Publications by authors named "Shengli Yan"

32 Publications

The effects of adipose-derived mesenchymal stem cells combined with sodium selenite on Hashimoto's thyroiditis.

Am J Transl Res 2020 15;12(10):6422-6433. Epub 2020 Oct 15.

The Laboratory of Thyroid Diseases, The Affiliated Hospital of Qingdao University No. 16 Jiangsu Road, Qingdao, Shandong, China.

Recent research found that sodium selenite (NaSeO) could ameliorate oxidative damage in patients with Hashimoto's thyroiditis (HT). Additionally, the effects of adipose-derived mesenchymal stem cells (AMSCs) in an animal model of HT were also reported. However, the effects of AMSCs combined with NaSeO on HT are unknown. We investigated the combined effects of AMSCs and NaSeO in a rat model of HT and the in vitro effect of NaSeO on AMSCs using gene microarray analyses. In the HT rat model, the combination of AMSCs and NaSeO restored thyroid tissue structure to that of normal controls and increased the levels of most antioxidant and inflammatory cytokines examined, but decreased the levels of interleukin 10 (IL-10) in HT thyroid tissues. At 0.5-20 µM, NaSeO promoted AMSC growth and increased the levels of reduced glutathione and total antioxidant capacity in AMSCs (<0.05). NaSeO increased the levels of hepatocyte growth factor (HGF), transforming growth factor beta (TGF-β), and stem cell factor (SCF) in AMSC culture supernatants. The results of the gene microarray analyses showed that the expression levels of certain genes involved in mitosis, DNA replication and repair, ubiquitination, synthesis and metabolism, and mitochondrial transport changed in response to NaSeO treatment. In conclusion, the combination of AMSCs and NaSeO restored the function and structure of the thyroid in an HT model, and NaSeO promoted the growth, improved the secretion, and the antioxidant capacity of AMSCs in vitro. This combination treatment may provide a new therapy for patients with HT.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653570PMC
October 2020

Novel THRB mutation analysis in congenital hypothyroidism with thyroid dysgenesis.

J Cell Biochem 2018 11 3;119(11):9474-9482. Epub 2018 Aug 3.

Prenatal Diagnosis Center, Affiliated Hospital of Qingdao University, Qingdao, China.

Thyroid dysgenesis (TD) accounts for most cases of congenital hypothyroidism. Although mutations in thyroid hormone receptor β (THRB) have been identified in TD, the mutational spectrum of THRB and phenotype-genotype correlations have not been fully elucidated. In this study, we aimed to find mutations of THRB, examine the functions of these mutations, and attempt to elucidate the relationship between THRB and TD. Thus, we screened the exons of THRB in 280 patients with TD and 200 normal subjects in samples collected from China. We performed cell morphology assays, MTT assays, flow cytometric analyses, and a quantitative reverse-transcription polymerase chain reaction in human thyroid follicular epithelial cells (Nthy-ori cell line) to examine the impact of THRB mutations. In two unrelated patients, two novel missense mutations, c.76G>A (p.D26N) and c.107G>A (p.C36Y), were identified in THRB. Functional studies suggested that the C36Y mutant caused changes in morphology, inhibiting cell proliferation and promoting apoptosis in a human thyroid cell line. In addition, we found that messenger RNA expressions of thyroglobulin (TG) and the Na /I symporter (NIS) were decreased in a time-dependent manner in mutant THRB compared with the wild type. To our knowledge, this is the first study to document the prevalence of THRB mutations and the genotype-phenotype spectrum of TD in a Chinese population. We characterized the function of a C36Y mutation, which reduced cell proliferation and increased cell death in thyroid epithelial cells. This study provides further evidence for genetic THRB defects and disease mechanisms in TD.
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http://dx.doi.org/10.1002/jcb.27264DOI Listing
November 2018

Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis.

Clin Chim Acta 2017 Jul 25;470:36-41. Epub 2017 Apr 25.

Genetic Medicine Center, Xuzhou Maternal and Children Health's Hospital, Xuzhou 221009, China. Electronic address:

Background: The abnormal expression of certain transcription factors (NKX2.1, FOXE1, NKX2.5, and PAX8) and thyroid stimulating hormone receptor (TSHR) genes has been associated with athyreosis, which is a form of thyroid dysgenesis (TD). We aimed to identify candidate gene mutations in CH patients with athyreosis and to establish the genotype-phenotype correlations in a Chinese population.

Methods: The exons and flanking sequences of NKX2.1, FOXE1, NKX2.5, PAX8, and TSHR were screened by next-generation sequencing and further confirmed by direct Sanger sequencing. The mutation frequencies were calculated and compared against databases. The relationship between genotype and phenotype was also determined.

Results: Seven variants were detected in TSHR-p.P52T, p.G132R, p.M164K, p.R450H, p.C700E, p.A522V, and p.R528S. The p. G132R, p. M164K and p. R528S variants were first identified in public databases. Five variants (p.G44D, p.G360V, p.R401Q, p.L418I, and p.E453Q) were found in NKX2.1 and one variant (p.P243T) was detected in FOXE1. In addition, one variant (p.N291I) was found in NKX2.5 and two variants (p.A355V and c.-26G>A) were detected in PAX8.

Conclusions: Our study indicated that TSHR mutations have phenotypic variability and has further expanded the mutation spectrum of TSHR. We also revealed that the rate of NKX2.1, FOXE1, NKX2.5, and PAX8 mutations were low in patients with CH and athyreosis, in contrast to the higher rate of TSHR mutations.
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http://dx.doi.org/10.1016/j.cca.2017.04.020DOI Listing
July 2017

Identification and characterization of novel PAX8 mutations in Congenital Hypothyroidism(CH) in a Chinese population.

Oncotarget 2017 Jan;8(5):8707-8716

Department of Endocrinology, The Affiliated Hospital of Qingdao University, Qingdao, China.

Objective: Based on mutations in PAX8 is associated with thyroid dysgenesis. We aim to identify and characterize PAX8 mutations in a large cohort of congenital hypothyroidism(CH) from thyroid dysgenesis in Chinese population.

Methods: We screened 453 unrelated Chinese patients with CH from thyroid dysgenesis for PAX8 mutations by sequencing the whole coding regions of PAX8 on genomic DNA isolated from blood. Cell transfection assays using various vector constructs and induced mutagenesis as well as electrophoretic mobility shift assays were used to investigate the effects of selected mutations on the transcribing and binding activities of PAX8 at the promoters of target genes for thyroglobulin (TG) and thyroperoxidase (TPO).

Results: Five PAX8 mutations were found, yielding a mutation prevalence of 5/453 (1.1%). We selected two mutations in the critical paired domain of PAX8 and generated mutants D94N and G41V. We demonstrated G41V was unable to bind the specific sequence in the promoters of TG and TPO and activate them. D94N could bind to TG and TPO promoters and normally activate the TG promoter transcription but not the TPO promoter transcription. We also demonstrated a dominant negative role of the PAX8 mutants in impairing the function of the wild-type PAX8.

