1型糖尿病遗传学研究新进展

1型糖尿病是一种遗传因素和环境因素相互作用,共同参与的复杂遗传病.除家系连锁研究和候选基因关联研究发现的5个易感位点外,全基因组关联研究及后续研究已发现30余个新的易感位点.     

NLRP2基因多态性与中国汉族人群1型糖尿病的关联研究

目的探讨在中国汉族人群中核苷酸结合寡聚化结构域样受体蛋白2(NLRP2)基因的单核苷酸多态性(SNP)与经典1型糖尿病(T1DM)的相关性。方法选取就诊于中南大学湘雅二医院代谢内分泌科的510例经典T1DM患者及本地区531名无血缘关系的健康志愿者为研究对象。利用质谱法对其NLRP2基因的rs1043673位点进行基因分型。两组间一般资料的比较采用Mann-Whitney U检验和χ2检验,T1DM患者组与对照组之间基因型及等位基因频率分布的比较采用χ2检验和logistic回归分析。NLRP2多态性与各项临床特征的分析采用Kruskal-Wallis H检验。结果NLRP2基因rs1043673位点的等位基因及基因型在两组之间的分布无明显差异。在T1DM患者中,rs1043673多态性与空腹C肽(P=0.029)、餐后2 h C肽(P=0.017)以及GADA的抗体滴度(P=0.043)均有关。结论NLRP2基因的rs1043673多态性与中国汉族T1DM患者的临床特征有关。     

自发性1型糖尿病NOD小鼠胰腺微小RNA表达谱分析

目的 分析1型糖尿病（T1DM）小鼠胰腺中微小RNA表达谱,筛查T1DM相关微小RNA.方法 20只雌性6～8周龄T1 DM小鼠,体重（21 ±3）g,15周始测定血糖.于18、25周分期处死,18周处死的3只小鼠采用芯片方法分析T1DM小鼠胰腺中微小RNA表达谱;所有小鼠胰腺病苏木精-伊红染色和胰岛炎分级标准分级（胰岛炎0级;胰岛炎2级;胰岛炎3级＋胰岛萎缩＋显性糖尿病）.胰腺提取RNA,经定量逆转录PCR（qRT-PCR）验证.结果 微小RNA芯片结果在聚类分析中,无胰岛炎归为一类,中度和重度胰岛炎归为一类.20只小鼠中有13只小鼠发生显性糖尿病,并存在0～3级的胰岛炎,2级、3级胰岛炎分别有21、31个微小RNA显著变化.对已报道的7个免疫相关微小RNA单独分析,6种无明显变化,但凋亡相关微小RNAmiR-125b存在下调趋势,miR-125b-5p下降倍数在NOD007、NOD006中分别为0.42和0.60倍,miR-125b＊和miR-125b-3p均在2级胰岛炎变化最大,分别为0.05和0.36倍.定量PCR发现miR-125b表达在无胰岛炎组和胰岛炎组存在差异.结论 微小RNA表达随胰岛炎进展而变化,提示微小RNA在T1DM的发病中起重要作用.miR-125b参与了调节T1DM胰岛炎中胰岛细胞凋亡.     

2型糖尿病PGC-1α基因单核苷酸多态性筛查及Gly482Ser变异分析

对120例T2DM和106例NGT研究对象，筛查其PGC-1α基因的单核苷酸多态性（SNP）时应用PCR-SSCP和DNA测序法。发现了4种SNP，即394Thr→Thr，482G1y→Ser，528Thr→Thr，612Thr→Met。其中，PGC-1α基因的482Gly→Ser多态性相关于T2DM的发生。     

CASP1基因rs1785882多态性与汉族人群1型糖尿病相关性研究

目的 探讨中国汉族人群半胱氨酸天冬氨酸特异性蛋白酶(CASP1)基因单核苷酸多态性rs1785882与经典T1DM的相关性.方法 本研究为病例对照研究,采用质谱法对就诊于中南大学湘雅二医院代谢内分泌科的510例经典T1DM患者(T1DM组)和本地区531名无血缘关系的健康对照(NC组)的CASP1基因rs1785882...     

MicroRNA相关遗传变异在1型糖尿病发病机制中的作用

1型糖尿病是一种多基因遗传病.MicroRNA是自然存在的、内源性干扰RNA,通过重要的转录后调节机制引起目的基因翻译水平沉默.在肿瘤等领域的研究发现,microRNA在体细胞、生殖细胞可出现多态性和突变,提示microRNA在遗传性疾病中具有潜在重要作用.MicroRNA可能与胰岛β细胞的分泌功能、脂肪细胞分化、脂代谢和能量代谢等有关.本文旨在探讨microRNA(本身及靶点)的遗传变异与1型糖尿病发病机制的关系.     

