不同胰岛自身抗体阳性1型糖尿病临床特征分析

目的探讨单独或合并锌转运体8自身抗体(ZnT8A)、谷氨酸脱羧酶抗体(GADA)及蛋白酪氨酸磷酸酶抗体(IA-2A)阳性患者的1型糖尿病(T1DM)患者临床特征。方法采用放射配体检测法检测中南大学湘雅二医院1999—2009年收治的539例T1DM患者的ZnT8A、GADA及IA-2A,并将其分成三个亚组进行比较。结果(1)单一ZnT8A阳性组较抗体阴性组病程更长,胰岛素用量更大,收缩压更低,合并代谢综合征比例更少。单一ZnT8A阳性组较单一GADA阳性组BMI、WHR及空腹C肽值更高(P<0.05),而糖化血红蛋白水平更低(P<0.05);(2)多个抗体阳性组起病年龄显著低于抗体阴性组(P<0.05);1个抗体阳性患者的空腹C肽及餐后2 h C肽显著低于抗体阴性组(P<0.05);3个抗体阳性患者较1个抗体阳性患者的起病年龄更小(P<0.01),BMI更低(P<0.05),病程更短(P<0.05)。(3)合并任意两种抗体阳性中"GADA阳性与IA-2A阳性"组餐后C肽最低(P<0.01),空腹C肽也较低,但差异无统计学意义(P>0.05)。结论单独或合并ZnT8A,GADA及IA-2A的T1DM临床特征分析对临床具有重要的指导意义。     

胰岛自身抗体与1型糖尿病

1617例糖尿病患者中自身抗体阳性率29．7％。单一抗体的阳性率明显低于3种抗体联合检测。多种胰岛自身抗体联合检测可提高1型糖尿病早期诊断的敏感性。谷氨酸脱羧酶抗体为成年糖尿病患者预示胰岛素依赖的较好的筛查试验，与酪氨酸蛋白磷酸酶抗体联合检测可达近100％的预报价值；而青少年糖尿病患者则还需检测胰岛细胞抗体。     

胰岛自身抗体与1型糖尿病

1型糖尿病是一种针对胰岛β细胞的自身免疫性疾病,患者体内有多种胰岛自身抗体存在,主要包括胰岛细胞抗体、胰岛素自身抗体、谷氨酸脱羧酶抗体,酪氨酸磷酸酶抗体等。随着这些抗体本质渐被揭示,检测方法趋于自动化,衡量标准趋于国际化,它们不仅被用于1型糖尿病的诊断和筛查,而且在对本病病因、发病机制和防治的研究中都起到了很大作用。     

1型糖尿病与HLA-DQB1基因及自身抗体相关性研究

采用基因分型技术,确定32例1型糖尿病患者及23例正常对照的HLA-DQB1等位基因.用酶联免疫吸附法测定血清中谷氨酸脱羧酶抗体(GADA)、胰岛细胞抗体(ICA)及胰岛素自身抗体(IAA).结果在1型患者中,DQB1*0201、*0303、*0604等位基因频率显著高于对照(P＜0.05),DQB1*0301则低于对照(P＜0.05),其余DQB1等无显著性差异.等位基因为DQB1*0201的患者中GADA阳性率显著高于阴性率.结论在中国汉族人群中,DQB1*0201、*0303、*0604是1型糖尿病易感性等位基因,DQB1*0301是1型糖尿病保护性等位基因.DQB1*0201可能对GADA的产生起允许作用.     

2型糖尿病患者红细胞葡萄糖转运蛋白的功能研究

目的探讨2型糖尿病患者新鲜血红细胞葡萄糖转运蛋白1(GLUTl)的功能改变特征以及血糖控制对患者红细胞GLUTl功能的影响.方法2型糖尿病患者17例与健康成年人11例为对照,制备红细胞悬液,采用2-deoxy-[3H]-D-glucose法测定红细胞葡萄糖摄入并进行动力学分析.结果生理及高糖浓度下,糖尿病患者红细胞的葡萄糖摄入均显著高于正常对照组[(385±56.8)nmol/105cell@h-lvs(321±38.5)nmol/105cell@h-1,P＜0.0l],动力学分析表明,患者红细胞GLUTl与葡萄糖的亲和力(1/Km)较对照组降低(P＜0.01),但GLUTI介导的葡萄糖转运最大速率(Vmax)显著高于正常组(P＜0.01).将糖尿病患者按糖化血红蛋白水平分为血糖控制良好组(H-bA1c＞7%)和血糖控制欠佳组(HbA1c≤7%)进行分析比较,血糖控制欠佳组患者红细胞GLUT1的Km较血糖控制良好组显著升高[(2.63±0.64)nnol/Lvs(1.87±0.61)mmol/L,P＜0.05],糖摄入及Vmax的增加幅度也较血糖控制良好组更为明显.结论糖尿病患者红细胞GLUTI功能发生了明显的改变,表现为患者红细胞上具有转运活性的GLUT1数目增加,使细胞在生理糖浓度下的糖摄入增加,以血糖控制欠佳组增加幅度更为显著,同时该组患者红细胞GLUT1与底物亲和力降低,表明血糖控制可在一定程度上延缓GLUT1功能的恶化,由此对延缓糖尿病慢性并发症可能有助益.     