Conclusion: We for the first time documented the prevalence and characterized the function of PAX8 mutations in CH in Chinese population. The study specifically demonstrated the role of novel mutations D94N and G41V in impairing the function of PAX8, providing further evidence for genetic PAX8 defects as a disease mechanism in CH.
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http://dx.doi.org/10.18632/oncotarget.14419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5352434PMC
January 2017

Long term effect and safety of Wharton's jelly-derived mesenchymal stem cells on type 2 diabetes.

Exp Ther Med 2016 Sep 26;12(3):1857-1866. Epub 2016 Jul 26.

Department of Anesthesiology, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China.

Cellular therapies offer novel opportunities for the treatment of type 2 diabetes mellitus (T2DM). The present study evaluated the long-term efficacy and safety of infusion of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC) on T2DM. A total of 61 patients with T2DM were randomly divided into two groups on the basis of basal therapy; patients in group I were administered WJ-MSC intravenous infusion twice, with a four-week interval, and patients in group II were treated with normal saline as control. During the 36-month follow-up period, the occurrence of any adverse effects and the results of clinical and laboratory examinations were recorded and evaluated. The lack of acute or chronic adverse effects in group I was consistent with group II.. Blood glucose, glycosylated hemoglobin, C-peptide, homeostasis model assessment of pancreatic islet β-cell function and incidence of diabetic complications in group I were significantly improved, as compared with group II during the 36-month follow-up. The results of the present study demonstrated that infusion of WJ-MSC improved the function of islet β-cells and reduced the incidence of diabetic complications, although the precise mechanisms are yet to be elucidated. The infusion of WJ-MSC may be an effective option for the treatment of patients with type 2 diabetes.
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http://dx.doi.org/10.3892/etm.2016.3544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4997981PMC
September 2016

Genetic and functional analysis of two missense mutations in congenital hypothyroidism and goiter.

Oncotarget 2018 Jan 11;9(4):4366-4374. Epub 2016 Jul 11.

Graduate School, Peking Union Medical College, Beijing, 100000, China.

Mutations in the dual oxidase 2 gene () impair hydrogen peroxide (HO) production and cause dyshormonogenesis. In addition, these mutations have been implicated in autosomal recessive congenital hypothyroidism (CH) with goiter. In this study, we identified mutations that were causative for CH and explored the effects of these mutations on DUOX2 function. Blood samples were collected from 10 infants born with CH and goiter to unrelated parents. We extracted genomic DNA and sequenced all exons by polymerase chain reaction direct sequencing. The effects of mutations were characterized by HO production assays and cycloheximide (CHX) chase experiments. Sequence analysis revealed one novel mutation and one known mutation in unrelated families: c.1060C>T (p.R354W) and c.3616 G>A (p.A1206T). Both mutations impaired HO production. CHX chase experiments demonstrated the mutants had shorter half-lives and degraded more rapidly than wild-type Our study identified two novel mutations in Chinese patients with CH and goiter, which were responsible for the deficit in the organification process.
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http://dx.doi.org/10.18632/oncotarget.10525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5796979PMC
January 2018

Serum Uric Acid Levels and Outcomes After Acute Ischemic Stroke.

Mol Neurobiol 2016 Apr 7;53(3):1753-1759. Epub 2015 Mar 7.

Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, 266003, China.

Previous studies assessing the association between serum uric acid levels and neurological outcome after acute ischemic stroke reported conflicting results. A systematic review and meta-analysis were conducted to assess the impact of serum uric acid levels on outcome after acute ischemic stroke. Pubmed, Embase, Web of Science, and Google scholar were searched through September 26, 2014 to identify eligible published or unpublished studies on the association between serum uric acid levels and outcome after acute ischemic stroke. Hazard ratio (HR) for poor outcome or mean differences of serum uric acid levels with 95% confidence intervals (95% CIs) were pooled using meta-analysis. The primary outcome was occurrence of poor outcomes, while the secondary outcome was the mean differences of serum uric acid levels in patients with good or poor outcomes. Ten eligible studies with a total of 8131 acute ischemic stroke patients were included into the meta-analysis. Compared with low serum uric acid level, high serum uric acid level was associated better outcome after acute ischemic stroke (HR = 0.77, 95% CI 0.68-0.88, P = 0.0001). Sensitivity analysis further identified the prognostic role of serum uric acid levels on outcome after acute ischemic stroke. Patients with good outcomes had a higher serum uric acid level compared with those with poor outcome (mean difference = 30.61 μmol/L, 95% CI 20.13-41.08, P < 0.00001). There was no obvious risk of publication bias in the meta-analysis. This meta-analysis supports that serum uric acid level has a protective effect on neurological outcome after acute ischemic stroke. High uric acid level at the onset is a biomarker of better prognosis in patients with acute ischemic stroke.
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http://dx.doi.org/10.1007/s12035-015-9134-1DOI Listing
April 2016

Effects of autologous adipose-derived stem cell infusion on type 2 diabetic rats.

Endocr J 2015 21;62(4):339-52. Epub 2015 Mar 21.

Stem Cell Research Center, The Affiliated Hospital of Qingdao University, Qingdao 266003, China.

The effects and possible mechanisms of adipose-derived stem cells (ASC) infusion on type 2 diabetic rats were investigated in this study. Twenty normal male Sprague-Dawley rats were included in normal control group, and 40 male diabetic rats were randomly divided into diabetic control group and ASC group (which received ASC infusion). After therapy, levels of fasting plasma glucose (FPG), HbA1c, serum insulin and C-peptide, recovery of islet cells, inflammatory cytokines, and insulin sensitivity were analyzed. After ASC infusion, compared with diabetic control group, hyperglycemia in ASC group was ameliorated in 2 weeks and maintained for about 6 weeks, and plasma concentrations of insulin and C-peptide were significantly improved (P<0.01). Number of islet β cells and concentration of vWF in islets in ASC group increased, while activity of caspase-3 in islets was reduced. Moreover, concentrations of TNF-α, IL-6 and IL-1β in ASC group obviously decreased (P<0.05). The expression of GLUT4, INSR, and phosphorylation of insulin signaling molecules in insulin target tissues were effectively improved. ASC infusion could aid in T2DM through recovery of islet β cells and improvement of insulin sensitivity. Autologous ASC infusion might be an effective method for T2DM.
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http://dx.doi.org/10.1507/endocrj.EJ14-0584DOI Listing
February 2016

Association between height and thyroid cancer risk: a meta-analysis of prospective cohort studies.

Int J Cancer 2015 Sep 9;137(6):1484-90. Epub 2015 Mar 9.

Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, 266003, China.

