Functional Polymorphisms of the Type 1 and Type 2 Iodothyronine Deiodinase Genes in Autoimmune Thyroid Diseases

Graves’ disease (GD) and Hashimoto’s disease (HD) are major autoimmune thyroid diseases (AITDs), and their pathological conditions vary among patients. Type 1 iodothyronine deiodinase (D1) and type 2 iodothyronine deiodinase (D2) convert from thyroxine (T4) to triiodothyronine (T3). However, few findings have been described concerning the association between polymorphisms in D1 and D2 genes and AITD. Therefore, we genotyped D1 rs11206244, D2 rs225014, and rs12885300 polymorphisms in 134 GD patients, including 54 patients with intractable GD and 44 patients with GD in remission and 132 HD patients, including 57 patients with severe HD, 45 patients with mild HD, and 84 healthy controls using PCR-RFLP. In the D2 rs225014 polymorphism, the TT genotype, which was correlated with higher D2 activity, was less frequent in AITD, especially in HD, than in control subjects (P = 0.0032 and 0.0002, respectively). Moreover, they were also less frequent in HD than in GD (P = 0.0199). The TT genotype and T allele were less frequent in severe HD and mild HD than in control subjects (P = 0.0003, 0.0006, 0.0432, and 0.0427, respectively). In conclusion, the low frequency of the TT genotype D2 rs225014 polymorphism was associated with the development of AITD and severity of HD.     

糖尿病患者甲状腺功能的变化

目的:分析糖尿病患者的甲状腺功能状态.方法:应用微粒子酶免分析(MEIA)检测108例糖尿病患者及50例正常对照者的血清游离T3(FT3)、游离T4(FT4)、促甲状腺素(TSH)水平,并测定糖尿病患者的空腹血糖(FPG),结合病程等因素进行相关分析.结果:糖尿病患者的血清FT3、FT4水平显著低于对照组(P＜0.05),且与血糖、病程呈负相关,甲状腺功能异常者占43.5%,其中34.3%呈功能减退,9.2%呈功能亢进.结论:糖尿病患者甲状腺功能异常的发生率高,尤以甲状腺功能减退的患病率高.     

Association of Cytotoxic T Lymphocyte Antigen-4 Gene Polymorphisms and HLA Class II Alleles with the Development of Type 1 Diabetes in Korean Children and Adolescents

We studied the association of cytotoxic T lymphocyte antigen-4 gene (CTLA4) polymorphisms with the development of type 1 diabetes (T1D) in Korean children and adolescents. A total of 176 Korean subjects (92 females and 84 males) with childhood-onset T1D were studied. The A/G polymorphism at position 49 in CTLA4 exon 1 and the C/T polymorphism at position -318 in the CTLA4 promoter were analyzed by PCR-RFLP methods. The genotype and allele frequencies of the CTLA4 polymorphisms in the T1D patients were not different from those in the controls. These polymorphisms were not associated with the clinical characteristics or the development of autoimmune thyroid disease in the T1D patients. The frequency of the A allele was significantly higher in the patients that did not have two out of the three susceptible HLA-DRB1 alleles, which were DRB1*0301, *0405 and *09012, compared to the controls (P<0.05). These results suggest that CTLA4 polymorphisms do not directly confer any susceptibility to T1D. However, a CTLA4-mediated susceptibility effect on the development of T1D might be significant in children and adolescents that do not have susceptible HLA class II alleles.     

Soluble HLA Class I Antigens in Patients with Type I Diabetes and Their Family Members

Our objective was to study a possible contribution of MHC genes to S-HLA-I secretion in patients with Type I diabetes. Quantitatively, we used a highly sensitive enzyme-linked immunoassay to measure S-HLA-I in the serum of a total of 39 patients with Type I diabetes, as well as 36 kinships of 12 diabetic patients and 82 normal individuals with known HLA-phenotypes.

