Xianghai Zhou

Human Serum Metabonomic Analysis Reveals Progression Axes for Glucose Intolerance and Insulin Resistance Statuses

Understanding the metabolic basis of glucose intolerances and insulin resistance is essential to facilitate early diagnosis, satisfactory therapies and personalized treatments of type 2 diabetes (T2DM). Here, we analyzed the serum metabolic variations from 231 human participants with normal glucose tolerance (NGT, n = 80, M/F = 34/46, mean age 53 +/- 10 years), impaired glucose regulation (IGR, n = 77, M/F = 33/44, mean age 51 +/- 10 years) and T2DM (n = 74, M/F = 32/42, mean age 51 +/- 9 years) to establish the relationship between the serum metabolite compositions and the development of diabetes. By using the proton nuclear magnetic resonance spectroscopy in conjunction with the multivariate data analysis, we found that the development of both glucose intolerances and insulin resistances are closely correlated with the progressive changes of human serum metabonome. Compared with NGT subjects, the IGR and T2DM participants showed clear dysfunctions of choline metabolism, glucose metabolism, lipid and amino acid metabolisms, and disruptions of TCA cycle. The insulin resistance statuses were closely associated with the serum metabonomic changes in terms of glucose, fatty acid and protein/amino acid metabolisms. We also found greater metabonomic heterogeneity among the populations with T2DM and high insulin resistance status. These findings provide useful information to bridge the gaps in our understandings to the metabolic alterations associated with the progression of glucose intolerances and insulin resistance status.

Performance of an A1C and fasting capillary blood glucose test for screening newly diagnosed diabetes and pre-diabetes defined by an oral glucose tolerance test in Qingdao, China.

OBJECTIVE The studys goal was to evaluate the performance of A1C and fasting capillary blood glucose (FCG) tests as mass screening tools for diabetes and pre-diabetes, as determined by the standard oral glucose tolerance test (OGTT). RESEARCH DESIGN AND METHODS Data from 2,332 individuals aged 35–74 years who participated in a population-based cross-sectional diabetes survey in Qingdao, China, were analyzed. A 2-h 75-g OGTT was used to diagnose diabetes. The performance of A1C and FCG was evaluated against the results of the OGTTs by using receiver operating characteristic curve (ROC) analysis. RESULTS The prevalence of newly diagnosed diabetes and pre-diabetes (impaired fasting glucose and/or impaired glucose tolerance) was 11.9 and 29.5%, respectively. For subjects with newly diagnosed diabetes, the area under the ROC curve was 0.67 for A1C and 0.77 for FCG (P < 0.01) in men and 0.67 and 0.75 (P < 0.01) in women, whereas for pre-diabetes, these values were 0.47 and 0.64 (P < 0.001) in men and 0.51 and 0.65 (P < 0.001) in women. At the optimal A1C cutoff point of ≥5.6% for newly diagnosed diabetes, sensitivities (specificities) were 64.4% (61.6%) for men and 62.3% (63.3%) for women. CONCLUSIONS As a screening tool for newly diagnosed diabetes and pre-diabetes, the FCG measurement performed better than A1C in this general Chinese population.

Implication of genetic variants near SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, FTO, TCF2, KCNQ1, and WFS1 in type 2 diabetes in a Chinese population.

BackgroundRecently, several genome-wide and candidate gene association studies have identified many novel genetic loci for type 2 diabetes (T2D); among these genes, CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 are the most important. We aimed to determine the effects of these genetic loci associated with T2D in the Chinese Han population of China.MethodsSingle-nucleotide polymorphisms (SNPs) in or near CDKAL1, IGF2BP2, SLC30A8, CDKN2A/B, HHEX, FTO, TCF2, KCNQ1, and WFS1 genes were genotyped in a case-control Chinese Han sample living in Beijing, China involving 1024 patients with T2D and 1005 control subjects.ResultsIn Chinese Han, we replicated the associations between 7 genetic loci and T2D, with risk allele-specific odds ratios (ORs) as follows: 1.27 (95% CI, 1.11-1.45; p = 0.0008) for CDKAL1-rs10946398, 1.26 (95% CI, 1.08-1.47; p = 0.003) for IGF2BP2-rs4402960, 1.19 (95% CI, 1.04-1.37; p = 0.009) for SLC30A8-rs13266634, 1.22 (95% CI, 1.06-1.41; p = 0.005) for CDKN2A/B-rs10811661, 1.20 (95% CI, 1.01-1.42; p = 0.03) for HHEX-rs5015480, 1.37 (95% CI, 1.19-1.69; p = 1.0 × 10-4) for KCNQ1-rs2237892, and 1.24 (95% CI, 1.01-1.52; p = 0.046) for FTO-rs8050136 after adjustment for age, gender, and body mass index. Not only did an association between WFS1-rs6446482 and early-onset T2D exist in the subgroup analysis, but TCF2-rs7501939 and WFS1-rs6446482 were also confirmed to confer risk for T2D in this meta-analysis. Moreover, the relationship between FTO-rs8050136 and body mass index, together with the effect of CDKAL1-rs10946398 on beta cell function, was also observed in the control individuals.ConclusionsOur findings support the important contribution of these genetic loci to susceptibility for T2D in the Chinese Han population in Beijing of China.