While several epidemiological studies have investigated the relationship between height and risk for thyroid cancer, the results were inconsistent. In the present study, a systematic review and meta-analysis of prospective cohort studies was conducted to assess the impact of height on thyroid cancer risk. Online databases were searched up to December 30, 2014, for prospective cohort studies on the association between height and thyroid cancer risk. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model of meta-analysis. In all, 11 articles were included in this meta-analysis, including 15 prospective cohort studies, containing 6,695,593 participants and 7,062 cases of thyroid cancer. By comparing the highest versus the lowest categories of height, we reported that risk of thyroid cancer was increased with height in both men (summary RR = 1.40, 95%CI 1.09-1.78, p = 0.008) and women (summary RR = 1.54, 95%CI 1.30-1.83, p < 0.001). The summary RR of thyroid cancer per 5-cm increase in height was 1.16 (95%CI 1.09-1.23, p < 0.001). The results were similar among men (per 5-cm increase RR = 1.13, 95%CI 1.03-1.23, p = 0.011) and women (per 5-cm increase RR = 1.18, 95%CI 1.10-1.27, p < 0.001). No obvious risk of publication bias was observed. Our meta-analysis provides strong evidence for a dose-response relationship between height and risk of thyroid cancer in both men and women.
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http://dx.doi.org/10.1002/ijc.29487DOI Listing
September 2015

A novel missense mutation (I26M) in DUOXA2 causing congenital goiter hypothyroidism impairs NADPH oxidase activity but not protein expression.

J Clin Endocrinol Metab 2015 Apr 12;100(4):1225-9. Epub 2015 Feb 12.

Prenatal Diagnosis Center (S.L.), Genetic Laboratory (S.L.), and Departments of Endocrinology (L.L., S.Y.) and Ultrasonography (X.N.), The Affiliated Hospital of Qingdao University, Qingdao 266003, China; Department of Clinical Laboratory (D.L.), Linyi People's Hospital, Shandong University, Linyi 276003, China; Graduate School (H.X.), Peking Union Medical College, Beijing 100730, China; and World Health Organization Collaborating Centre for Research in Human Reproduction (H.X.), and National Research Institute for Family Planning (H.X.), Beijing 100081, China.

Context: Dual-oxidase maturation factor 2 (DUOXA2) is a component of the thyroid hydrogen peroxidase (H2O2) generator, which is crucial for hormone synthesis. Genetic defects in DUOXA2 lead to an impairment of the H2O2-generating system, in turn causing congenital hypothyroidism (CH) with goiter.

Case Description: Our study aimed to identify DUOXA2 mutations associated with Chinese congenital goiter hypothyroidism patients and to examine the molecular mechanism underlying the genotype-phenotype relationship. All exons and flanking sequences of DUOXA2 in 75 unrelated CH with goiter patients were amplified by PCR and directly sequenced. DUOXA2 and DUOX2 protein expression levels were detected by Western blotting, and nicotinamide adenine dinucleotide phosphate oxidase activity was determined by measuring H2O2 generation in HeLa cells. A novel heterozygous missense mutation, c.C78G (p.I26M), and a homozygous nonsense mutation, c.C738G (p.Y246X), in DUOXA2 were identified in CH patients with mild transient and mild permanent goiter, respectively. In vitro experiments showed that the mutant I26M protein expression levels did not differ from those of wild-type DUOXA2 but that mutant I26M resulted in a complete deficiency of H2O2 generation.

Conclusions: We identified a novel DUOXA2 mutation (I26M) causing CH with goiter, which affected H2O2 generation but did not alter the protein expression levels, further confirming the essential role of DUOXA2 in thyroid hormone synthesis.
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http://dx.doi.org/10.1210/jc.2014-3964DOI Listing
April 2015

Thyrotropin and Alzheimer's Disease Risk in the Elderly: a Systematic Review and Meta-Analysis.

Mol Neurobiol 2016 Mar 23;53(2):1229-1236. Epub 2015 Jan 23.

Department of Endocrinology, Affiliated Hospital of Qingdao University, Qingdao, 266003, China.

Although several epidemiological studies assessed the relationship between thyrotropin and risk of Alzheimer's disease in the elderly, the results were inconsistent. A systematic review and meta-analysis of cohort studies was conducted to assess the impact of serum thyrotropin levels on Alzheimer's disease risk. PubMed, Embase, and Web of Science were searched through September 20, 2014 to identify cohort studies on the relationship between serum thyrotropin levels and risk of Alzheimer's disease in the elderly. Pooled relative risks (RR) and 95% confidence intervals (95% CI) were calculated to assess the risk of Alzheimer's disease according to serum thyrotropin levels. Eight prospective cohort studies were included, with a total of 9456 participants and 640 cases of Alzheimer's disease. Low thyrotropin level was significantly associated with an increased risk of Alzheimer's disease (fixed RR = 1.69, 95% CI 1.31-2.19, P < 0.001; I(2) = 38.0%). High thyrotropin level was also significantly associated with an increased risk of Alzheimer's disease (fixed RR = 1.70, 95% CI 1.18-2.45, P = 0.005; I(2) = 42.2%) when compared with normal thyrotropin level. When using random effect model, low thyrotropin level was still significantly associated with risk of Alzheimer's disease (random RR = 1.65, 95% CI 1.14-2.37, P = 0.007), but high thyrotropin level was not (random RR = 1.54, 95% CI 0.88-2.68, P = 0.129). When investigating thyrotropin levels continuously, an inverse but not significant association between serum thyrotropin levels and Alzheimer's disease risk was observed (per standard deviation increment of thyrotropin: RR = 0.89, 95% CI 0.78-1.01, P = 0.06; I(2) = 31.3%). This meta-analysis supports that low thyrotropin level is significantly associated with an increased risk of Alzheimer's disease in the elderly.
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http://dx.doi.org/10.1007/s12035-014-9078-xDOI Listing
March 2016

Serum Uric Acid Levels and Diabetic Peripheral Neuropathy in Type 2 Diabetes: a Systematic Review and Meta-analysis.

Mol Neurobiol 2016 Mar 12;53(2):1045-1051. Epub 2015 Jan 12.

Department of Endocrinology, Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266003, China.