脂联素受体1基因多态性与2型糖尿病相关性研究

目的研究西安地区汉族人群中脂联素受体1（AdipoR1）的两个单核苷酸多态性（SNP）位点与2型糖尿病（T2DM）的关系。方法采用突变特异性扩增系统（ARMS）结合测序方法对西安地区100例T2DM患者（T2DM组）及84名正常对照者（NC组）AdipoRl基因的两个SNP位点进行分析。结果（1）AdipoR1基因SNP-106A／G、SNP 5843A／G在DM组与NC组间基因型频率及等位基因频率差异无统计学意义。（2）AdipoR1基因5843G／G型T2DM患者的诊断年龄明显早于A／A型＋A／G型。结论在西安地区的汉族人群中，AdipoR1基因-106A／G、5843A／G的单个核苷酸多态性可能与T2DM的发病无关。携带5843G／G基因型的T2DM患者发病年龄较早。     

PKBα/Akt1基因多态性与2型糖尿病的相关性研究

目的 研究蛋白激酶B α亚型(PKBα,也称Akt1)基因单核苷酸多态性(SNP)与上海地区汉族人群2型糖尿病易感性的关系.方法 利用等位基因特异PCR技术对460例2型糖尿病患者及444名正常对照者(NC组)Akt1基因3个标签SNP位点rs2494743、rs2494738和rs3001371进行基因分型.结果 位点rs2494738和rs3001371的基因型分布在糖尿病组和NC组之间呈现显著性差异(均P＜0.01);rs2494738和rs3001371等位基因频率在2型糖尿病组和NC组的分布也呈现显著性差异(均P＜0.01);rs2494738的多态性与2型糖尿病发生风险呈等位基因计量效应关系.但rs2494743基因型和等位基因分布在NC组与2型糖尿病组中差异无统计学意义.单倍型分析结果显示3个单倍型频率在2型糖尿病组和NC组之间也存在显著差异(均P＜0.01).结论 在上海地区的汉族人群中,Akt1基因可能是2型糖尿病的易感基因之一;其SNP位点rs2494738和rs3001371变异可能与2型糖尿病发病相关.     

NLRP2基因多态性与中国汉族人群1型糖尿病的关联研究

目的 探讨在中国汉族人群中核苷酸结合寡聚化结构域样受体蛋白2(NLRP2)基因的单核苷酸多态性(SNP)与经典1型糖尿病(T1DM)的相关性。方法 选取就诊于中南大学湘雅二医院代谢内分泌科的510例经典T1DM患者及本地区531名无血缘关系的健康志愿者为研究对象。利用质谱法对其NLRP2基因的rs1043673位点进行基因分型。两组间一般资料的比较采用Mann-Whitney U检验和χ2检验,T1DM患者组与对照组之间基因型及等位基因频率分布的比较采用χ2检验和logistic回归分析。NLRP2多态性与各项临床特征的分析采用Kruskal-Wallis H检验。结果 NLRP2基因rs1043673位点的等位基因及基因型在两组之间的分布无明显差异。在T1DM患者中,rs1043673多态性与空腹C肽(P＝0.029)、餐后2 h C肽(P＝0.017)以及GADA的抗体滴度(P＝0.043)均有关。结论 NLRP2基因的rs1043673多态性与中国汉族T1DM患者的临床特征有关。     

1型糖尿病研究新进展

40年前创立的青少年糖尿病研究基金会((JDRF)是一个致力于通过支持研究来探寻1型糖尿病(TIDM)及其并发症治疗方法的组织.20世纪70年代有学者提出,TIDM和2型糖尿病(T2DM)的发病机制有根本的不同,T1DM与主要组织相容性复合体的人白细胞抗原(HLA)有独特相关性,有胰岛细胞自身抗体.     

Frequency of Hashimoto's thyroiditis in children with type 1 diabetes mellitus

A total of 1419 children with type 1 diabetes mellitus was investigated in order to assess the true frequency of Hashimoto's thyroiditis (HT), diagnosed by microsomal and/or thyroglobulin autoantibodies, by ultrasound and in many cases also by fine needle biopsy. According to these criteria, 55 cases (3.9%) of HT were identified, a number significantly higher (P<0.0001) than the distribution reported in the normal paediatric population. No typical antibody pattern was seen prior to the onset of HT, nor was an antibody threshold level found which could have been diagnostic for this disease. Patients with subclinical hypothyroidism were treated withl-thyroxine and were investigated regarding the behaviour of anti-thyroid autoantibodies; however, no significant changes were seen. The data showed a high frequency of HT in diabetic children, and therefore we recommend that children with type 1 diabetes mellitus should be screened for thyroid autoantibodies and those positive should undergo periodic thyroid function testing.A collaborative study of the AASGPED-Alpe Adria Study Group of Pediatric Endocrinology and Diabetology     