葡萄糖转运蛋白与2型糖尿病

葡萄糖转运蛋白与２型糖尿病赵维纲肖新华综述王审校２型糖尿病的高血糖与胰岛素分泌缺陷、肝糖输出（ＨＧＯ）增多和周围胰岛素抵抗有关。三者在糖尿病发病中的原发作用尚不明确，然而大量研究表明葡萄糖转运异常可能构成其共同基础。胰岛β细胞的胰岛素分泌有赖于葡萄...     

胰岛B细胞凋亡与1型糖尿病

胰岛B细胞凋亡与死亡受体Fas及其配体（FasL）系统、Bcl－2家族、胱氨酸门冬氨酸蛋白裂解酶（caspase）家族及线粒体的功能密切相关,同时受胰岛素、葡萄糖等多种因素的影响。浸润细胞可通过FasL、穿孔素／颗粒酶B,肿瘤坏死因子－α、干扰素－γ、白介素－1β以及一氧化氮等多效应分子导致胰岛B细胞凋亡,而通过去除和（或）抑制促凋亡因素如诱导免疫耐受、免疫豁免,阻断凋亡效应分子作用以及直接干预细胞凋亡过程等均可阻止或延缓胰岛B细胞的凋亡,将为临床1型糖尿病的防治提供新的途径。     

胆固醇酯转运蛋白基因多态性与2型糖尿病合并冠心病的关系

以PCR-RFLP检测胆固醇酯转运蛋白(CETP)基因TagⅠB多态性。CETP基因第1内含子TagⅠ B2B2基因型可能是糖尿病患者冠心病发生的保护性基因型。     

胰岛B细胞凋亡与1型糖尿病

胰岛B细胞凋亡与死亡受体Fas及其配体 (FasL)系统、Bcl 2家族、胱氨酸门冬氨酸蛋白裂解酶 (caspase)家族及线粒体的功能密切相关 ,同时受胰岛素、葡萄糖等多种因素的影响。浸润细胞可通过FasL、穿孔素 /颗粒酶B ,肿瘤坏死因子 α、干扰素 γ、白介素 1 β以及一氧化氮等多效应分子导致胰岛B细胞凋亡 ,而通过去除和 (或 )抑制促凋亡因素如诱导免疫耐受、免疫豁免 ,阻断凋亡效应分子作用以及直接干预细胞凋亡过程等均可阻止或延缓胰岛B细胞的凋亡 ,将为临床 1型糖尿病的防治提供新的途径。     

B淋巴细胞与自身免疫型1型糖尿病

1型糖尿病（T1DM）分为2种亚型：自身免疫型（1A）和特发型（1B）。其中,1A型是一种T、B淋巴细胞共同参与的慢性自身免疫性疾病,而B细胞在1A型糖尿病中的作用较为复杂。目前对1A型糖尿病中B细胞的关注已远不止其分泌自身抗体的功能。随着对B细胞在T1DM中作用的不断探索,以B细胞为治疗靶点的研究正逐渐成为热点。本文主要探讨B细胞通过促进和抑制自身免疫反应在1A型糖尿病中发挥的双重作用。     

Autoantibodies to zinc transporter 8 and SLC30A8 genotype stratify type 1 diabetes risk