Previous studies suggested a possible association between serum uric acid levels and peripheral neuropathy in patients with type 2 diabetes, but no definite evidence was available. A systematic review and meta-analysis of relevant studies were performed to comprehensively estimate the association. Pubmed, Web of Science, Embase, and China Biology Medicine (CBM) databases were searched for eligible studies. Study-specific data were combined using random-effect or fixed-effect models of meta-analysis according to between-study heterogeneity. Twelve studies were finally included into the meta-analysis, which involved a total of 1388 type 2 diabetic patients with peripheral neuropathy and 4746 patients without peripheral neuropathy. Meta-analysis showed that there were obvious increased serum uric acid levels in diabetic patients with peripheral neuropathy (weighted mean difference [WMD] = 50.03 μmol/L, 95% confidence interval [95%CI] 22.14-77.93, P = 0.0004). Hyperuricemia was also significantly associated with increased risk of peripheral neuropathy in patients with type 2 diabetes (risk ratio [RR] = 2.83, 95%CI 2.13-3.76, P < 0.00001). Meta-analysis of two studies with adjusted risk estimates showed that hyperuricemia was independently associated with increased risk of peripheral neuropathy in type 2 diabetic patients (RR = 1.95, 95%CI 1.23-3.11, P = 0.005). Type 2 diabetic patients with peripheral neuropathy have obvious increased serum uric acid levels, and hyperuricemia is associated with increased risk of peripheral neuropathy. Further prospective cohort studies are needed to validate the impact of serum uric acid levels on peripheral neuropathy risk.
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http://dx.doi.org/10.1007/s12035-014-9075-0DOI Listing
March 2016

Effect of intensive insulin therapy on first-phase insulin secretion in newly diagnosed type 2 diabetic patients with a family history of the disease.

Exp Ther Med 2015 Feb 8;9(2):612-618. Epub 2014 Dec 8.

Department of Endocrinology, Stem Cell Research Center, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong 266003, P.R. China.

Intensive insulin treatment is known to improve β-cell function in the majority of patients with newly diagnosed type 2 diabetes mellitus (T2DM), and family history (FH) is known to be an important independent risk factor for T2DM. Thus, the aim of the present study was to investigate the difference in first-phase insulin secretion and the effect of intensive insulin therapy on the improvement of β-cell function between T2DM patients with and without a FH of diabetes. Patients with newly diagnosed T2DM and healthy controls were divided into groups according to their FH of diabetes. Improvement in β-cell function was evaluated with an arginine stimulation test after two weeks of continuous subcutaneous insulin infusion (CSII). Compared with the control group, the level of fasting insulin and the homeostasis model assessment of insulin resistance (HOMA2-IR) were higher in the DM group, while the homeostasis model assessment of β-cell insulin secretion (HOMA2-%β) and the first-phase peak ratio were lower (P<0.05). In addition, the first-phase peak ratio in the FH- control group was higher compared with that in the FH+ control group (P=0.023). Following CSII, all the patients achieved excellent blood glucose control in 6.2±3.6 days, without severe adverse effects. In the DM groups, the fasting insulin level and HOMA2-IR were lower, while the HOMA2-%β and first-phase peak ratio were higher, when compared with the values prior to treatment, particularly in the FH- DM group. The HOMA2-%β in the FH+ DM group was lower compared with the FH- DM group (P=0.027). Therefore, T2DM patients with and without a FH of the disease were shown to have a good response to CSII in the improvement of insulin resistance and β-cell function; however, the improvements were less significant in patients with a FH compared with patients without a FH of diabetes.
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http://dx.doi.org/10.3892/etm.2014.2114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4280938PMC
February 2015

Main air pollutants and diabetes-associated mortality: a systematic review and meta-analysis.

Eur J Endocrinol 2014 Nov;171(5):R183-90

Department of EndocrinologyThe Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, ChinaDepartment of RheumatologyFirst Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaEssencemed ClinicWeifang 261000, China

Objective: Exposure to high levels of air pollutants may be linked to diabetes-associated mortality, but the associations remain unclear. To assess the associations between main air pollutants and diabetes-associated mortality, a systematic review and meta-analysis was performed.

Methods: PubMed, Embase and Web of Science were searched for studies investigating the associations between increments in gaseous (nitrogen dioxide (NO2), sulphur dioxide, ozone (O3) and carbon monoxide) and particulate matter (PM; diameter<2.5 μm (PM2.5) or <10 μm (PM10)) air pollutants and diabetes-associated mortality. Using a random-effects model, relative risks (RRs) and 95% CIs were calculated per interquartile range (IQR) increment or per 10 μg/m3 increment in pollutant concentrations.

Results: Out of 925 identified articles, 36 were reviewed in depth and 12 studies from 13 articles satisfying the inclusion criteria (five time-series, five case-crossovers and two cohorts) were finally included. Increased risk of diabetes-associated mortality was associated with higher levels of PM2.5 (per 10 μg/m3: RR=1.123, 95% CI 1.036-1.217, P=0.005, I2=96.1%), PM10 (per 10 μg/m3: RR=1.008, 95% CI 1.004-1.013, P<0.001, I2=0%), NO2 (per 10 μg/m3: RR=1.024, 95% CI 1.007-1.041, P=0.006, I2=49.7%) and O3 (per IQR increment: RR=1.065, 95% CI 1.017-1.115, P=0.007, I2=0.0%). No obvious risk of publication bias was observed.

Conclusions: Exposure to high levels of air pollutants is significantly associated with an increased risk of diabetes-associated mortality.
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http://dx.doi.org/10.1530/EJE-14-0287DOI Listing
November 2014

Effect of long-term exposure to air pollution on type 2 diabetes mellitus risk: a systemic review and meta-analysis of cohort studies.

Eur J Endocrinol 2014 Nov;171(5):R173-82

Department of EndocrinologyThe Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, ChinaEssencemed ClinicWeifang 261000, ChinaDepartment of RheumatologyFirst Affiliated Hospital of Nanjing Medical University, Nanjing 210029, ChinaDepartment of Urinary SurgerySouthwest Hospital Affiliated to Third Military Medical University, Chongqing 400038, China

Objective: To assess the effect of long-term exposure to air pollution on type 2 diabetes risk, a meta-analysis of prospective cohort studies was performed.

Methods: Literature search was conducted with Pubmed, Embase, and Web of Science for prospective cohort studies investigating the association of type 2 diabetes risk with increments in particulate matter (PM, diameter<2.5 μm (PM2.5) or <10 μm (PM10)) or nitrogen dioxide (NO2). We used a random-effects model to calculate the overall relative risk (RR) with 95% CI.

Results: Of 808 identified articles, ten cohort studies were finally included, which involved a total of 2 37,1 907 participants and 21,095 incident cases of type 2 diabetes. Elevated risk of type 2 diabetes was significantly associated with long-term exposures to high levels of PM2.5 (RR=1.28, 95% CI 1.06-1.55, P=0.009, I2=83.5%), PM10 (RR=1.15, 95% CI 1.02-1.30, P=0.022, I2=0%), and NO2 (RR=1.12, 95% CI 1.02-1.23, P=0.015, I2=63.5%). When using standardized risk estimates, the RRs of type 2 diabetes were significant for increments in concentrations of PM2.5 (1.39 per 10 μg/m3 increment, 95% CI 1.14-1.68, P=0.001), PM10 (1.34 per 10 μg/m3 increment, 95% CI 1.22-1.47, P<0.001), and NO2 (1.11 per 10 μg/m3 increment, 95% CI 1.07-1.16, P<0.001). No obvious evidence of publication bias was observed.