S-HLA-I levels were abnormally elevated in patients or their non-diabetic relatives compared to normal controls (p < 0.0009). No complete HLA-haplotype had been identified to be correlated with high or low S-HLA-I secretion. Only the HLA-A23 or A24 (splits of HLA-A9) positive individuals sera were found to contain high S-HLA-I concentrations in all populations studied. The difference in S-HLA-I levels of HLA-A24 patients (n = 4) or their HLA-A24 positive non-diabetic relatives (n = 10) to the group of HLA-A24 normal controls (n = 15) was statistically highly significant (p < 0.0005 and p < 0.0009, respectively). The results suggests that HLA-A24 may confer additional independent risk for the disease expression in male children but not in female siblings. Nevertheless, the data implies that the patients or their non-diabetic relatives carrying the HLA-A24 have increased risk of developing ICA associated with high S-HLA-I levels compared to HLA-A24 negative probands or their kinships with low levels of S-HLA-I. This effect occurred irrespective to other diabetes related HLA-DR alleles.

In summary, the results show a pronounced genetic heterogeneity of Type I diabetes with MHC control of the expression of S-HLA-I and possible involvement of hormonal factors that might potentiate a specific synthesis of S-HLA-I. The findings have implications for identifying individuals with a possible risk for developing the disease.     

HLA and H2 Class II Transgenic Mouse Models to Study Susceptibility and Protection in Autoimmune Thyroid Disease

Using single H2 and HLA class II transgenic mice, in the absence of endogenous H2 class II molecules, we have studied the permissiveness of class II molecules for experimental autoimmune thyroiditis (EAT). Resistant strains expressing susceptible class II molecules, H2A^k or HLA-DR3, developed EAT, clearly demonstrating the importance of class II gene inheritance. Polymorphism for HLA-DRB1 was observed, as DR3, but not DR2 or DR4, molecules were permissive for EAT induction with either mouse (m) or human (h) thyroglobulin (Tg). HLA-DQ polymorphism was also detectable, as hTg-induced EAT developed in DQ8⁺, but not DQ6⁺, mice. Class II gene interactions leading to reduced EAT severity were observed in H2 transgenic mice, when H2E transgene was expressed in H2A⁺ mice or H2A molecules were introduced into our novel H2A^-E⁺ transgenic model. Similarly, in DR3⁺ mice, only the DQ8 transgene reduced EAT severity, depending on both background genes (C57BL/10 or NOD) and Tg species. Based on computer-predicted, class II-binding motifs, potential pathogenic Tg peptides, either unique to hTg (H2A^-E⁺ model) or shared between mTg and hTg (HLA-DR3⁺ model), were identified. We have also developed a Graves' disease model by immunizing DR3⁺ mice with TSH receptor DNA. Thus, transgenic models are excellent tools to study human autoimmune thyroid diseases in the context of murine EAT.     

2型糖尿病患者血清甲状腺激素水平的变化及临床意义探讨

目的 了解2型糖尿病患者血清甲状腺激素水平的变化情况,并探讨其临床意义.方法 选择2013年1月至2014年8月间在我院就诊的120例2型糖尿病患者,运用放射免疫技术检测血清中游离三碘甲状腺原氨酸(FT3)、游离甲状腺激素(FT4)以及促甲状腺激素含量(TSH),并与我院体检中心120例健康体检者进行比较;将120例糖尿病患者依据糖化血红蛋白水平的高低分为四组:＜5.5％组,5.5％ ～6.5％组,6.6％ ～9.5％组,＞9.5％组,并测定甲状腺激素水平.结果 2型糖尿病患者FT3明显低于正常组,差异有统计学意义(P＜0.05),而FT4及TSH与正常组相比差异无统计学意义(P＞0.05).糖化血红蛋白水平在5.5％ ～6.5％组、6.6％ ～9.5％组、＞9.5％组FT3含量明显低于＜5.5％组,差异有统计学意义(P＜0.05);而糖化血红蛋白水平中FT4与TSH各组比较差异无统计学意义(P＞0.05).结论 糖尿病患者血清甲状腺激素水平主要是FT3含量下降,其下降程度和糖尿病的严重程度成正比,因此,血清FT3水平可作为评价糖尿病患者病情严重程度的重要指标之一.     

