Serum Tsukushi levels are elevated in newly diagnosed type 2 diabetic patients.

AIMS: Tsukushi, a newly identified hepatokine, has been recently characterized as a potent modifier in lipid metabolism and energy homeostasis, but the role of Tsukushi in diabetes remains almost unknown. We detected for the first time the serum Tsukushi levels in newly diagnosed type 2 diabetes, exploring the relationship between Tsukushi and various metabolic parameters. METHODS: A total of 172 participants were recruited, including 86 patients with newly diagnosed type 2 diabetes and 86 subjects with normal glucose tolerance according to oral glucose tolerance test. Serum Tsukushi was measured by ELISA. The insulin resistance, pancreas ß-cell function and insulin sensitivity were determined by homeostasis model assessment (HOMA-IR, HOMA-ß), Stumvoll insulin sensitivity index (ISIstumvoll) and Stumvoll metabolic clearance rate (MCRstumvoll). RESULTS: Serum Tsukushi was significantly higher in type 2 diabetes than in normal glucose tolerance [1.22(0.86,1.74) vs 0.8(0.5,1.38) ng/mL; P < 0.001]. Multiple regression analysis showed that BMI, 2-h post-OGTT glucose and TC were independently related factors influencing Tsukushi. Logistic regression analyses demonstrated that Tsukushi was associated with higher risk of type 2 diabetes independently. CONCLUSIONS: Circulating Tsukushi levels significantly increase in patients with type 2 diabetes, which suggest that Tsukushi may play a role in type 2 diabetes pathogenesis.

Efficacy and Safety of Dulaglutide by Baseline HbA1c in Chinese Patients with Type 2 Diabetes: A Post Hoc Analysis.

INTRODUCTION: To evaluate the efficacy and safety of dulaglutide 0.75 and 1.5 mg in patients with type 2 diabetes mellitus (T2DM) by baseline glycated hemoglobin (HbA1c) < 8.5% or ≥ 8.5% after 26 weeks of treatment. METHODS: Assessment of the Weekly AdministRation of dulaglutide in Diabetes (AWARD) China 1 (CHN1) study (NCT01644500, n = 556) included patients on dulaglutide vs. glimepiride who were treatment naïve or on monotherapy but discontinued therapy. AWARD-CHN2 (NCT01648582, n = 591) patients were on dulaglutide vs. insulin glargine and continued on metformin and/or sulfonylurea. Mean daily dose of glimepiride and insulin glargine was 2.51 mg and 21.0 IU, respectively. Post hoc analyses were conducted based on mixed-model repeated measures using a modified intent-to-treat analysis set with only the Chinese population. Change from baseline in HbA1c and body weight was analyzed by individual study. RESULTS: In the two studies, 70.1% of patients in AWARD-CHN1 and 59.7% in AWARD-CHN2 had baseline HbA1c < 8.5% (mean HbA1c 7.4% and 7.6%, respectively) and 29.9% in AWARD-CHN1 and 40.3% in AWARD-CHN2 had baseline HbA1c ≥ 8.5% (mean HbA1c 9.2% and 9.4%, respectively). In AWARD-CHN1, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.1% and - 2.2%; dulaglutide 0.75 mg: - 0.9% and - 2.0%; glimepiride: - 0.7% and - 1.4%. In AWARD-CHN2, the HbA1c reductions at 26 weeks with baseline HbA1c < 8.5% and ≥ 8.5%, respectively, were dulaglutide 1.5 mg: - 1.2% and - 2.3%; dulaglutide 0.75 mg: - 1.0% and - 1.7%; and insulin glargine: - 0.6% and - 1.7%. Irrespective of baseline HbA1c, body weight decreased with both dulaglutide doses and increased with either glimepiride or insulin glargine at 26 weeks. Dulaglutide demonstrated low incidence of hypoglycemia in both doses in the two trials. Hypoglycemia incidence was generally lower in patients with baseline HbA1c ≥ 8.5%. CONCLUSIONS: Dulaglutide demonstrated significantly greater HbA1c reduction with weight loss and lower risk of hypoglycemia compared with active comparators in Chinese patients with T2DM irrespective of baseline HbA1c, with much greater HbA1c reductions in patients with a higher baseline HbA1c. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01644500 and NCT01648582.