类泛素样蛋白4基因A/G163单核苷酸多态性与中国儿童1型糖尿病遗传易感性的关系初探

目的 了解类泛素样蛋白4(SUMO4)基因A/G163单核苷酸多态性与中国儿童1型糖尿病遗传易感性的关系.方法 选取2006年4月至2009年4月于北京儿童医院就诊的无血缘关系的165例儿童1型糖尿病患者及160名正常对照者为研究对象,运用聚合酶链式反应-限制性片段长度多态(PCR-RFLP)技术对SUMO4 163位点的等位基因进行分型.结果 SUMO4 G163等位基因在1型糖尿病患儿中的频率(38.2%)明显高于对照组(28.7%),差异具有统计学意义(P<0.05,OR=1.51,95% CI 1.03～2.13);GG基因型在1型糖尿病患儿中的频率也明显高于正常对照组,差异具有统计学意义(17%vs正常对照8%,P<0.05).SUMO4基因G163等位基因的频率分布在患儿发病年龄、性别、病程、胰岛残存功能,酮症发生情况方面的差异无统计学意义(均P>0.05).结论 SUMO4基因A/G163多态性与中国儿童1型糖尿病的遗传易感性存在显著的相关性;SUMO4基因G163与中国儿童1型糖尿病患者不同临床状态之间无显著相关性.     

Exocrine pancreas functions in children with type 1 diabetes mellitus

Background and study aimWe evaluated exocrine pancreas functions using a noninvasive indicator in a case–control study conducted on children and adolescents diagnosed with type 1 diabetes mellitus.Patients and methodsSixty-seven patients who participated in a summer camp were enrolled in this study. Nineteen healthy children in the same age group were assigned to the control group. Fecal pancreatic elastase was assayed using the enzyme-linked immunosorbent assay technique. Values higher than 200 µg/g were considered an indication of sufficient exocrine pancreatic functioning, values between 100 µg/g and 200 µg/g were considered mild exocrine pancreatic insufficiency, and values below 100 µg/g were considered severe exocrine pancreatic insufficiency.ResultsThe mean concentration of fecal elastase was 158.38 ± 59.67 µg/g. The patients were assigned to three groups according to these values. Thirteen patients (22%) had sufficient fecal elastase levels, whereas 36 patients (62%) had mildly insufficient levels, and nine patients (16%) had severely insufficient fecal elastase concentrations. The levels of fecal elastase, amylase, lipase, and zinc were significantly different between the patients and controls (p < 0.001). Only the duration of diabetes was significantly different between patients with different severities of exocrine pancreatic insufficiency (p = 0.037). Additionally, the group with severe pancreatic insufficiency had more frequent hypoglycemic attacks.ConclusionExocrine pancreatic insufficiency may develop in children with diabetes, and hypoglycemia attacks are observed more frequently depending on the severity of pancreatic insufficiency.     

中国人2型糖尿病患者胰岛素受体底物-1基因变异的研究

确定中国人胰岛素受体底物－１基因变异是否与２型糖尿病相关。方法用聚合酶链反应－单链构象多态性分析方法筛选了６８例中国人２型糖尿病患者和６８例正常对照组的胰岛素受体底物－１基因的＋１７００－＋４４３７ｂｐ片段。再将单链构象多态性有改变的全部片段进行ＤＮＡ序列分析。     

Association analysis of proopiomelanocortin (POMC) haplotypes in type 1 diabetes in a UK population

Aim

To assess the association of POMC haplotype-tagged single nucleotide polymorphisms (htSNPs) with the development of type 1 diabetes (T1D) in a Caucasian population.

Methods

All exons, intron 1, and approximately 6-kb upstream and 3-kb downstream of the POMC gene were bidirectionally resequenced to identify DNA polymorphisms in 30 individuals. Allele frequencies were determined (60 chromosomes) and efficient htSNPs were selected using the htSNP2 programme. Genotyping was performed in 390 cases, 339 controls and 245 T1D parent-offspring trios, using Taqman, Sequenom and direct-sequencing technologies.

Results

Thirteen polymorphisms (two novel) with a minor allele frequency greater than 1% were identified. Six POMC htSNPs (rs3754863 G > A, ss161151662 A > G, rs3754860 C > T, rs1009388 G > C, rs3769671 A > C, rs1042571 G > A) were identified. Allele and haplotype frequencies were similar between case and control groups (P > 0.60 by permutation test), and assessment of allele transmission distortion from informative parents to affected offspring also failed to find any association. Stratification of these analyses for age-at-onset and HLA-DR risk group (DR3/DR4) revealed no significant associations. A haplotype block of 9.86-kb from rs3754863 to rs1042571 was identified, encompassing the POMC gene. Comparison of haplotype frequencies identified the GGCGAG haplotype as protective against T1D in 12.9% of cases vs. 18.3% of controls: χ² = 8.18, Pc = 0.03 by permutation test.