Role of Vitamin D in Intima Media Thickness in Patients with Type 1 Diabetes Mellitus

Increased carotid intima media thickness indicates subclinical atherosclerosis. We evaluated the relation between vitamin D level and intima media thickness in patients with type 1 DM. 93 patients (female/male: 48/45, aged 31.5 ± 11.9 years, A1c 9.48 ± 2.43, vitamin D [15.9 (12.1–19.2)]) with type 1 DM were included into the study. Common carotid artery IMT was measured by real time B mode ultrasonography (MyLab 70 XVG, Esaote SpA, Genoa, Italy). Vitamin D was measured using radioimmunassay. Male and female patients (n = 14, 15%) had similar rates of plaque presence (p = 0.377). IMT was similar according to gender. IMT [0.45 (0.40–0.50)] was positively correlated with age, duration of diabetes, creatinine, LDL/HDL ratio, and ALP. Median IMT was higher in current smokers, patients with retinopathy, and nephropathy, and overweight/obese patients. IMT was not different according to vitamin D status. However calcium level corrected for albumin was in positive correlation with mean IMT (r = 0.221, p = 0.033). We detected high frequency of vitamin D deficiency (78%) defined as less than 20 ng/ml. Vitamin D and diabetes control defined as A1c have no effect on intima media thickness in type 1 DM. Traditional cardiovascular risk factors including age, duration of DM, smoking, and BMI adversely affect intima media thickness.     

前臂骨密度及血清IGF-1在2型糖尿病的特点

观察 2型糖尿病患者不同性别、不同年龄阶段以及肥胖与非肥胖状态下IGF - 1血清浓度及前臂骨密度水平。 2型糖尿病 10 0人 ,ELISA法测定血清IGF - 1浓度 ,双能X光骨密度检测仪 (DXA)测量前臂超远端及远端 1/ 3交界处骨密度、骨矿含量及T积分。结果表明 ,骨质疏松症的发病率为 14% ( <5 0岁组 )到 73 % ( >70岁组 ) ,总发病率为 3 3 % (超远端 )和2 7% (远端 )。其中女性发病率为 47.7%和 2 2 .7% ,男性为 2 1.4%和 3 0 .4%。BMD、BMC、IGF - 1血清水平随增龄逐渐低降 ,5 0岁以后女性BMD、BMC较男性显著下降。肥胖者的BMD、BMC较非肥胖者高 ,骨质疏松症的发生率低。IGF - 1在男性与女性之间及肥胖与非肥胖者之间均无差异。 2型糖尿病患者骨质疏松症的发病率女性高于男性 ,非肥胖者高于肥胖者 ,IGF- 1、年龄、体重、雌激素是影响骨代谢的相关因素 ,IGF - 1与年龄和体重无关。男性前臂中远端骨质疏松明显 ,而女性则远端明显     

糖皮质激素受体遗传多态性与2型糖尿病相关性研究

目的 探讨糖皮质激素受体(GR)单核苷酸多态性与2型糖尿病(T2MD)易感性及人体体型的相关性.方法 采用病例-对照研究设计,从解放军总医院健康体检中心的体检患者中,募集40例T2MD患者和127例对照.结合三种不同的SNP位点选择方法,采用上海天昊生物科技有限公司的iMLDRTM多重SNP分型技术对入选SNP位点进行基因分型.采用非条件Logistic回归,校正年龄、性别、吸烟、饮酒后,分析基因型与T2MD易感性的关系.得到的阳性位点,进一步采用协方差分析,校正年龄、性别、吸烟、饮酒后,评价其与体重指数(BMI)和腰臀比(WHR)的相关性.结果 共选取14个SNP位点,其中rs10052957突变型在病例组中频率为零,故未纳入统计分析.所有的13个SNP位点在病例和对照组中的基因分型均符合Hardy-Weinberg平衡.rs9324924 TT基因型(OR [95％CI]=3.12[1.06 ～9.17],P=0.039)和rs9324921 AA基因型(OR [95％CI]=14.92[1.39～160.60],P=0.026)发生T2DM的风险较野生型增高,且两基因型的BMI[P=0.023 (rs9324924);P=0.002(rs9324921)]、WHR[P=0.033 (rs9324924);P=0.003(rs9324921)]也较野生型明显增高.结论 在本研究中,GR基因rs9324924、rs9324921与T2DM易感性和体型有关,其中纯和突变型T2DM发病风险明显增加,且更具有肥胖倾向.     