Genetic Study in a Large Cohort Supported Different Pathogenesis of Graves' Disease and Hashimoto's Hypothyroidism.

CONTEXT: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases. OBJECTS: To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT. DESIGN: In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age. RESULTS: We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10-8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed. CONCLUSION: Our findings suggested that the pathogenesis of HT and GD was different.

Ertapenem versus piperacillin/tazobactam for diabetic foot infections in China: a Phase 3, multicentre, randomized, double-blind, active-controlled, non-inferiority trial.

OBJECTIVES: Few randomized controlled studies have compared antibiotic regimens against diabetic foot infections (DFIs) in Chinese patients. We evaluated the efficacy and safety of ertapenem versus piperacillin/tazobactam for the treatment of DFIs in Chinese patients. METHODS: Patients with moderate to severe DFIs requiring parenteral antibiotics were randomized in a 1 : 1 ratio to receive ertapenem (1.0 g once daily) or piperacillin/tazobactam (4.5 g every 8 h) by 30 min intravenous (iv) infusions for ≥5 days. The primary outcome was favourable clinical response at discontinuation of iv therapy (DCIV). An evaluable-patient population was identified for primary analysis of non-inferiority at -15%. Safety was assessed. ClinicalTrials.gov: NCT01370616. RESULTS: Of 565 patients randomized, 443 patients (ertapenem = 219 and piperacillin/tazobactam = 224) were clinically evaluable for primary analysis. In the clinically evaluable population, the proportions of patients with favourable clinical response at DCIV were 93.6% (205/219) and 97.3% (218/224) in the ertapenem and piperacillin/tazobactam groups, respectively (difference: -3.8%, 95% CI: -8.3%, 0.0%). Ertapenem had a significantly lower favourable clinical response rate (91.5% versus 97.2%, 95% CI for difference: -12.1%, -0.3%) at DCIV in severe DFI patients. In the modified ITT population, 88.8% (237/267) and 90.6% (241/266) of patients in the ertapenem and piperacillin/tazobactam groups, respectively, had favourable clinical responses at DCIV (difference: -1.9%, 95% CI: -7.3%, 3.3%). Microbiological eradications of causative pathogens and adverse events were similar between treatment groups. CONCLUSIONS: Treatment with ertapenem was non-inferior to piperacillin/tazobactam in Chinese patients with DFIs. Ertapenem treatment resulted in a markedly lower rate of clinical resolution in severe DFIs.

Comparison of carotid and lower limb atherosclerotic lesions in both previously known and newly diagnosed type 2 diabetes mellitus.

AIMS/INTRODUCTION: To compare carotid and lower limb atherosclerotic lesions, and examine if carotid atherosclerotic lesions are in line with lower limb atherosclerotic lesions, and can reflect generalized atherosclerosis in inpatients with type 2 diabetes. MATERIALS AND METHODS: This was an observational study carried out in 867 Chinese inpatients with type 2 diabetes, including 573 previously known and 294 newly diagnosed patients. Ultrasonographic assessments of intima-media thickness (IMT), plaques, and stenosis in the carotid and lower limb arteries were evaluated. Atherosclerotic lesions between the carotid and lower limb arteries were compared in both previously known and newly diagnosed diabetes, respectively. RESULTS: In both the known (77.3% vs 49.4%, P < 0.001) and the newly diagnosed diabetes (55.4% vs 29.9%, P < 0.001), the prevalence of atherosclerotic plaques was significantly higher in the lower limb arteries than in the carotid arteries. Likewise, the prevalence of stenosis was also significantly higher (P < 0.001) in the lower limb arteries (16.9%) than in the carotid arteries (4.2%) in the established diabetes patients. However, there was no significant difference in the mean IMT between common carotid and common femoral arteries in both the previously known (0.90 ± 0.24 mm vs 0.89 ± 0.20 mm, P = 0.675) and the newly diagnosed diabetes patients (0.86 ± 0.22 mm vs 0.85 ± 0.16 mm, P = 0.436). CONCLUSIONS: Carotid plaques might underestimate generalized plaques in inpatients with type 2 diabetes, as shown by its significantly lower prevalence compared with that of the lower extremity arteries. A combined carotid and lower limb ultrasound examination can improve the detection of atherosclerotic lesions in inpatients with type 2 diabetes.

