿生长,并引起成年的胰岛素抵抗、糖耐量减低、糖尿病和高血压。     

低出生体重与胰岛素抵抗

近年来，越来越多的证据显示低出血体重与成年期的胰岛素抵抗综合征的发生密切相关，其发生机制尚不清楚，可能的发生机制如下：（1）宫内不良环境影响关键阶段胎儿的发育，影响胎儿组织的生长和分化，使胰岛β细胞数量减少和功能减低；（2）宫内不良环境的刺激导致持续的下丘脑－垂体－肾上腺轴活动增强，此外，还可选择性地抑制胎盘11β－羟甾类脱氢酶的功能，导致内源性糖皮质激素过多进入胎儿体内；（3）可能存在某种基因基础，导致胎儿宫内发育迟缓及成年期的胰岛素抵抗，由基因决定的胰岛素抵抗减弱了胰岛素介导的胎儿生长，并引起成年的胰岛素抵抗、糖耐量减低、糖尿病和高血压。     

小于胎龄与胰岛素抵抗和糖尿病

小于胎龄是导致胰岛素抵抗综合征的一个重要危险因素,但其发生机制尚不明确.流行病学研究发现,早期营养与成年发生代谢综合征密切相关.现对宫内营养程序化与小于胎龄儿成年后胰岛素抵抗、糖尿病的关系作一综述.     

小于胎龄儿营养程序化与成人代谢综合征

小于胎龄儿(SGA)是成人代谢综合征(MS)的高危人群.SGA由于对宫内不利营养环境的适应性改变,导致机体多种激素重整,尤其是产生胰岛素抵抗并持续至成年期,使SGA罹患2型糖尿病等代谢综合征的易患性增加.利用"营养程序化"的作用,在出生早期生长发育的敏感时期予SGA高蛋白等热能饮食的营养干预,有可能避免胰岛素抵抗或减轻其程度,降低SGA在成年后发生MS的易患性.     

宫内发育迟缓引起胰岛素抵抗的遗传与营养学机制

过去十几年的研究证据表明,胎儿宫内发育迟缓(in鄄trauterine growth retardation,IUGR)与胰岛素抵抗的发生发展存在联系。但有关这种联系的具体机制尚未明确,未来十年的挑战将是发现这种联系的细胞学和分子生物学机制,这将有可能提出一些干预方法以降低糖尿病所带来的影响。现从基因水平和营养学角度对这种联系可能的细胞学和分子生物学机制作一综述。1基因因素胎儿发育和胰岛素抵抗之间的联系可能存在基因基础。众所周知,胰岛素在胎儿发育中起主要的作用,它可以保证胎儿在营养供应良好的条件下有相应的生长率,胰岛素抵抗将影响胎儿的正…     

变应性支气管哮喘的表观遗传学

表观遗传学主要研究转录前基因在染色质水平的结构修饰对基因功能的影响,其主要调控机制包括DNA甲基化、组蛋白修饰、染色质重建和非编码RNA调控等多个方面.流行病学调查提示遗传和环境因素与支气管哮喘发生明确相关,由于人类遗传背景短期内不可能发生明显变化,因此,表观遗传修饰在环境和遗传因素之间起到重要的调控作用.某些不能用DNA序列变化解释的现象可能是基因表达过程中表观遗传修饰改变所致,使得机体能适应环境因素变化的结果.该文通过探讨辅助T细胞表观遗传修饰来了解表观遗传学和支气管哮喘的关系及其影响因素.     

原发性免疫缺陷病：中国儿科医师面临的机遇与挑战北大核心CSCD

人体防御系统可能受到数百个基因调控,这些基因中的某一个或几个发生突变、缺失、插入或拷贝数变异等经典遗传学改变,或发生由环境因素导致的表观遗传学改变（可遗传至子代）,均可能出现免疫缺陷病表现.此前所谓“原发性免疫缺陷病（primary immunodeficiency diseases,PID）”,主指因涉及免疫系统功能的基因发生经典遗传学变异导致的免疫细胞、免疫分子功能缺陷,临床表现为易患感染、恶性肿瘤和自身免疫的一类疾病.     

儿童青少年2型糖尿病的流行现状、危险因素及病理生理学机制的研究进展

儿童青少年2型糖尿病发病率日益增高,了解该病的流行现状、危险因素及病理生理学机制十分重要.该病的流行存在明显种族差异性,其危险因素包括肥胖、2型糖尿病家族史、母亲妊娠期高血糖、胎儿宫内发育迟缓及出生体质量异常等,主要通过胰岛素抵抗和胰岛素分泌缺陷这两大病理生理学机制影响血糖.     

