IGF-1、IGF-BP-1、IGF-BP-3与糖尿病及糖尿病微血管并发症

糖尿病影响循环中胰岛素样生长因子的水平和活性,不同类型的糖尿病对胰岛素样生长因子活性的影响是不同的.糖尿病患者体内胰岛素样生长因子的紊乱,可能参与糖尿病肾病、糖尿病视网膜病变的发生、发展.胰岛素样生长因子结合球蛋白-1可能对微血管病变起保护作用,胰岛素样生长因子结合球蛋白-3参与微血管病变的发病机制不明.     

胰岛素样生长因子-1系统与糖尿病肾病

糖尿病(DM)状态下,肾脏胰岛素样生长因子-1(IGF-1)浓度升高。IGF-1具有刺激系膜基质成分生成,减少系膜细胞中胶原蛋白降解,诱导肾脏中缓激肽和肾素基因表达,并促进系膜细胞产生一氧化氮,增加系膜细胞对葡萄糖的摄入等作用。IGF-1的生物学行为是通过IGF-1受体来介导的,而IGF-1与受体间的相互作用是由IGF-1结合蛋白(IGFBP)来调节。DM时,肾脏IGFBP、IGF-1受体水平均发生变化。IGFs通过一个包括IGF-1、IGFBP以及IGF-1受体的复杂系统,在糖尿病肾病的发生发展中起着重要作用。     

胰岛素样生长因子1与2型糖尿病尿白蛋白排泄率关系的临床研究

目的 探讨尿和血胰岛素样生长因子1(IGF-1)水平与2型糖尿病(T2DM)尿白蛋白排泄率的关系.方法 根据尿白蛋白排泄率(UAER)将80例T2DM患者分为正常白蛋白尿组(N-UAlb)32例,微量白蛋白尿组(M-UAlb)28例和大量白蛋白尿组(L-UAlb)20例.另设对照(NC)组20名.检测4组尿和血IGF-1水平.结果 (1)与NC组比较,T2DM三组血IGF-1明显降低,三组间血IGF-1水平无明显差异;(2)N-UAlb组尿IGF-1与NC组相比无明显差异;M-UAlb组和L-UAlb组尿IGF-1排泄较N-UAlb组显著增高;(3)尿IGF-1排泄与UAER和尿视黄醇结合蛋白排泄率呈正相关; 结论 2型糖尿病肾病尿IGF-1排泄的增加,提示可能有肾组织局部合成和分泌IGF-1的增加,后者可能是2型糖尿病肾病的发病机制之一.     

胰岛素样生长因子-1与糖尿病微血管并发症

本文介绍了胰岛素样生长因子-1(IGF-1)、IGF受体及IGF结合蛋白的结构和作用,其在维持血糖内环境稳定方面的作用,及其与糖尿病微血管病变(糖尿病肾病、糖尿病视网膜病和糖尿病神经病变)的关系.     

生长激素/胰岛素样生长因子-1轴与糖尿病研究进展

糖尿病是一组以长期高血糖为主要特征的代谢综合征,是由于胰岛素缺乏和(或)胰岛素生物作用障碍导致的糖代谢紊乱,同时伴有脂肪、蛋白质、水、电解质等代谢障碍,并可并发眼、肾、神经、心血管等多脏器慢性损害[1].近年的研究表明[2,3],糖尿病时存在生长激素(GH)/胰岛素样生长因子-1(IGF-1)轴的异常,表现为循环中GH升高、IGF-1水平低下,并伴有胰岛素样生长因子结合蛋白(IGFBPs)的改变,这些异常改变与胰岛素缺乏、GH分泌调节紊乱、高血糖等有关.GH/IGF-1轴的异常不仅加重糖尿病时糖、脂肪与蛋白质代谢的紊乱,而且对糖尿病慢性并发症的发生发展具有重要作用,纠正该轴的异常可使糖尿病及其慢性并发症有不同程度的恢复[3].     