Genome-wide association study identifies a novel susceptibility gene for serum TSH levels in Chinese populations.

Thyroid-stimulating hormone (TSH) is a sensitive indicator of thyroid function. High and low TSH levels reflect hypothyroidism and hyperthyroidism, respectively. Even within the normal range, small differences in TSH levels, on the order of 0.5-1.0 mU/l, are associated with significant differences in blood pressure, BMI, dyslipidemia, risk of atrial fibrillation and atherosclerosis. Most of the variance in TSH levels is thought to be genetically influenced. We conducted a genome-wide association study of TSH levels in 1346 Chinese Han individuals. In the replication study, we genotyped four candidate SNPs with the top association signals in an independent isolated Chinese She cohort (n = 3235). We identified a novel serum TSH susceptibility locus within XKR4 at 8q12.1 (rs2622590, Pcombined = 2.21 × 10(-10)), and we confirmed two previously reported TSH susceptibility loci near FOXE1 at 9q22.33 and near CAPZB at 1p36.13, respectively. The rs2622590_T allele at XKR4 and the rs925489_C allele near FOXE1 were correlated with low TSH levels and were found to be nominally associated to patients with papillary thyroid carcinoma (PTC) (OR = 1.41, P= 0.014 for rs2622590_T, and OR = 1.61, P= 0.030 for rs925489_C). The rs2622590 and rs925489 genotypes were also correlated with the expression levels of FOXE1 and XKR4, respectively, in PTC tissues (P = 2.41 × 10(-4) and P= 0.02). Our findings suggest that the SNPs in XKR4 and near FOXE1 are involved in the regulation of TSH levels.

Refined association of TSH receptor susceptibility locus to Graves' disease in the Chinese Han population.

BACKGROUND: Convincing evidence has demonstrated the association of TSH receptor (TSHR) with Graves' disease (GD) in the Chinese Han population. OBJECTIVE: The aim of this study was to identify the causal variants for GD in the region encompassing TSHR by a refining association study. DESIGN AND METHODS: GD patients (1536) and 1516 sex-matched controls were recruited in the first stage, and an additional 3832 GD patients and 3426 sex-matched controls were recruited in the replication stage. Genotyping was performed using Illumina Human660-Quad BeadChips or TaqMan single nucleotide polymorphism (SNP) Genotyping Assays and the Fluidigm EP1 platform. RESULTS: When the results of regression analysis for 74 genotyped SNPs and 922 imputed SNPs in the first-stage cohort were combined, rs179243 and rs3783949 were the probable susceptibility SNPs associated with GD in TSHR. Eleven SNPs, including rs179243 and rs3783949, were selected to further refine the association in the replication study. Finally, rs12101261 and rs179243 were confirmed as independent GD susceptibility variants in the replication and combined populations. Further, we also found that the rate of persistent TSHR autoantibody positivity (pTRAb+) was significantly higher in the GD patients with the susceptible genotypes rs12101261 or rs179243 than in the GD patients carrying the protective genotypes, after the GD patients had been treated for more than 1 year. CONCLUSIONS: These findings indicate that rs12101261 and rs179243 are the possible causal SNPs for GD susceptibility in the TSHR gene and could serve as genetic markers to predict the outcome of pTRAb+ in GD patients.

Identification of BACH2 as a susceptibility gene for Graves' disease in the Chinese Han population based on a three-stage genome-wide association study.