Conclusion: Long-term exposure to high levels of main air pollutants is significantly associated with elevated risk of type 2 diabetes mellitus.
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http://dx.doi.org/10.1530/EJE-14-0365DOI Listing
November 2014

Significant association between MTHFR C677T polymorphism and thyroid cancer risk: evidence from a meta-analysis.

Genet Test Mol Biomarkers 2014 Oct 9;18(10):695-702. Epub 2014 Jul 9.

1 Department of Endocrinology, The Affiliated Hospital of Medical College, Qingdao University , Qingdao, China .

Background: Many studies were published to assess the associations of methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism with thyroid diseases, including thyroid cancer, but the results were controversial.

Methods: A comprehensive search was performed in the Pubmed, Embase, and Chinese Biomedical Database (CBM) databases or published studies investigating the associations of MTHFR C677T polymorphism with thyroid diseases. Odds ratios (OR) and 95% confidence intervals (95% CI) were used to assess the possible associations.

Results: Nine studies with a total of 2421 individuals were finally included into the meta-analysis. Meta-analysis of nine studies showed that there was no association between MTHFR C677T polymorphism and thyroid diseases (OR (T vs. C) =1.09, 95% CI 0.94-1.26, p=0.25; OR (TT vs. CC) =1.04, 95% CI 0.75-1.42, p=0.83; OR (TT vs. CC/CT) =1.13, 95% CI 0.86-1.50, p=0.37; OR (TT/CT vs. CC) =1.22, 95% CI 0.88-1.68, p=0.24). Meta-analysis of studies on thyroid cancer showed that there was an obvious association between MTHFR C677T polymorphism and increased risk of thyroid cancer in Caucasians (OR (T vs. C) =1.30, 95% CI 1.03-1.65, p=0.03; OR (TT vs. CC) =2.06, 95% CI 1.04-4.10, p=0.04; OR (TT vs. CC/CT) =2.02, 95% CI 1.02-3.92, p=0.04). There was no obvious risk of publication bias in the meta-analysis.

Conclusion: This meta-analysis suggests that there is a significant association between MTHFR C677T polymorphism and thyroid cancer risk in Caucasians.
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http://dx.doi.org/10.1089/gtmb.2014.0029DOI Listing
October 2014

Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes.

Clin Endocrinol (Oxf) 2014 Sep 19;81(3):452-7. Epub 2014 May 19.

Department of Endocrinology, The Affiliated Hospital of Medical College, Qingdao University, Qingdao, China.

Objective: The aim of this study was to screen for DUOX2, TPO and TG mutations in Chinese patients with congenital hypothyroidism (CH) and goitre and to define the relationships between DUOX2 genotypes and clinical phenotypes.

Methods: Blood samples were collected from 67 patients with CH and goitre in Shandong Province, China. Genomic DNA was extracted from peripheral blood leucocytes. PCR and direct sequencing were used to analyse all exons of DUOX2, TPO and TG. Detailed medical records were then collected, and the relationship between DUOX2 genotype and the clinical phenotype of CH and goitre caused by DUOX2 mutations was investigated.

Results: Analysis of DUOX2 revealed nine mutations, including one novel nonsense mutation (p.W734X), six novel missense mutations (p.N100D, p.S660L, p.A1131S, p.W1181G, p.A1206T and p.R1267W) and two recurrent mutations (p.R701X and p.R1110Q) in 10 patients from 10 unrelated families. Monoallelic and compound heterozygous mutations in DUOX2 were associated with permanent or transient CH. No mutation was found after screening all exons of TPO and TG.

Conclusion: Our study identified DUOX2 mutations in 14·9% of Chinese patients investigated with CH and goitre. Because the relationships between DUOX2 genotypes and clinical phenotypes are extremely complex, however, further studies are needed to identify more mutations in known genes which are involved in CH and goitre.
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http://dx.doi.org/10.1111/cen.12469DOI Listing
September 2014

Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia).

Diabetes Metab Res Rev 2014 Nov;30(8):726-35

Chinese People's Liberation Army General Hospital, Beijing, China.

Background: This study assessed the efficacy and safety of the once-daily glucagon-like peptide-1 receptor agonist, lixisenatide, in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin ± sulfonylurea.

Methods: In this 24-week, double-blind, placebo-controlled, multinational study, patients were randomized to lixisenatide 20 µg once daily or placebo. The primary endpoint was absolute change in glycated haemoglobin (HbA1c ) from baseline to week 24.

Results: A total of 391 patients were randomized. Lixisenatide significantly reduced HbA1c levels compared with placebo (LS mean difference: -0.36%, p = 0.0004). A significantly higher proportion of lixisenatide-treated patients achieved HbA1c targets of <7% (p = 0.003) and ≤6.5% (p = 0.001) versus placebo. Lixisenatide was associated with a statistically significant reduction in 2-h postprandial plasma glucose after a standardized breakfast versus placebo (LS mean difference: -4.28 mmol/L, p < 0.0001) and a significant reduction in fasting plasma glucose (p = 0.0109). There was no difference in weight loss versus placebo, with a modest reduction in body weight reported for both groups (lixisenatide: -1.50 kg, placebo: -1.24 kg; p = 0.296). The incidence of treatment-emergent adverse events (TEAEs) was 64.3% with lixisenatide versus 47.4% with placebo, with serious TEAEs reported in 1.5% versus 2.1% of patients, respectively. The most common TEAE in the lixisenatide group was nausea (16.3% vs 2.6% with placebo). The incidence of symptomatic hypoglycaemia was 5.6% with lixisenatide treatment and 2.6% with placebo (p = 0.1321), with no severe symptomatic hypoglycaemia events reported.

Conclusions: In Asian patients with type 2 diabetes mellitus insufficiently controlled on metformin ± sulfonylurea, lixisenatide significantly improved glycaemic control and was well tolerated during the 24-week study.
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http://dx.doi.org/10.1002/dmrr.2541DOI Listing
November 2014

Effect and mechanisms of human Wharton's jelly-derived mesenchymal stem cells on type 1 diabetes in NOD model.

Endocrine 2015 Feb 4;48(1):124-34. Epub 2014 Mar 4.

Stem Cell Research Center, The Affiliated Hospital of Medical College, Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, China.