胰岛素样生长因子-1与糖尿病的关系研究进展

胰岛素样生长因子-1(IGF-1)是一种具有胰岛素样作用,可促进细胞生长、发育,参与机体多种生理、病理过程的多肽类因子。近年来的研究发现IGF-1与糖尿病(DM)关系密切,DM病人血IGF-1水平降低,生长激素水平升高,单用胰岛素治疗不能使其恢复正常;而组织器官中IGF-1水平变化可能与DM血管并发症有关。有学者将IGF-1用于DM与胰岛素抵抗的治疗取得了比较好的临床效果,为DM的治疗提供了广阔的前景。     

糖尿病大鼠外周神经病变与胰岛素样生长因子-1基因表达的关系

胰岛素样生长因子-1(IGF-1)是一种神经营养因子，肝组织可能是其主要来源^[1,2]，IGF-1肽可通过内分泌发挥生物学作用，促进外周神经轴突结构蛋白神经丝和微管的合成，并与髓鞘代谢有关^[3]。研究发现，实验性糖尿病(DM)状态下，肝组织IGF-1基因表达下降^[1]。我们在此基础上，进一步探讨长期DM对肝组织IGF-1基因表达及其对外周神经病变的致病作用。     

62例2型糖尿病患者血IGF-1、IGFBP-3水平测定及与糖尿病视网膜病变的相关性

用ELASA法对62例2型糖尿病患者（糖尿病组）及30例健康人（对照组）进行血胰岛素样生长因子-1（IGF-1）、胰岛素样生长因子结合蛋白-3（IGFBP-3）及空腹血糖（FPG）、糖化血红蛋白（HbA1c）水平测定,分析IGF-1、IGFBP-3与糖尿病视网膜病变（DR）的相关性。结果 糖尿病组血IGF-1、IGFBP-3水平显著低于对照组（P〈0.01、0.05）,其中合并增殖性DR者显著高于非增殖性DR者（P〈0.05）;血IGF-1与IGFBP-3水平呈正相关（r^2=0.71,P〈0.01）,糖尿病组IGF-1与HbA1c呈正相关（r^2=0.31,P〈0.01）。认为IGF-1及IGFBP-3可能参与了糖尿病DR的发生和发展。     

中老年高血压及糖尿病患者IGF-1、GH、IR含量检测

目的探讨中老年原发性高血压(EH)及2-糖尿病(2-DM)患者与胰岛素样生长因子-1(IGF-1)、生长激素(GH)、胰岛素抵抗(IR)的相关关系。方法将68例中老年高血压患者分为2组,其中单纯EH38例,EH伴2-DM30例。正常中老年人对照组30例,用放免法检出血清中IGF-1、GH、胰岛素(INS)、血糖的水平。结果EH组、EH+DM组的血清IGF-1水平显著低于对照组、IR指数及GH水平均显著高于对照组。结论IGF-1、GHI、R可能与高血压、糖尿病的发生、发展密切相关。     

004 空腹IGFBP-1与糖耐量及心血管危险紧密相关

本研究检测了胰岛素样生长因子系统在大血管疾病中的致病作用. 对象和方法随机选取欧洲白人和巴基斯坦人272例,除外已患有糖尿病者.受试者空腹口服75 g葡萄糖,0和2 h分别取静脉血测血糖.除常规指标的检测外,还测量空腹胰岛素样生长因子-1(IGF-1)、IGF-2、胰岛素样生长因子结合蛋白-1(IGFBP-1)及胰岛素,应用稳态模型(HOMA)计算胰岛素敏感性(HOMA-S)、β细胞功能(HOMA-B).     

Identification of insulin-like growth factor-binding protein-2 (IGF-BP-2) and a low molecular weight IGF-BP in human seminal plasma.

Three distinct binding proteins for the insulin-like growth factors (IGF-BPs) have recently had their cDNAs cloned and sequenced. We have evaluated IGF-BP expression in normal, oligospermic and azospermic human seminal plasma (SP), and have identified IGF-BP-2 in all samples. Additionally, SP contains a non-glycosylated low molecular weight IGF-BP (24K), which does not appear to be structurally or immunologically related to IGF-BP-1, -2 or -3.     

Characterization of MTHFR,GSTM1, GSTT1, GSTP1, and CYP1A1 genotypes in childhood acute leukemia

The role of methylenetetrahydrofolate reductase (MTHFR C677T), glutathione S-transferases (GSTM1 and GSTT1 null, GSTP1 Ile105Val), and cytochromes p450 (CYP1A1*2A) genotypes in the etiology of childhood leukemia was simultaneously investigated. 144 Turkish children with acute lymphoblastic leukemia (ALL) and 33 with acute nonlymphoblastic leukemia (ANLL) were studied and compared with 185 healthy pediatric controls. The frequency of MTHFR genotype was insignificantly higher in ALL (7.7%) and ANLL (6.3%) than in controls (4.4%). Equal distribution of the GSTM1 null genotype was detected between ALL patients and controls (55%), while its incidence was slightly higher in ANLL patients (61.3%). Although GSTT1 null genotype was insignificantly lower in ALL patients (20.9%) than controls (22.7%), it was significantly underrepresented in ANLL patients (6.5%) (P = 0.05, OR 0.24, 95% CI 0.05-1.03). The homozygous frequency of GSTP1 genotype did not differ significantly between groups of ALL (3.7%), ANLL patients (9.1%) and controls (4.9%). Homozygous CYP1A1*2A genotype was underrepresented in ALL patients (1%) as compared to control (4.8%) but the differences did not reach to statistical significance (OR 0.21; 95% CI 0.03-1.72). Homozygosity for this genotype was not detected in ANLL patients. No particular association was noted between different combinations of combined genotypes and risk of development of childhood ALL and ANLL. These results suggested that there are no significant associations between the studied genotypes and the risk of developing either form of acute leukemia except GSTT1 null and homozygosity for CYP1A1 genotypes that may play protective roles in the development of ANLL in Turkish children.     