The BACH2 gene regulates B cell differentiation and function and has been reported to be a shared susceptibility gene for several autoimmune diseases. Our previous genome-wide association study (GWAS) indicated that several single nucleotide polymorphisms (SNPs) in the BACH2 gene are associated with Graves' disease (GD) in the Chinese Han population; however, the association did not achieve genome-wide significance levels. Recently, this association of BACH2 with GD was confirmed in Caucasians in the UK population, but fine mapping in this region has not yet been reported. Here, we provide a refined analysis of a 331-kb region in the BACH2 gene, which harbors 359 SNPs, using GWAS data from 1,442 GD patients and 1,468 controls. The SNPs rs2474619 and rs9344996 were implied as the independent variants associated with GD by forward and two-locus logistic regression analysis. We genotyped eight out of 10 tagSNPs with P < 1 × 10(-3) in 3,508 GD patients and 3,209 controls, the results also showed that rs2474619 was independently associated with GD in the combined population from GWAS and the second stage (P = 1.81 × 10(-5)). The rs2474619 and rs9344996 were further genotyped in the third stage cohorts, and rs2474619 showed evidence of association with GD at genome-wide significance levels in the combined population (P = 3.28 × 10(-8), odds ratio = 1.13). The association of rs9344996 with GD can be explained by its linkage to rs2474619 in the combined population. Our study clearly demonstrated that BACH2 is a susceptibility gene for GD in the Chinese Han population and further supported rs2474619, in intron 2 of BACH2, is the best association signal with GD. However, the mechanism by which BACH2 confers increased risk of GD requires further study.

Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis.

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.

A refined study of FCRL genes from a genome-wide association study for Graves' disease.

To pinpoint the exact location of the etiological variant/s present at 1q21.1 harboring FCRL1-5 and CD5L genes, we carried out a refined association study in the entire FCRL region in 1,536 patients with Graves' disease (GD) and 1,516 sex-matched controls by imputation analysis, logistic regression, and cis-eQTL analysis. Among 516 SNPs with P<0.05 in the initial GWAS scan, the strongest signals associated with GD and correlated to FCRL3 expression were located at a cluster of SNPs including rs7528684 and rs3761959. And the allele-specific effects for rs3761959 and rs7528684 on FCRL3 expression level revealed that the risk alleles A of rs3761959 and C of rs7528684 were correlated with the elevated expression level of FCRL3 whether in PBMCs or its subsets, especially in CD19(+) B cells and CD8(+) T subsets. Next, the combined analysis with 5,300 GD cases and 4,916 control individuals confirmed FCRL3 was a susceptibility gene of GD in Chinese Han populations, and rs3761959 and rs7528684 met the genome-wide association significance level (P(combined) = 2.27×10(-12) and 7.11×10(-13), respectively). Moreover, the haplotypes with the risk allele A of rs3761959 and risk allele C of rs7528684 were associated with GD risk. Finally, our epigenetic analysis suggested the disease-associated C allele of rs7528684 increased affinity for NF-KB transcription factor. Above data indicated that FCRL3 gene and its proxy SNP rs7528684 may be involved in the pathogenesis of GD by excessive inhibiting B cell receptor signaling and the impairment of suppressing function of Tregs.

A genome-wide association study identifies two new risk loci for Graves' disease.

Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.

Functional SNPs in the SCGB3A2 promoter are associated with susceptibility to Graves' disease.

Graves' disease (GD) is one of the most common human autoimmune diseases, and recent data estimated a prevalence of clinical hyperthyroidism of 0.25-1.09% in the population. Several reports have linked GD to the region 5q12-q33; and a locus between markers D5s436 and D5s434 was specifically linked to GD susceptibility in the Chinese population. In the present study, association analysis was performed using a large number of single-nucleotide polymorphisms (SNPs) at this locus in 2811 patients with GD recruited from different geographic regions of China. The strongest associations with GD in the combined Chinese Han cohorts were mapped to two SNPs in the promoter (pSNP) of SCGB3A2 [SNP76, rs1368408, P = 1.43 x 10(-6), odds ratio (OR) = 1.28 and SNP75, -623 - -622, P = 7.62 x 10(-5), OR = 1.32, respectively], a gene implicated in immune regulation. On the other hand, pSNP haplotypes composed of the SNP76 (rs1368408)+SNP74 (rs6882292) or SNP76+SNP75 (-623 approximately -622, AG/T) variants are correlated with high disease susceptibility (P = 0.0007, and P = 0.0192, respectively) in this combined Chinese Han cohort. Furthermore, these haplotypes were associated with reduced SCGB3A2 gene expression levels in human thyroid tissue, while functional analysis revealed a relatively low efficiency of SCGB3A2 promoters of the SNP76+SNP75 and SNP76+SNP74 haplotypes in driving gene expression. These results suggest that the SCGB3A2 gene may contribute to GD susceptibility.