Type 1 diabetes is an autoimmune disease that results from an inflammatory destruction of β-cells in islets. Mesenchymal stem cells derived from Wharton's jelly (WJ-MSCs) own a peculiar immunomodulatory feature and might reverse the inflammatory destruction and repair the function of β-cells. Sixty NOD mice were divided into four groups, including normal control group, WJ-MSCs prevention group (before onset), WJ-MSCs treatment group (after onset), and diabetic control group. After homologous therapy, onset time of diabetes, levels of fasting plasma glucose (FPG), fed blood glucose and C-peptide, regulation of cytokines, and islet cells were examined and evaluated. After WJ-MSCs infusion, FPG and fed blood glucose in WJ-MSCs treatment group decreased to normal level in 6-8 days and maintained for 6 weeks. Level of fasting C-peptide of these mice was higher compared to diabetic control mice (P=0.027). In WJ-MSCs prevention group, WJ-MSCs played a protective role for 8-week delayed onset of diabetes, and fasting C-peptide in this group was higher compared to the other two diabetic groups (P=0.013, 0.035). Compared with diabetic control group, frequencies of CD4+CD25+Foxp3+ Tregs in WJ-MSCs prevention group and treatment group were higher, while levels of IL-2, IFN-γ, and TNF-α were lower (P<0.001); the degree of insulitis was also depressed, especially for WJ-MSCs prevention group (P<0.05). Infusion of WJ-MSCs could aid in T1DM through regulation of the autoimmunity and recovery of islet β-cells no matter before or after onset of T1DM. WJ-MSCs might be an effective method for T1DM.
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http://dx.doi.org/10.1007/s12020-014-0219-9DOI Listing
February 2015

Hypothermia induced by adenosine 5'-monophosphate attenuates injury in an L-arginine-induced acute pancreatitis rat model.

J Gastroenterol Hepatol 2014 Apr;29(4):742-8

Gout Laboratory, Shandong Provincial Key Laboratory of Metabolic Diseases, Qingdao, China.

Background And Aim: This study sought to investigate the effects of hypothermia induced by adenosine 5'-monophosphate (5'-AMP) on L-arginine (L-Arg)-induced acute pancreatitis in rats.

Methods: The rats were divided into four groups: the control group, the acute pancreatitis group, the 5'-AMP pretreatment group, and the 5'-AMP posttreatment group. Rats in all groups, except for the control group, received two injections of 2.5 g/kg body weight (intraperitoneally) L-Arg, with an interval of 1 h between the injections. Subsequently, the rats were observed to assess whether hypothermia induced by 5'-AMP could effectively inhibit inflammation associated with L-Arg-induced acute pancreatitis in rats.

Results: Hypothermia induced by 5'-AMP produced protective effects in our acute pancreatitis model. These effects exhibited the following manifestations: (i) a significant reduction in rat mortality rates; (ii) a significant decrease in the occurrence of pancreatic edema; (iii) significant reductions in serum amylase (P < 0.001), interleukin-6 (P < 0.001), interleukin-1β (P < 0.001) and tumor necrosis factor-α (P < 0.001); (iv) the significant inhibition of nuclear factor-κB (NF-κB) activation in rats that were pre- and posttreated with 5'-AMP compared with rats that were only injected with L-Arg; and (v) significant decreases in the occurrence of pancreatic interstitial edema, inflammatory cell infiltration, hemorrhage, and acinar cell necrosis.

Conclusions: Hypothermia induced by 5'-AMP could inhibit the acute inflammatory reaction and NF-κB activation associated with acute pancreatitis.
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http://dx.doi.org/10.1111/jgh.12448DOI Listing
April 2014

Effect of combined therapy of human Wharton's jelly-derived mesenchymal stem cells from umbilical cord with sitagliptin in type 2 diabetic rats.

Endocrine 2014 Mar 18;45(2):279-87. Epub 2013 May 18.

Stem Cell Research Center, The Affiliated Hospital of Medical College, Qingdao University, No. 16, Jiangsu Road, Qingdao, 266003, China.

Type 2 diabetes mellitus is the most common endocrine disease all over the world, while existing therapies can only ameliorate hyperglycemia or temporarily improve the response to insulin in target tissues, they cannot retard or improve the progressive β-cell dysfunction persistently. Combined therapy of stem cells and sitagliptin might resolve this problem, we verified this hypothesis in a diabetic rat model. Except ten Wistar rats in normal control group, diabetic rats were divided into diabetic control group, WJ-MSCs group, sitagliptin group and WJ-MSCs + sitagliptin group and received homologous therapy. Ten weeks after therapy, diabetic symptoms, FPG and GHbA1c in WJ-MSCs group, sitagliptin group and WJ-MSCs + sitagliptin group were significantly less than those in diabetic control group (P < 0.05), while fasting C-peptide and number of β cells in WJ-MSCs group and WJ-MSCs + sitagliptin group was significantly higher than those in diabetic control and sitagliptin group (P < 0.01). Glucagon and number of α cells in sitagliptin group and WJ-MSCs + sitagliptin group were significantly lower than those in WJ-MSCs group and diabetic control group (P < 0.01). No symptoms of rejection and toxic effect were observed. Combined therapy of WJ-MSCs and sitagliptin can effectively ameliorate hyperglycemia, promote regeneration of islet β cells and suppress generation of islet α cells in diabetic rats, presenting a new therapy for type 2 diabetes although the exact mechanisms are unclear.
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http://dx.doi.org/10.1007/s12020-013-9984-0DOI Listing
March 2014

Efficacy and safety of linagliptin added to metformin and sulphonylurea in Chinese patients with type 2 diabetes: a sub-analysis of data from a randomised clinical trial.

Curr Med Res Opin 2013 Aug 4;29(8):921-9. Epub 2013 Jun 4.

Peking Union Medical College Hospital, Beijing, China.

Objectives: To evaluate the efficacy and safety of linagliptin in Chinese patients with type 2 diabetes mellitus (T2DM) inadequately controlled by metformin and sulphonylurea.

Research Design And Methods: Data for a pre-defined Chinese subgroup who participated in a Phase III randomised, placebo-controlled, 24 week trial (NCT00602472) were analysed. The primary endpoint was change in HbA1c from baseline to 24 weeks. Apart from safety endpoints, secondary endpoints included changes in FPG and measures of insulin secretion and resistance.

Results: A total of 192 Chinese patients with T2DM participated in the pre-defined analysis; 144 and 48 patients received linagliptin or placebo, respectively, added to metformin and sulphonylurea. Baseline characteristics (mean [±SD]) for linagliptin and placebo were similar: HbA1c: 8.1% (±0.85) and 8.1% (±0.84); body mass index: 25.9 (±3.2) and 25.6 (±3.4) kg/m², respectively. Placebo-corrected mean (±SE) change in HbA1c from baseline at 24 weeks was -0.68% (0.14) with linagliptin-based treatment (95% CI: -0.96 to -0.39; P<0.0001). Placebo-corrected mean (±SE) change in FPG from baseline at 24 weeks with linagliptin was -18.8 (6.5) mg/dL (-1.0 [0.4] mmol/L; 95% CI: -31.7 to -5.9; P=0.0044). Overall adverse event (AE) rates with linagliptin and placebo including background medication were similar (38.9% and 43.8%, respectively). Drug-related AEs were reported by 12.5% and 2.1% of linagliptin and placebo patients, respectively. Differences were due to hypoglycaemia (10.4% and 0.0%, respectively). No severe hypoglycaemia was reported in either group of this sub-population.