Conclusion

The POMC SNP haplotype GGCGAG may have a protective effect against T1D in the UK population. However, this finding needs to be replicated, and the cellular and molecular processes influenced by this POMC haplotype determined to fully appreciate its impact.     

Relation of genetic polymorphisms in microRNAs with diastolic and systolic function in type 2 diabetes mellitus

Background and aimsType 2 diabetes mellitus (T2DM) has high risk of developing cardiac dysfunction, increasing of either cardiovascular death or hospitalization for heart failure. MicroRNAs (miRNA) affect cardiac function of T2DM. The aim of this study was to investigate the relationships between five miRNA single nucleotide polymorphisms (SNP) and diastolic and systolic function of T2DM.Methods and resultsThree hundred untreated T2DM subjects were included. Each subject underwent SNP genotyping, conventional echocardiography, tissue doppler imaging, and speckle tracking imaging. The effects of miRNA SNPs on diastolic and systolic function were evaluated. The diastolic function of T2DM subjects with miR-133a-1-rs8089787 wild genotype or let-7f-rs10877887 variant genotype was lower than those with miR-133a-1-rs8089787 variant genotype or let-7f-rs10877887 wild genotype, manifesting as higher left atrial volume index, lower mean E′, and higher E/E’ (P < 0.05). There were no significant effects of miR-133a-2-rs13040413, let-7a-1-rs13293512 and miR-27a-rs895819 on the diastolic function of T2DM subjects (P > 0.05). These five miRNA SNPs had no effect on the systolic function of T2DM subjects (P > 0.05).ConclusionsMiRNA-133a-1-rs8089787 and let-7f-rs10877887 were associated with impaired cardiac diastolic function in T2DM. The findings may be a promising therapeutic targets for preventing diastolic dysfunction in T2DM.     

Neutrophils in type 1 diabetes

Type 1 diabetes is an autoimmune disease that afflicts millions of people worldwide. It occurs as the consequence of destruction of insulin‐producing pancreatic β‐cells triggered by genetic and environmental factors. The initiation and progression of the disease involves a complicated interaction between β‐cells and immune cells of both innate and adaptive systems. Immune cells, such as T cells, macrophages and dendritic cells, have been well documented to play crucial roles in type 1 diabetes pathogenesis. However, the particular actions of neutrophils, which are the most plentiful immune cell type and the first immune cells responding to inflammation, in the etiology of this disease might indeed be unfairly ignored. Progress over the past decades shows that neutrophils might have essential effects on the onset and perpetuation of type 1 diabetes. Neutrophil‐derived cytotoxic substances, including degranulation products, cytokines, reactive oxygen species and extracellular traps that are released during the process of neutrophil maturation or activation, could cause destruction to islet cells. In addition, these cells can initiate diabetogenic T cell response and promote type 1 diabetes development through cell–cell interactions with other immune and non‐immune cells. Furthermore, relevant antineutrophil therapies have been shown to delay and dampen the progression of insulitis and autoimmune diabetes. Here, we discuss the relationship between neutrophils and autoimmune type 1 diabetes from the aforementioned aspects to better understand the roles of these cells in the initiation and development of type 1 diabetes.     

1型糖尿病青少年儿童心理行为问题研究进展

逐步走向青春期的1型糖尿病青少年儿童,容易出现治疗依从性差、代谢控制不良等问题,更是心理障碍的高危人群.其常常表现出抑郁、进食行为问题、家庭冲突、恐惧低血糖等心理问题,这些问题会进一步恶化糖尿病治疗的依从性以及血糖控制,故需要尽早筛查和干预.     

Pupillary size in children and adolescents with type 1 diabetes

Pupillary adaptation to darkness was studied in 63 children and adolescents with Type 1 diabetes using a simple portable pupillometer. Results were compared with those in a group of age-related non-diabetic children and expressed as the ratio of the pupil diameter to the iris diameter (pupil diameter %). In the diabetic patients the pupil diameter % was 61.1 +/- 5.8 (44.4-71.9) % compared with 64.2 +/- 4.1 (53.2-72.6) % in the control subjects (p less than 0.001). Abnormal pupillary adaptation to darkness was found more commonly than abnormal heart rate variation in response to a variety of stimuli in the diabetic patients. Pupillary adaptation to darkness may be useful as an indicator of subclinical autonomic neuropathy in diabetic children.