Neonatal diabetes: a disease linked to multiple mechanisms]

Transient (TNDM) and Permanent (PNDM) Neonatal Diabetes Mellitus are rare conditions occurring in about 1: 300,000 live births. In TNDM growth retarded infants develop diabetes in the first few weeks of life only to go into remission in a few months with possible relapse to a permanent diabetes state usually around adolescence or as adults. We believe that pancreatic dysfunction in this condition is maintained throughout life with relapse initiated at times of metabolic stress such as puberty or pregnancy. In PNDM, insulin secretory failure occurs in the late fetal or early postnatal period. A number of conditions are associated with PNDM, some of which have been elucidated at the molecular levels. Among those, the very recently elucidated mutations in KCNJ11 and ABCC8 gene, encoding the Kir6.2 and SUR1 subunit of the pancreatic K(ATP) channel involved in regulation of insulin secretion accounts for one third to a half of the PNDM cases. Patients with TNDM are more likely to have intrauterine growth retardation and less likely to develop ketoacidosis than patients with PNDM. In TNDM, patients are younger at the diagnosis of diabetes and have lower initial insulin requirements. Considerable overlap occurs between the two groups, so that TNDM cannot be distinguished from PNDM based on clinical features. Very early onset diabetes mellitus seems to be unrelated to autoimmunity in most instances. Recurrent diabetes is common in patients with "transient" neonatal diabetes mellitus and, consequently, prolonged follow-up is imperative. Molecular analysis of chromosome 6 anomalies, the KCNJ11 and ABCC8 genes encoding Kir6.2 and SUR1 provide a tool to identify transient from permanent neonatal diabetes mellitus in the neonatal period. This analysis also has potentially important therapeutic consequences leading to transfer some patients, those with mutations in KCNJ11 and ABCC8 from insulin therapy to sulfonylureas. Realizing how difficult it is to take care of a child of this age with diabetes mellitus should prompt clinicians to transfer these children to specialized centers. Insulin therapy and high caloric intake are the basis of the treatment. Insulin pump may offer an interesting therapeutic tool in this age group in experienced hands.     

Genes with linkage or association with type 2 diabetes mellitus

Complex diseases, such as type 2 diabetes mellitus (T2DM), arise from metabolic disruptions with genetic and environmental components. Multiple genes are responsible for the genetic susceptibility to T2DM. The contribution of these genes to the diabetic phenotype may be modest, variable among different populations, and dependent on interactions with other genes and the environment. The methods of genetic dissection based on linkage, allele sharing, and linkage disequilibrium may lack the statistical power to detect weak associations in heterogeneous populations. Nevertheless, genes involved in insulin signaling, insulin secretion, insulin resistance, glucose metabolism, obesity, diabetes comorbidity and the hormone processing protease genes have been associated with T2DM. New research strategies are improving the methods of genetic dissection and include genomic sequence information to characterize profiles of sequence variants that predispose to T2DM.     

新生儿糖尿病研究进展

新生儿糖尿病是一组异质性单基因遗传病,常被误诊为1型糖尿病.永久性新生儿糖尿病与免疫无关,主要与KCNJ 11、ABCC8和胰岛素基因等基因突变有关;多以酮症酸中毒起病,伴宫内发育迟缓、脱水.基因检测有助于疾病分型,并可根据不同致病基因进行靶向治疗.对于ATP敏感的K+通道基因突变的永久性新生儿糖尿病患儿可口服磺脲类降...     

No evidence for additional imprinting defects in Silver-Russell syndrome patients with maternal uniparental disomy 7 or 11p15 epimutation

Silver-Russell syndrome (SRS) is mainly characterised by intrauterine and postnatal growth retardation (IUGR and PNGR), asymmetry, clinodactyly V and craniofacial abnormalities. More than 35% of patients carry a hypomethylation of the telomeric imprinting centre region 1 (ICR1) in 11p15; single patients show a maternal duplication of 11p15. An additional 7-10% of patients with SRS have maternal uniparental disomy of chromosome 7 (mUPD7). Another disorder caused by epigenetic defects is transient neonatal diabetes mellitus (TNDM) which is associated with loss of methylation (LOM) in 6q24. After detecting methylation loss at multiple imprinted loci in patients with TNDM, Mackay et al. recently proposed the existence of a maternal hypomethylation syndrome presenting as TNDM. They therefore concluded that patients with other disorders associated with LOM at one (maternally) methylated locus might also carry LOM at multiple loci. Similar observations have also been reported in Beckwith-Wiedemann syndrome (BWS): nearly 25% of patients displayed abnormal methylation patterns of ICRs additional to those in 11p15. To show whether general hypomethylation is a common phenomenon in imprinting disorders we carried out methylation analyses for the imprinted regions 14q32, 6q24 and the centromeric imprinting region ICR2 on 11p15 for 10 patients with SRS carrying mUPD7 and 22 patients with LOM at the telomeric imprinting region ICR1. We showed that further epigenetic defects did not occur in the groups of SRS with LOM of ICR1 or mUPD7, and that these subentities do not belong to the diseases with a general hypomethylation defect, such as TNDM and BWS.     