Conclusion: Linagliptin in combination with metformin and sulphonylurea has a favourable safety profile and is an efficacious and well tolerated treatment option for Chinese patients with inadequately controlled T2DM. Reduction of sulphonylurea dose should be considered to minimise risk of hypoglycaemia. Although the findings of this pre-specified sub-analysis may be limited by the number of patients in the subgroup, the results were generally consistent with those for the overall population. CLINICALTRIALS IDENTIFIER: NCT00602472.
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http://dx.doi.org/10.1185/03007995.2013.805123DOI Listing
August 2013

Hypothermia induced by adenosine 5'-monophosphate attenuates early stage injury in an acute gouty arthritis rat model.

Rheumatol Int 2013 Aug 14;33(8):2085-92. Epub 2013 Feb 14.

Department of Biochemistry and Molecular Biology, The University of Texas Medical School at Houston, Houston, TX 77030, USA.

To investigate whether the hypothermia induced by Adenosine 5'-Monophosphate (5'-AMP) could attenuate early stage injury in a rat acute gouty arthritis model. Ankle joint injection with monosodium urate monohydrate crystals (MSU crystals) in hypothermia rat model which was induced by 5'-AMP and then observe whether hypothermia induced by 5'-AMP could be effectively inhibit the inflammation on acute gouty arthritis in rats. AMP-induced hypothermia has protective effects on our acute gouty arthritis, which was demonstrated by the following criteria: (1) a significant reduction in the ankle swelling (p < 0.001); (2) a significant decrease in the occurrence of leukocyte infiltration and mild hemorrhage; (3) a significant reduction in the presence of serum Interleukin-1β (IL-1β, p < 0.001) and metalloproteinase-9 (MMP-9, p < 0.001); and (4) a significant inhibition in the Nuclear Factor -κappaB (NF-κB) activity (p < 0.001). AMP-induced hypothermia could inhibit acute inflammation reaction and protect the synovial tissue against acute injury in a rat acute gouty arthritis model.
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http://dx.doi.org/10.1007/s00296-013-2676-5DOI Listing
August 2013

Long term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells from the umbilical cord for newly-onset type 1 diabetes mellitus.

Endocr J 2013 16;60(3):347-57. Epub 2012 Nov 16.

Stem Cell Research Center, the Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China.

Type 1 diabetes mellitus (T1DM) is an autoimmune disorder resulted from T cell-mediated destruction of pancreatic β-cells, how to regenerate β-cells and prevent the autoimmune destruction of remnant and neogenetic β-cells is a tough problem. Immunomodulatory propertity of mesenchymal stem cell make it illuminated to overcome it. We assessed the long-term effects of the implantation of Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) from the umbilical cord for Newly-onset T1DM. Twenty-nine patients with newly onset T1DM were randomly divided into two groups, patients in group I were treated with WJ-MSCs and patients in group II were treated with normal saline based on insulin intensive therapy. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 21 months, the occurrence of any side effects and results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I compared with group II, both the HbA1c and C peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of WJ-MSCs for the treatment of newly-onset T1DM is safe and effective. This therapy can restore the function of islet β cells in a longer time, although precise mechanisms are unknown, the implantation of WJ-MSCs is expected to be an effective strategy for treatment of type1 diabetes.
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http://dx.doi.org/10.1507/endocrj.ej12-0343DOI Listing
September 2013

Long term effects of the implantation of autologous bone marrow mononuclear cells for type 2 diabetes mellitus.

Endocr J 2012 13;59(11):1031-9. Epub 2012 Jul 13.

Stem Cell Research Center, the Affiliated Hospital of Medical College, Qingdao University, Qingdao 266003, China.

Previous studies have shown that several types of stem cells can differentiate into insulin-secreting islet beta-cells and that these cells can reduce blood glucose in some trials, but there has been no report of a long-term follow-up. We assessed the long-term effects of the use of autologous bone marrow mononuclear cells in the treatment of type 2 diabetes mellitus (T2DM). Based on the willingness to receive implantation of bone marrow mononuclear cells, One hundred and eighteen patients with T2DM were divided into two groups; the patients in group I were treated with autologous bone marrow mononuclear cells and patients in group II were treated with insulin intensification therapy. Mononuclear cells from bone marrow were injected back into the patient's pancreas via a catheter. Patients were followed-up after the operation at monthly intervals for the first 3 months and thereafter every 3 months for the next 33 months, the occurrence of any side effects and the results of laboratory examinations were evaluated. There were no reported acute or chronic side effects in group I and both the HbA1c and C-peptide in group I patients were significantly better than either pretherapy values or group II patients during the follow-up period. These data suggested that the implantation of autologous bone marrow mononuclear cells for the treatment of T2DM is safe and effective. This therapy can partially restore the function of islet beta-cells and maintain blood glucose homeostasis in a longer time.
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http://dx.doi.org/10.1507/endocrj.ej12-0092DOI Listing
May 2013

Clinical and genetic analysis of a compound heterozygous mutation in the thyroglobulin gene in a Chinese twin family with congenital goiter and hypothyroidism.

Twin Res Hum Genet 2012 Feb;15(1):126-32

Shandong Provincial Key Laboratory of Metabolic Disease, The Affiliated Hospital of Medical College, Qingdao University, China.

Mutations in the thyroglobulin (TG) gene, which has an estimated incidence of approximately 1 in 100,000 new-borns, cause autosomal recessive congenital hypothyroidism. The mutational spectrum of the TG gene and the phenotype-genotype correlations have not yet fully been established. We report a compound heterozygous mutation in the TG gene in a Chinese twin family with congenital goiter and hypothyroidism. We also describe the gene mutation associated with the genotype-phenotype of these children with congenital goiter and hypothyroidism. The whole coding sequence of the TG gene was analyzed by direct sequence, and the identified changes in the sequence were tested for benign polymorphism by denaturing high-performance liquid chromatography screening of the mutation and sequencing 200 chromosomes from normal controls. Analysis of the TG gene of the affected twin revealed a compound heterozygous mutation, including a novel missense mutation G2687A, which is predicted to result in a glutamine to arginine substitution at codon 877, and a known nonsense mutation C7006T, predicted to result in an arginine to stop codon at codon 2317. Analysis of 200 normal chromosomes did not identify the same change in healthy subjects. This is the first report of a TG gene mutation in the Chinese Han population. Our study provides further evidence that mutations in the TG gene cause congenital goiter and hypothyroidism, demonstrates genetic heterogeneity of the mutation, and increases our understanding of phenotype-genotype correlations in congenital hypothyroidism.
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http://dx.doi.org/10.1375/twin.15.1.126DOI Listing
February 2012

Risk factors for gout developed from hyperuricemia in China: a five-year prospective cohort study.

Rheumatol Int 2013 Mar 29;33(3):705-10. Epub 2012 Apr 29.

Qingdao University, Qingdao, China.