Aims/hypothesis  Our aim was to determine the relationships between autoantibodies to zinc transporter 8 (ZnT8), genotypes of the ZnT8-encoding gene SLC30A8 and type 1 diabetes risk. Methods  ZnT8 autoantibodies (ZnT8A) were measured in sera of 1,633 children with a first-degree family history of type 1 diabetes and who were prospectively followed from birth. Antibodies were measured by Protein A-based radiobinding assays and COOH-terminal (R325, W325 or Q325 variants) or NH₂-terminal constructs of human ZnT8. SLC30A8 genotyping at single-nucleotide polymorphism (SNP) rs13266634 was performed on 1,170 children. Results  Antibodies against COOH-terminal ZnT8 constructs (ZnT8A-COOH) developed in 58 children as early as 9 months of age (median 3 years). They were detected in 55 of 128 (43%) children with autoantibodies to insulin, GAD and/or insulinoma-associated protein 2 and 34 of 42 (81%) who progressed to diabetes. The additional presence of ZnT8A-COOH stratified diabetes risk in islet autoantibody-positive children (p < 0.0001). SLC30A8 genotype strongly influenced ZnT8A type and diabetes risk in ZnT8A-COOH-positive children. Antibody binding against the ZnT8 R325 variant was strictly correlated with the number of the corresponding SLC30A8 R325-encoding alleles, whereas binding against the W325 variant was highest in children who had SLC30A8 W325-encoding alleles (p = 0.001). Moreover, ZnT8A-COOH-positive children who carried homozygous SLC30A8 SNP rs13266634 genotypes progressed faster to diabetes than those who were heterozygous (59% [95% CI 42.3–75.7%] vs 22% [95% CI 0–44.3%] within 5 years; p = 0.01). Conclusions/interpretation  Autoimmunity against the COOH-terminal region of ZnT8 is a highly relevant prognostic feature in childhood type 1 diabetes. Risk stratification in ZnT8A-COOH-positive children is further improved by SLC30A8 genotyping. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorised users. P. Achenbach and V. Lampasona contributed equally to this study     

锌转运体8自身抗体的放射配体检测法

目的建立锌转运体8自身抗体（ZnT8A）的放射配体检测法（RLA）。方法采用重组人ZnT8质粒,经试管内转录与翻译,获得“S-ZnT8抗原,35S-ZnT8与血清在自制旋转孵育器上旋转温育后,用蛋白A-琼脂糖沉淀免疫复合物。免疫复合物经TBST缓冲液洗涤后,用多功能闪烁发光分析仪检测沉淀物放射性计数值。参加国际糖尿病免疫学会（IDS）和美国疾病预防控制中心联合举办的第六次糖尿病自身抗体国际标准化评估（DAsP2009）,评价该方法的敏感性和特异性。检测429例1型、855例2型糖尿病患者以及405例正常人ZnT8A水平,初步评价其临床应用价值。结果该方法批内CV3．9N～9．8N,批间CV4．3％～13．8％;DASP2009显示,该方法敏感性66％,特异性100％。受试者操作特性曲线（ROC）分析显示,曲线下面积为0．879±0．034;该方法阳性阈值ZnT8A指数为0．011（405名正常人的99％百分位点）,检测1型糖尿病患者阳性率24．0％,高于初诊2型糖尿病患者1．3％和健康人0．99％（P均do．01）。结论建立的RLA法检测ZnT8A敏感性高、特异性强、重复性好,可应用于自身免疫糖尿病的诊断与分型。     

锌转运体8及其自身抗体

锌是胰岛素储存和分泌机制中的一个重要组分,β细胞需要有效且特异的转运体来累积足够量的锌.锌转运体8(ZnT8)是新近发现的一种1型糖尿病自身抗原,具有高度β细胞特异性,通过影响锌离子浓度而在胰岛素合成和分泌中发挥重要作用.ZnT8自身抗体对自身免疫性糖尿病(尤其对其他自身抗体阴性者)有着重要的诊断与预测价值.ZnT8基因(SLC30A8基因)多态性影响ZnT8自身抗体的特异性.     

Different role of zinc transporter 8 between type 1 diabetes mellitus and type 2 diabetes mellitus

Diabetes can be simply classified into type 1 diabetes mellitus and type 2 diabetes mellitus. Zinc transporter 8 (ZnT8), a novel islet autoantigen, is specifically expressed in insulin‐containing secretory granules of β‐cells. Genetic studies show that the genotypes of SLC30A8 can determine either protective or diabetogenic response depending on environmental and lifestyle factors. The ZnT8 protein expression, as well as zinc content in β‐cells, was decreased in diabetic mice. Thus, ZnT8 might participate in insulin biosynthesis and release, and subsequently involved deteriorated β‐cell function through direct or indirect mechanisms in type 1 diabetes mellitus and type 2 diabetes mellitus. From a clinical feature standpoint, the prevalence of ZnT8A is gradiently increased in type 2 diabetes mellitus, latent autoimmune diabetes in adults and type 1 diabetes mellitus. The frequency and epitopes of ZnT8‐specific T cells and cytokine release by ZnT8‐specific T cells are also different in diabetic patients and healthy controls. Additionally, the response to ZnT8 administration is also different in type 1 diabetes mellitus and type 2 diabetes mellitus. In the present review, we summarize the literature about clinical aspects of ZnT8 in the pathogenesis of diabetes, and suggest that ZnT8 might play a different role between type 1 diabetes mellitus and type 2 diabetes mellitus.     