PICCO指导重症急性胰腺炎早期液体复苏的效果评价

目的 探讨脉搏连续心排血量（PICCO）指导早期液体复苏对重症急性胰腺炎（SAP）的临床意义。方法 选择我院消化科自2013年1月～2015年1月收治并应用PICCO指导早期液体复苏的37例SAP患 者作为PICCO组，同期选择应用中心静脉压（CVP）指导液体复苏的39例SAP患者作为对照组，比较两组48h内液体出入量、血管活性药物使用时间，以及机械通气时间、ICU住院时间和28天病死率。并应用受试者工作特征性（ROC）曲线分析28天病死率的危险因素。结果 共有76例患者入选，其中男41例，年龄58.76±13.84岁。两组间年龄、性别比例、入院血糖、血乳酸、血肌酐、氧和指数、平均动脉压、APACHE II 评分均无显著差异（P>0.05）。PiCCO组患者的0～6h补液量明显多于对照组（P<0.05），而6～72h补液量较对照组明显减少（P＜0.05）。PICCO组患者的血液净化率、机械通气时间、ICU住院时间均显著减少（P<0.05），但是两组患者应用血管活性药物的比例、导管相关感染率和28天病死率均无显著差别（P>0.05）。ROC曲线发现年龄（AUC 0.71, 95% CI, 0.63～0.76，P=0.03）和APACHE II评分（AUC 0.78, 95% CI, 0.67～0.91，P=0.02）为预测28天病死率的重要因素。结论PiCCO可以精确指导SAP患者早期液体复苏，并减少机械通气时间和ICU住院时间。     

The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China.

AIM: High incidence rates of hepatocellular carcinoma (HCC) in Guangxi, China, are primarily due to heavy aflatoxin B1 (AFB1) exposure via corn and groundnut consumption. This study was designed to examine the polymorphisms associated of three carcinogen-metabolizing genes (namely: GSTM1, GSTT1, and HYL1*2) and one DNA-repair gene (namely: XRCC1), and investigate their role as susceptibility markers for HCC. METHODS: We conducted a case-control study including 257 cases of cancer and 649 hospital-based age, sex, ethnicity, and hepatitis B virus infection-matched controls to examine the role of genetic polymorphisms of four genes (GSTM1, GSTT1, HYL1*2, and XRCC1) in the context of HCC risk for the Guangxi population. Genomic DNA isolated from 2ml whole blood was used to genotype GSTM1, GSTT1, HYL1*2, and XRCC1 by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: GSTT1-null genotype was not significantly associated with the risk of HCC, but GSTM1-null genotype [adjusted odds ratio (OR)=2.29, 95% confidence interval (CI)=1.59-3.31], HYL1*2 genotypes with 113 His allele (namely: YH/HH, adjusted OR=2.55, CI=1.78-3.65), and XRCC1 genotypes with 399 Gln allele (namely: AG/GG, adjusted OR=2.47, CI=1.72-3.54) increased the HCC risk. Compared with those individuals who did not express any putative risk genotypes as reference (OR=1), individuals featuring all of the putative risk genotypes [GSTM1-null, HYL1*2-YH/HH, and XRCC1-AG/GG] did experience a significantly greater cancer risk (adjusted OR=10.83, CI=5.44-21.59, P(interaction)<0.01). Additionally, the risk of HCC did appear to differ more significantly among individuals featuring risk genotypes and high-level or long-term AFB1 exposure, whose adjusted ORs (CIs) were 52.44 (17.51-157.08) and 326.93 (38.58-2770.52), respectively. CONCLUSIONS: The results suggest that carcinogen metabolism and DNA-repair pathways may simultaneously modulate the risk of HCC for Guangxi population, and, particularly for these having high-level or long-term AFB1 exposure.     