The aim of the study was to investigate the factors that promote the development of gout in Chinese patients with hyperuricemia. Chinese cohort with 659 patients with hyperuricemia who had no history of gout at base line had been followed up for 5 years. The baseline data of the general states (gender, age, occupation and education level), lifestyle and behavior (smoking, drinking, and diet), the major chronic diseases (diabetes and hypertension), family history and gout attacks, physical examination (height, weight and blood pressure), and blood parameters (creatinine, urea nitrogen, triglycerides, total cholesterol and high-density lipoprotein cholesterol) were recorded before the follow-up. Over the five-year period, 75 hyperuricemia patients developed gout. In the logistic regression model, shrimp intake and shell intake were the risk factors (P = 0.038 and P < 0.001, respectively) and, combined with diabetes, also served as risk factor for gout developed from hyperuricemia, with relative risk (RR) of 2.571 (95 % confidence interval (95 % CI), 1.110-5.953), and females served as protective factors of gout, with RR of 0.113 (95 % CI, 0.041-0.312, referred to male). We identified that shrimp intake and shell intake, combined with diabetes, were the independent risk factors, and females served as protective factors of gout in those suffering from hyperuricemia in coast regions of Shandong province, China.
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http://dx.doi.org/10.1007/s00296-012-2439-8DOI Listing
March 2013

Multiple single nucleotide polymorphisms in the human urate transporter 1 (hURAT1) gene are associated with hyperuricaemia in Han Chinese.

J Med Genet 2010 Mar 14;47(3):204-10. Epub 2009 Oct 14.

Gout laboratory, Medical School Hospital of Qingdao University, Qingdao, China.

Objective: The present study investigated whether single nucleotide polymorphisms (SNPs) in the human urate transporter 1 (hURAT1) gene are associated with primary hyperuricaemia (HUA) in Han Chinese people.

Methods: A total of 538 subjects (215 cases and 323 control subjects) were recruited from Qingdao, China. SNPs in potentially functional regions of the gene were identified and genotypes determined by direct sequencing. Association analyses were conducted using Fisher's exact test and logistic regression assuming a genotype model.

Results: By sequencing the promoter, 10 exons, and the exon-intron junctions of the hURAT1 gene, 14 SNPs were identified. Two of the SNPs identified were associated with susceptibility to HUA. The first was a rare intron 3 (11 G-->A) SNP (p=0.0005), where carriers of the 'A' allele had a 3.4-fold (95% CI 1.67 to 6.93) increased risk of HUA. The second was a common exon 8 (T1309C) SNP (rs7932775), where carriers of one and two 'C' alleles had respective fold increased risks of 1.64 (95% CI 1.07 to 2.52) and 2.32 (95% CI 1.37 to 3.95). These SNPs had a joint additive effect of risk of HUA, with those individuals carrying at least one 'A' allele at the intron 3 SNP and two 'C' alleles at rs7932775 having a 5.88-fold (95% CI 1.25 to 15.57) increased risk of HUA in comparison to those with no risk alleles.

Conclusion: In conjunction with other studies, our results suggest that there are multiple genetic variants within or near hURAT1 that are associated with susceptibility to HUA in Han Chinese, including a novel SNP located in intron 3.
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http://dx.doi.org/10.1136/jmg.2009.068619DOI Listing
March 2010

Insulin resistance acts as an independent risk factor exacerbating high-purine diet induced renal injury and knee joint gouty lesions.

Inflamm Res 2009 Oct 31;58(10):659-68. Epub 2009 Mar 31.

Department of Endocrinology, Medical School Hospital of Qingdao University, 16 Jiangsu Road, 266003, Qingdao, People's Republic of China.

Objective And Design: Insulin resistant Otsuka-Long-Evans-Tokushima Fatty (OLETF) and its control Long-Evans Tokushima Ohtsuka (LETO) rats were used to generate a model for acute hyperuricemia. Upon the onset of insulin resistance OLETF rats were feed with high-purine diet, and the development of acute hyperuricemic renal injury and gouty-like lesions was monitored. Rosiglitazone was also administered to demonstrate whether improved insulin sensitivity would prevent high-purine diet induced renal injury and gouty-like lesions.

Results: Otsuka-Long-Evans-Tokushima Fatty rats showed significant higher incidence of hyperuricemia as compared to the control LETO rats (77 vs. 36.1%, P < 0.05), indicating that insulin resistance exacerbates the development of hyperuricemia following high-purine load. Consistent with this observation, improvement of insulin sensitivity by administration of rosiglitazone significantly reduced high-purine diet induced renal injury and gouty-like lesions. It was found that insulin resistance is associated with impaired capability for maintaining the homeostasis of renal uric acid excretion and reabsorption. Upon high-purine load, insulin resistance enhances urate reabsorption as manifested by up-regulated URAT1 expression and reduces urate excretion as characterized by down-regulated UAT expression.

Conclusions: Our data demonstrated strong evidence indicating that insulin resistance acts as an independent risk factor predisposing OLETF rats more susceptible to the development of hyperuricemia and gouty arthritis following high-purine load.
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http://dx.doi.org/10.1007/s00011-009-0031-9DOI Listing
October 2009

Dietary and lifestyle changes associated with high prevalence of hyperuricemia and gout in the Shandong coastal cities of Eastern China.

J Rheumatol 2008 Sep 15;35(9):1859-64. Epub 2008 Jul 15.

Department of Endocrinology, Medical School Hospital of Qingdao University, Qingdao, China.

Objective: To demonstrate the prevalence of hyperuricemia and gout associated with dietary and lifestyle changes and evaluate the implication of metabolic disorders to the development of hyperuricemia.

Methods: Data collected from 5,003 subjects randomly recruited from 5 coastal cities (Qingdao, Rizhao, Yantai, Weihai, and Dongying) of Shandong province in Eastern China were analyzed.

Results: Overall, the prevalence for hyperuricemia and gout in the studied populations was 13.19% and 1.14%, respectively. The prevalence was significantly higher in men as compared to women (18.32% vs 8.56% for hyperuricemia, 1.94% vs 0.42% for gout). Hyperuricemia was more common in men over age 30 and in women over age 50. A significant steady increase for the prevalence was noted as compared to the previous published data. Urban residents showed much higher prevalence of hyperuricemia as compared to rural residents (14.9% vs 10.1%, p = 0.004). Similarly, higher prevalence was noted in the developed city compared to the less developed city (18.02 vs 5.3%). These discrepancies were highly correlated with economic development as manifested by the increase of daily consumption of meat and seafood. Additionally, alcohol, overweight or obesity, hypertension, and abnormal triglycerides were highly associated with higher prevalence of hyperuricemia. Moreover, hyperuricemia is likely a risk factor for the development of diabetes mellitus.

Conclusion: There was a remarkable increase for the prevalence of hyperuricemia and gout, which is highly correlated with the development of the economy as manifested by dietary and lifestyle changes.
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September 2008