PTPN22 Single-Nucleotide Polymorphisms in Iranian Patients with Type 1 Diabetes Mellitus

Background: PTPN22 plays a crucial role in regulating the function of various cells of the immune system, particularly T cells. Polymorphisms of the PTPN22 gene have been associated with many autoimmune diseases, including type 1 diabetes (T1D) which is a T-cell-mediated disease.

Objective: The present study was aimed at genotyping of an Iranian population for five polymorphisms of the PTPN22 gene.

Methods: The study population consisted of 99 T1D patients and 100 healthy controls. We genotyped five single-nucleotide polymorphisms (SNPs) (rs12760457, rs1310182, rs1217414, rs33996649, and rs2476601) of the PTPN22 gene.

Results: Regarding the variant rs2476601, genotypes AG and GG were increased and decreased in T1D patients compared with controls, respectively. Further, alleles G and A of this SNP were found to be decreased and increased in T1D patients, respectively (p value = 0.001). However, T1D and control groups did not differ on genotype distribution or allele frequency for other investigated SNPs.

Conclusions: The PTPN22 rs2476601 minor allele (A) was associated with T1D in Iran, accounting for its pathophysiology in autoimmune diseases.     

2型糖尿病大鼠肾脏病变中血小板CD62P的变化及意义

目的探讨血小板CD62P在2型糖尿病大鼠肾脏病变不同阶段的变化及意义.方法 Wis-tar大鼠给予高脂高糖饲料喂养4周形成胰岛索抵抗后,腹腔注射小剂量链脲佐菌素(STZ,30 mg·kg-1)诱导形成2型糖尿病模型,分别在胰岛素抵抗期、糖尿病成模12周、22周检测各组大鼠血小板CD62P的表达、尿白蛋白排泄率及肾脏形态学改变.结果①胰岛素抵抗期,血小板CD62P已有增高趋势,但是与正常对照组相比统计学上无显著差异(P＞0.05).此时肾脏形态学、尿白蛋白排泄率无明显变化;②糖尿病成模12周时,血小板CD62P的表达较对照组显著增高(P＜0.001),尿白蛋白排泄率无明显变化,光镜下肾小球系膜基质明显增多;③在糖尿病成模22周时,血小板CD62P的表达与对照组相比无明显差异(P＞0.05),此时尿白蛋白排泄率较对照组显著增高(P＜0.01),肾小球形态学改变表现为弥漫性硬化和纤维化.结论 2型糖尿病大鼠肾脏病变过程中,血小板CD62P的表达可能与病变的不同阶段有关.     

载脂蛋白E基因多态性与2型糖尿病的关系

目的:探讨载脂蛋白E基因型与2型糖尿病的易感性。方法:应用multi-ARMS快速分型法对316例T2DM患者、512例健康对照人群的ApoE基因第4外显子112位Cys/Arg和158位Arg/Cys进行检测;随机抽取分型标本进行DNA测序法验证。结果:ε2/2、ε2/3、ε3/3、ε4/2、ε4/3、ε4/4基因型在二组中的频率分布为:0.6%,5.7%,72.8%,1.9%,14.9%,4.1%(T2DM组);0.6%,9.4%,70.1%,1.8%,17.0%,1.2%(对照组)。二组间差异有显著性统计学意义(χ2=11.45,P<0.05),T2DM组ε4/4基因型频率明显高于对照组(4.11%VS1.17%)。结论:ApoEε4/4基因型可能与T2DM的易感性有关。     

LOX-1在2型糖尿病下肢动脉硬化闭塞症中的表达及其作用

目的:观察2型糖尿病下肢动脉硬化闭塞症中血凝素样氧化低密度脂蛋白受体-1(LOX-1)mRNA和蛋白表达,并探讨其作用机制。方法:对9例2型糖尿病下肢动脉硬化闭塞症患者(糖尿病组)和7例正常肾移植供肾者(对照组)动脉标本行HE染色,应用RT-PCR和Western-blot检测动脉组织匀浆中LOX-1的mRNA和蛋白水平。结果:与对照组相比,糖尿病组LOX-1mRNA和蛋白水平表达明显升高(P0.05)。结论:2型糖尿病患者可能通过上调LOX-1表达而更容易合并下肢动脉硬化闭塞症,LOX-1可能是动脉硬化闭塞症发生发展的一个关键因素。     

Pathogenetic Role of Dysbacteriosis in the Development of Complications of Type 1 Diabetes Mellitus in Children

A relationship between enteric microbiocenosis and severity of type 1 diabetes mellitus was detected. Microbiological analysis showed II-IV degree dysbacteriosis in all diabetic children. Long-term therapy with probiotics aimed at eradication of opportunistic microflora resulted in recovery of microbiocenosis, which was paralleled by improvement of the clinical status, regression of complications in children who were ill for a long time, and prevention of complications in children with newly detected diabetes. These results indicate the leading role of chronic enteric toxic infectious process in the development of complications of type 1 diabetes. The significance of infection in the pathogenesis of other noninfectious diseases in man is discussed.     