MChip, a low density microarray, differentiates among seasonal human H1N1, North American swine H1N1, and the 2009 pandemic H1N1

Please cite this paper as: Heil et al. (2010) MChip, a low density microarray, differentiates among seasonal human H1N1, North American swine H1N1, and the 2009 pandemic H1N1. Influenza and Other Respiratory Viruses 4(6), 411–416. Background  The MChip uses data from the hybridization of amplified viral RNA to 15 distinct oligonucleotides that target the influenza A matrix (M) gene segment. An artificial neural network (ANN) automates the interpretation of subtle differences in fluorescence intensity patterns from the microarray. The complete process from clinical specimen to identification including amplification of viral RNA can be completed in <8 hours for under US$10. Objectives  The work presented here represents an effort to expand and test the capabilities of the MChip to differentiate influenza A/H1N1 of various species origin. Methods  The MChip ANN was trained to recognize fluorescence image patterns of a variety of known influenza A viruses, including examples of human H1N1, human H3N2, swine H1N1, 2009 pandemic influenza A H1N1, and a wide variety of avian, equine, canine, and swine influenza viruses. Robustness of the MChip ANN was evaluated using 296 blinded isolates. Results  Training of the ANN was expanded by the addition of 71 well‐characterized influenza A isolates and yielded relatively high accuracy (little misclassification) in distinguishing unique H1N1 strains: nine human A/H1N1 (88·9% correct), 35 human A/H3N2 (97·1% correct), 31 North American swine A/H1N1 (80·6% correct), 14 2009 pandemic A/H1N1 (87·7% correct), and 23 negative samples (91·3% correct). Genetic diversity among the swine H1N1 isolates may have contributed to the lower success rate for these viruses. Conclusions  The current study demonstrates the MChip has the capability to differentiate the genetic variations among influenza viruses with appropriate ANN training. Further selective enrichment of the ANN will improve its ability to rapidly and reliably characterize influenza viruses of unknown origin.     

CYP1A1 , GSTM1 , GSTT1 and NQO1 polymorphisms and colorectal adenomas in Japanese men

AIM: To investigate the role of functional genetic poly-morphisms of metabolic enzymes of tobacco carcinogens in the development of colorectal adenomas. METHODS: The study subjects were 455 patients with colorectal adenomas and 1052 controls with no polyps who underwent total colonoscopy in a preretirement health examination at two Self Defense Forces hospitals. The genetic polymorphisms studied wereCYP1A1*2A (rs 4646903), CYP1A1*2C (rs 1048943), GSTM1 (null or non-null genotype), GSTT1 (null or non-null genotype) and NQO1 C609T (rs 1800566). Genotypes were determined by the polymerase chain reaction (PCR)-restriction fragment length polymorphism or PCR method using genomic DNA extracted from the buffy coat. Cigarette smoking and other life-style factors were ascertained by a self-administered questionnaire. The associations of the polymorphisms with colorectal adenomas were examined by means of OR and 95%CI, which were derived from logistic regression analysis. Statistical adjustment was made for smoking, alcohol use, body mass index and other factors. The gene-gene interaction and effect modification of smoking were evaluated by the likelihood ratio test. RESULTS: None of the five polymorphisms showed a significant association with colorectal adenomas, nor was the combination of GSTM1 and GSTT1 . A borderline significant interaction was observed for the combination of CYP1A1*2C and NQO1 (P = 0.051). The OR associated with CYP1A1*2C was significantly lower than unity among individuals with the NQO1 609CC genotype. The adjusted OR for the combination of the CYP1A1*2C allele and NQO1 609CC genotype was 0.61 (95%CI: 0.42-0.91). Although the interaction was not statistically significant (P = 0.24), the OR for individuals carrying the CYP1A1*2C allele and GSTT1 null genotype decreased significantly compared with those who had neither CYP1A1*2C allele nor GSTT1 null genotype (adjusted OR: 0.69, 95%CI: 0.49-0.97). Smoking did not modify the associations of the individual polymorphisms with colorectal adenomas. There w     