Apolipoprotein (a) levels in type 1 and type 2 diabetes mellitus

Type 1 and type 2 diabetes mellitus are both characterized by increased cardiovascular mortality and morbidity. Since several reports have indicated that apolipoprotein (a) [apo (a)] levels are positively associated with an increased risk of macrovascular disease, we investigated whether apo (a) levels are elevated in both types of diabetes mellitus and may thus represent an independent risk factor for atherosclerotic disease. Apo(a) concentrations in type 1 diabetic patients were not significantly different from matched controls (276±78 vs 149±46 units/l). Type 2 diabetic patients had considerably higher levels of apo (a) than matched controls (471±89 vs 221±61 units/l,P=0.06), though the difference was not statistically significant. However, concentrations of apo (a) were above 300 units/l in 36% of type 1 and 67% of type 2 diabetic patients, but in only 14% and 25% respectively of matched control subjects. Plasma triglycerides were positively and independently correlated with apo (a) levels in both diabetic and non-diabetic subjects. On the other hand, no significant correlation was found between apo (a) levels and glycosylated haemoglobin, total cholesterol or high density lipoprotein cholesterol in any of the groups studied. In conclusion, apo (a) levels are not significantly elevated either in type 1 or type 2 diabetic patients without proteinuria and in moderate metabolic control; however, levels above 300 units/l were 2.6 times more frequent in both types of diabetes mellitus than in carefully age-, sex-, and weight-matched control subjects.     

1型糖尿病患者的临床特点和多种胰岛自身抗体检出情况

目的分析1型糖尿病（T1DM）患者多种胰岛自身抗体的检出情况和不同类型T1DM的临床特征。方法选取2010年11月至2011年11月在中日友好医院住院的67例T1DM患者,分析其临床特征及胰岛细胞抗体（ICA）、胰岛素抗体（IAA）、谷氨酸脱羧酶抗体（GADA）[酶联免疫吸附试验（ELISA）法和免疫沉淀法（RIP）检测]、蛋白酪氨酸磷酸酶抗体（IA2A）和锌转运蛋白8抗体（ZnT8A）等6种胰岛自身抗体情况。结果本组T1DM共67例,其中经典型T1DM53例,成人迟发性自身免疫糖尿病（LADA）12例和暴发性1型糖尿病（FT1D）2例。起病年龄2～77岁,体质指数（BMI）（22±4）kg／m2,糖化血红蛋白（HbAlc）9．7％±2．4％,空腹C肽（0．3±O．4）μ／L。GADA（ELISA）阳性51例（76．1％）,GADA（RIP）阳性35例（52．2％）,IA2A阳性19例（28．3％）,ZnT8A阳性16例（23．9％）,IAA阳性16例（23．9％）,ICA阳性10例（14．3％）。前4种抗体检测方法至少1种阳性者共56例（83．6％）。51例ELISA法GADA阳性包括了35例RIP检测GADA阳性中的33例、19例IA2A阳性中15例及16例ZnT8A阳性中的14例。经典1型糖尿病在发病初至半年内需要胰岛素治疗,而LADA平均在发病3．9年后需要胰岛素治疗。2例FT1D患者起病急,发病时血糖分别为41．1和23．1mmol／L,HbAlc分别为7．8％和6．5％,空腹及餐后血C肽均小于0．03μg／L或不能测出。结论ELISA检0n．0GADA对1型糖尿病的诊断有较高敏感性,联合多种抗体检测对T1DM诊断作用有限。FT1D起病急骤,代谢紊乱更为严重。     

1型糖尿病诊断初期某些细胞因子的改变

目的 探讨细胞因子（CK）在1型糖尿病中的作用,了解其与糖尿病HLA易感基因及糖代谢的关系。方法 放免法或酶免法检测新诊断1型糖尿病病人血清6种CK、胰岛素和C肽;斑点杂交法检测4种糖尿病HLA易感基因;微柱法测定HbA1c。用SPSS软件处理数据。结果 病人组IL－2、IL－4低于对照组,IL－1β、IFN-γ/IL-4、IL－12／IL－4比值,都显著高于对照组;IFN－γ、IL-4、IL－1β分别与IL－12正相关,IL－12／IL－4与IFN－γ／IL－4正相关;空腹胰岛素与IL－1β和空腹C肽与IL－12分别呈正相关。结论 新诊断1型糖尿病病人存在IL－4、IL－2低下及IL－2β的分泌增高;1型糖尿病病人存在TH1优势;IL－12与IL－4正相关,表明了它们对TH1、TH2细胞的调节关系;CK与HbA1无显著相关性;HLA－DQB1＊0201携带者TNF－α较高。     

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