Young Age and HLA Markers Enhance the Risk of Progression to Type 1 Diabetes in Antibody-Positive Siblings of Diabetic Children

The contribution of autoantibodies, HLA markers and age to long-term estimates of risk of type 1 diabetes were examined after a median of 11 years (range 7.5–14) during the follow-up in a cohort of 234 siblings (aged 2–29 years) of French children with recent-onset type 1 diabetes, of whom 12 (5.1%) developed diabetes. We evaluated islet cell antibodies (ICA) by indirect immunofluorescence and autoantibodies to insulin (IAA), to the 65 kDa isoform of glutamic acid decarboxylase (GADA) and to the IA-2 protein (IA-2A) by radioligand assay in sequential serum samples. Among the 234 siblings of type 1 diabetic patients screened, 27 were positive for at least one antibody, 11 of whom progressed to develop type 1 diabetes during the follow-up (sensitivity, 92%, predictive value, 41%). Among the four antibodies tested individually, ICA had the highest sensitivity (83%) but a poor predictive value (59%) and IA-2A the highest predictive value (70%). IAA and GADA both exhibited poor sensitivity and predictive value. Combinations of antibodies achieved better predictive values than antibodies tested individually. Satisfactory predictive values were obtained for the combination of GADA with IA-2A (83%), for any combination of at least two antibodies other than ICA (70%) and for the combination of ICA with at least one other antibody (69%). The risk estimates were highest in the presence of three or four antibodies, whether comprising ICA or not, but with a concomitant loss of sensitivity. For most antibody combinations, cumulative risks showed progression from approximately 50% after 5 years to 100% after 13 years. HLA-DR3/4 was significantly more frequent in siblings developing type 1 diabetes than in non-diabetic siblings (9/12vs.39/217, relative risk (RR)=14,P≤0.0001). The predictive value of HLA-DR3/4 was low (19%); however, taking into account the presence of HLA-DR3/4 in subjects who were positive for more than one antibody resulted in a higher predictive value (67%,vs.20% in non-DR3/4 subjects,P≤0.02). In addition, siblings developing diabetes were younger at entry than those who did not (mean =7.5 ±1.23vs.12.5 ±0.39 years, respectively;P≤0.01). Ten of 12 were aged less than 10 years compared with 106/222 non-diabetic siblings (RR =5.4,P≤0.03). Moreover, younger age was associated with a more rapid development of type 1 diabetes. In conclusion, our results show that the combination of IAA, GADA and IA-2A autoantibodies in sequential serum samples is satisfactory for the identification of subjects at risk of developing type 1 diabetes. Additional factors such as younger age and HLA-DR3/4 as markers of progression to disease may contribute to more efficient prediction in antibody positive subjects.     

初诊2型糖尿病患者甲状腺激素水平与糖代谢水平的关系研究

目的 探究初诊2型糖尿病(T2DM)患者甲状腺激素水平与糖代谢水平的关系及其临床价值.方法 选取2014年6月至2016年6月我院内分泌科收治的96例T2DM患者,测定所有患者甲状腺激素水平和糖代谢水平,采用Spearman相关分析其相关性.结果 不同性别在甲状腺激素水平及糖代谢指标及血脂指标差异不具有统计学意义(P＞0.05).随着FPG升高,TSH、T3等激素水平降低,差异具有统计学意义(P＜0.05).随着TSH水平升高,FPG、2h PG、HbA1c、HoMA-IR、TC和TG差异具有统计学意义(P＜0.05).FT3与BMI、FPG、2h PG、HbA1c呈负相关(r=-0.453、-0.522、-0.621、-0.461,P＜0.05),FT3、FT4和TSH与HoMA-IR呈正相关(r=0.861、0.701和0.746,P＜0.05),TSH与HbA1c呈负相关(r=-0.622,P＜0.05),TT3和TT4与BMI、FPG、2h PG、HbA1c、HoMA-IR、TC和TG无相关性(P＞0.05).结论 初诊2型糖尿病患者甲状腺激素水平对患者糖代谢水平评估具有重要意义.     