Analysis of HLA-DRB1, DQA1, DQB1 haplotypes in Sardinian centenarians

Some genetic determinants of longevity might reside in those polymorphisms for the immune system genes that regulate immune responses. Many longevity association studies focused their attention on HLA (the human MHC) polymorphisms, but discordant results have been obtained. Sardinians are a relatively isolate population and represent a suitable population for association studies. Some HLA-DR and DQ alleles form very stable haplotypes with a strong linkage disequilibrium. In a previous study on Sardinian centenarians we have suggested that HLA-DRB1 *15 allele might be marginally associated to longevity. HLA-DR,DQ haplotypes are in strong linkage disequilibrium and well conserved playing a role in the association to diseases. Hence, we have evaluated, by amplification refractory mutation system/polymerase chain reaction (ARMS-PCR) the HLADQA1 and HLA-DQB1 allele frequencies in 123 centenarians and 92 controls from Sardinia to assess whether the association to HLA-DRB1 *15 allele may be due to the other genes involved in the HLA-DR,DQ haplotypes. The frequencies of HLA-DQA1, DQB1 haplotypes were not significantly modified in centenarians. Nevertheless by evaluating the frequency of DRB1 *15 linked haplotypes, we observed a not significant increase in centenarians of HLA-DQA1 *01, DQB1 *05 and HLA-DQA1 *01,DQB1 *06 haplotypes. These data suggest that these haplotypes might have a role in determining life span expectancy and longevity.     

Association analyses of genetic polymorphisms of GSTM1, GSTT1, NQO1, NAT2, LPL, PRSS1, PSTI, and CFTR with chronic alcoholic pancreatitis in Japan

Background: Excessive consumption of alcohol is involved in the onset of pancreatitis. However, most of heavy drinkers do not always develop chronic pancreatitis. Various genetic factors appear to be involved in these individual differences in onset of chronic alcoholic pancreatitis. Here we investigated a possible association of alcoholic pancreatitis with polymorphisms of the various genes belong to the phase II detoxification enzymes responsible for metabolism of the oxidative compounds, and the several genes that have relevance to inherited pancreatitis. Methods: The subjects consisted of 53 patients with chronic alcoholic pancreatitis, 54 alcoholic patients without pancreatic dysfunction, and 42 healthy individuals. DNA was extracted from the peripheral nucleated blood cells of all subjects and genetic mutations and subtypes were analyzed by the PCR and RFLP methods. We examined the correlation between chronic alcoholic pancreatitis and variants of the phase II detoxification enzymes such as Glutathione S-transferase M1 (GSTM1), glutathione S-transferase theta 1 (GSTT1), NADPH-quinone oxidoreductase 1 (NQO1), and N-acetyl transferase (NAT2). In addition, genes of lipoprotein lipase (LPL), cationic trypsinogen (PRSS1), pancreatic secretory trypsin inhibitor (PSTI), and cystic fibrosis transmembrane conductance regulator (CFTR) were also analyzed. Results: Frequencies of the gene deletion of GSTM1 and GSTT1 in addition to the C-allele frequency of NQO1 tended to be higher in the alcoholic patients with (AlCP) or without pancreatic dysfunction (Alc) than in the healthy controls although the difference was not significant. The NAT2 gene showed no relation with Alc and AlCP patients. PSTI, LPL, PRSS1, and CFTR genes presented no association with chronic alcoholic pancreatitis. Conclusions: All genes analyzed in the present study lacked association with chronic alcoholic pancreatitis. However, the gene deletion of GSTM1 and GSTT1, and the C-allele of NQO1 cannot be ruled out for association with alcoholism.     

Role of CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 genes in the susceptibility to acute leukemias

Acute leukemias (ALs) are heterogeneous diseases. Functional polymorphisms in the genes encoding detoxification enzymes cause inter-individual differences, which contribute to leukemia susceptibility. The CYP2D6, CYP1A1, CYP2E1, GSTT1, and GSTM1 polymorphisms in ALL (n = 156) and AML (n = 94) patients and 140 healthy controls were genotyped by PCR and/or PCR-RFLP using blood or bone marrow samples. No association was observed between the GSTT1 gene deletion and patients (OR = 0.8, 95% CI = 0.4-1.7 for AMLs and OR = 0.9, 95% CI = 0.5-1.6 for ALLs). Patients with ALL and AML had a higher prevalence of the GSTM1 deletions compared to controls but only the difference among adult AML patients (OR = 2.1, 95% CI = 1.0-4.2) was statistically significant. The CYP2D6*3 variant allele frequency was lower in the overall acute leukemia patients (0.6%) compared to controls (P = 0.03). CYP2D6*1/*3 genotype frequency also showed a protective association in AML patients (OR = 0.09, 95% CI = 0.01-1.7; P = 0.04). We also found a risk association for CYP2E1*5 in ALL and AML (OR = 3.6, 95% CI = 1.4-9.4 and OR = 3.9, 95% CI = 1.4-10.5, respectively). No association was found for the studied CYP2D6*4, CYP1A1*2A, and GSTT1"null" variants and the risk of acute leuke-mia (ALL or AML). This case-control study suggests a contribution of CYP2E1, CYP2D6, and GSTM1 "null" variants to the development of acute leukemias.