The genetic basis of neonatal diabetes mellitus

Neonatal diabetes mellitus is a rare condition occurring within the first few months of life that can either be permanent or transient. Various genetic defects responsible for both permanent and transient neonatal diabetes have been identified. ATP-sensitive potassium (KATP) channels are key regulators of nutrient-induced insulin secretion in pancreatic beta cells. Activating mutations of the KATP channel, which prevent closure of the channel and thus inhibit insulin secretion, are now known to be the predominant cause of permanent neonatal diabetes. Transient neonatal diabetes may also be associated with activating mutations of the KATP channel. However, the majority of cases of transient neonatal diabetes have a mutation that maps to a locus on the long arm of chromosome 6, and mutations in two overlapping genes, ZAC and HYMA1, have been identified as the predominant cause of transient neonatal diabetes. These findings provide important insights into the molecular and genetic basis in the broad spectrum of diabetes mellitus.     

Insulin resistance in short children with intrauterine growth retardation

Scientific evidence is accumulating for an association between intrauterine growth retardation (IUGR) and an increased risk of developing adult degenerative diseases, such as essential hypertension, non-insulin-dependent diabetes mellitus and ischaemic heart disease. A possible underlying mechanism for these conditions is insulin resistance. In this paper, mechanisms and methods of measurement of insulin resistance are briefly reviewed, and recent studies on the evaluation of insulin resistance in short children with IUGR are summarized. In our experience, short prepubertal children with IUGR show consistent insulin resistance, which becomes particularly evident during pubertal development.     

Outpatient transition of an infant with permanent neonatal diabetes due to a KCNJ11 activating mutation from subcutaneous insulin to oral glyburide

Abstract:  Neonatal diabetes mellitus is rare, may either be transient or permanent, and may be caused by mutations in any of the several different genes. Until recently, most forms of permanent neonatal diabetes required lifelong subcutaneous insulin for management; however, permanent neonatal diabetes due to activating mutations in the KCNJ11 gene, which encodes the Kir6.2 protein subunit of the ATP-sensitive K⁺ (K_ATP) channel, may be amenable to oral sulfonylurea therapy. We describe a case of an 18-month-old infant with permanent neonatal diabetes due to an activating KCNJ11 mutation successfully transitioned from subcutaneous insulin therapy to oral sulfonylurea therapy in the outpatient setting.     

Insulin resistance in short children with intrauterine growth retardation

Chiarelli F, di Ricco L, Mohn A, De Martino M, Verrotti A. Insulin resistance in short children with intrauterine growth retardation. Acta Pædiatr 1999; Suppl 428: 62–5. Stockholm. ISSN 0803–5326
Scientific evidence is accumulating for an association between intrauterine growth retardation (IUGR) and an increased risk of developing adult degenerative diseases, such as essential hypertension, non-insulin-dependent diabetes mellitus and ischaemic heart disease. A possible underlying mechanism for these conditions is insulin resistance. In this paper, mechanisms and methods of measurement of insulin resistance are briefly reviewed, and recent studies on the evaluation of insulin resistance in short children with IUGR are summarized. In our experience, short prepubertal children with IUGR show consistent insulin resistance, which becomes particularly evident during pubertal development. □ Intrauterine growth retardation, insulin resistance, short children     

Epigenetic alterations in sperm associated with male infertility

The most common form of male infertility is a low sperm count, known as oligozoospermia. Studies suggest that oligozoospermia is associated with epigenetic alterations. Epigenetic alterations in sperm, which may arise due to the exposure of gametes to environmental factors or those that pre‐exist in the sperm of infertile individuals, may contribute to the increased incidence of normally rare imprinting disorders in babies conceived after assisted reproductive technology using the sperm of infertile men. Genomic imprinting is an important developmental process whereby the allelic activity of certain genes is regulated by DNA methylation established during gametogenesis. The aberrant expression of several imprinted genes has been linked to various diseases, malignant tumors, lifestyle and mental disorders in humans. Understanding how infertility and environmental factors such as reproductive toxicants, certain foods, and drug exposures during gametogenesis contribute to the origins of these disorders via defects in sperm is of paramount importance. In this review, we discuss the association of epigenetic alterations with abnormal spermatogenesis and the evidence that epigenetic processes, including those required for genomic imprinting, may be sensitive to environmental exposures during gametogenesis, fertilization and early embryonic development. In addition, we review imprinting diseases and their relationships with environmental factors. While the plasticity of epigenetic marks may make these more susceptible to modification by the environment, this also suggests that aberrant epigenetic marks may be reversible. A greater understanding of this process and the function of epidrugs may lead to the development of new treatment methods for many adult diseases in the future.