胆囊结石与2型糖尿病的共病机制

随着人们生活水平的提高,饮食结构发生转变,胆囊结石及2型糖尿病的发病率逐年上升,且2型糖尿病患者的胆囊结石患病率明显高于其他人群,以往大量研究认为糖尿病是胆囊结石的危险因素。随着研究的深入,发现胆囊结石的发生机制与血脂、胰岛素抵抗及部分脂肪因子因素密切相关,甚至认为胆囊结石是代谢综合征的另一种表现形式。而这些因素在2型糖尿病的发生发展中同样起着重要作用。本文就对胰岛素抵抗、脂代谢、瘦素及脂联素在胆囊结石与2型糖尿病的发病中的作用机制进行综述,并阐明这种共病机制的研究在实际临床工作中的意义。     

肾素-血管紧张素系统基因多态性与2型糖尿病患者癌症发生的相关性

目的 探讨肾素-血管紧张素系统的基因多态性与2型糖尿病患者罹患癌症的关系.方法 对1282例无癌症病史的2型糖尿病患者检测了血管紧张素原(angiotensinogen,AGT)M235T、血管紧张素转换酶(angiotensin-converting enzyme,ACE) I/D和Ⅰ型血管紧张素Ⅱ受体(angiotensinⅡtype Ⅰ receptor,AGTR1)A1166C多态性.癌症终点事件诊断为在随访期间首次发生的致死性或非致死性癌症.癌症发生与基因变异的关联性应用Cox比例风险模型分析,并校正了常见混杂因素.结果 在11.7(四分位数间距:8.7 ～12.7)年随访期间,104例2型糖尿病患者(8.1％)罹患了癌症.罹患癌症的患者年龄更大、并多为男性.经年龄校正后,他们基线BMI、收缩压、总胆固醇、低密度脂蛋白胆固醇和肾小球滤过率比未罹患癌症的患者低;而腰臀围比、糖化血红蛋白和尿白蛋白/肌酐比值比未罹患癌症的患者高.Cox回归分析显示,校正基线混杂因素后,携带ACE Ⅰ/D DD基因型与癌症发生独立相关,与Ⅱ/ID基因型携带者比较,风险比为1.86(95％ CI1.03～3.38,P=0.036).结论 在中国2型糖尿病患者中,携带ACE Ⅰ/D DD基因型与癌症发生风险的增高显著相关.     

辛伐他汀对2型糖尿病患者氧化应激的影响

为探讨辛伐他汀对2型糖尿病患者氧化应激的抑制作用及对血脂的影响,观察了辛伐他汀及安慰剂对168例2型糖尿病患者血清丙二醛(MDA)、超氧化物歧化酶(SOD)和血脂的影响.结果表明,与对照组相比,2型糖尿病患者血清SOD水平下降,MDA水平上升;辛伐他汀治疗12周后,患者血清SOD水平上升,而MDA水平明显下降,与治疗前相比有显著性差异(P＜0.05),安慰剂处理前、后患者血清SOD及MDA水平无显著性差异(P＞0.05).辛伐他汀治疗组TG、TC、LDL-C和VLDL-C水平较治疗前下降,而HDL-C水平与治疗前相比上升,有显著性差异(P＜0.05).安慰剂处理前、后患者血脂谱无显著性差异(P＞0.05).由此可见,辛伐他汀对2型糖尿病患者氧化应激有明显的抑制作用,且有益于血脂的调节.     

Role of Social Factors in Glycemic Control Among African American Children and Adolescents with Type 1 Diabetes

Objective

With the rising incidence of Type 1 diabetes (T1DM), it is important to recognize deficiencies in care and areas of improvement to provide better access to resources and education for T1DM patients. The objective of this study was to recognize social factors and compliance barriers affecting glycated hemoglobin (A1c) level in T1D patients among the minority population.