Meta-analysis of the association between SNPs in TCF7L2 and type 2 diabetes in East Asian population

AIMS To evaluate the effect of TCF7L2 on genetic susceptibility of type 2 diabetes (T2DM) in East Asian population by using the meta-analysis. METHODS Search all the publications about the association between TCF7L2 and T2DM in East Asian population from PubMed, CNKI and abstracts of major diabetes conferences. Perform the meta-analysis of all the validated studies and evaluate the association between rs7903146 T allele, rs12255372 T allele, rs11196205 C allele, rs290487 C allele and rs11196218 G allele of TCF7L2 and the risk of T2DM. RESULTS Eleven studies from nine eligible papers and one unpublished study of ours were included in the meta-analysis. Ten eligible studies were analyzed for rs7903146, five were analyzed for rs12255372 and rs11196205, and three were analyzed for rs290487 and rs11196218. We found that four SNPs (rs7903146, rs12255372, rs11196205, rs290487) in TCF7L2 were significantly associated with T2DM in East Asian populations. The rs11196218 also showed a marginal association. The estimated population-attributable risk (PAR) associated with analyzed SNPs ranged from 2% to 7%. CONCLUSIONS SNPs in TCF7L2 were strongly associated with the risk of T2DM in East Asian population. But the contribution of its genetic variants to the epidemic of type 2 diabetes in East Asian was relatively low.

Nonlaboratory-Based Risk Assessment Algorithm for Undiagnosed Type 2 Diabetes Developed on a Nation-Wide Diabetes Survey

OBJECTIVE To develop a New Chinese Diabetes Risk Score for screening undiagnosed type 2 diabetes in China. RESEARCH DESIGN AND METHODS Data from the China National Diabetes and Metabolic Disorders Study conducted from June 2007 to May 2008 comprising 16,525 men and 25,284 women aged 20–74 years were analyzed. Undiagnosed type 2 diabetes was detected based on fasting plasma glucose ≥7.0 mmol/L or 2-h plasma glucose ≥11.1 mmol/L in people without a prior history of diabetes. β-Coefficients derived from a multiple logistic regression model predicting the presence of undiagnosed type 2 diabetes were used to calculate the New Chinese Diabetes Risk Score. The performance of the New Chinese Diabetes Risk Score was externally validated in two studies in Qingdao: one is prospective with follow-up from 2006 to 2009 (validation 1) and another cross-sectional conducted in 2009 (validation 2). RESULTS The New Chinese Diabetes Risk Score includes age, sex, waist circumference, BMI, systolic blood pressure, and family history of diabetes. The score ranges from 0 to 51. The area under the receiver operating curve of the score for undiagnosed type 2 diabetes was 0.748 (0.739–0.756) in the exploratory population, 0.725 (0.683–0.767) in validation 1, and 0.702 (0.680–0.724) in validation 2. At the optimal cutoff value of 25, the sensitivity and specificity of the score for predicting undiagnosed type 2 diabetes were 92.3 and 35.5%, respectively, in validation 1 and 86.8 and 38.8% in validation 2. CONCLUSIONS The New Chinese Diabetes Risk Score based on nonlaboratory data appears to be a reliable screening tool to detect undiagnosed type 2 diabetes in Chinese population.

Association between KCNJ11 gene polymorphisms and risk of type 2 diabetes mellitus in East Asian populations: a meta-analysis in 42,573 individuals

A number of studies have been performed to identify the association between potassium inwardly-rectifying channel, subfamily J, member 11 (KCNJ11) gene and type 2 diabetes mellitus (T2DM) in East Asian populations, with inconsistent results. The main aim of this work was to evaluate more precisely the genetic influence of KCNJ11 on T2DM in East Asian populations by means of a meta-analysis. We identified 20 articles for qualitative analysis and 16 were eligible for quantitative analysis (meta-analysis) by database searching up to May 2010. The association was assessed under different genetic models, and the pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. The allelic and genotypic contrast demonstrated that the association between KCNJ11 and T2DM was significant for rs5210. However, not all results for rs5215 and rs5218 showed significant associations. For rs5219, the combined ORs (95% CIs) for allelic contrast, dominant and recessive models contrast (with allelic frequency and genotypic distribution data) were 1.139 (1.093–1.188), 1.177 (1.099–1.259) and 1.207 (1.094–1.332), respectively (random effect model). The analysis on the most completely adjusted ORs (95% CIs) by the covariates of rs5219 all presented significant associations under different genetic models. Population-stratified analysis (Korean, Japanese and Chinese) and sensitivity analysis verified the significant results. Cumulative meta-analysis including publication time and sample size illustrated the exaggerated genetic effect in the earliest studies. Heterogeneity and publication bias were assessed. Our study verified that single nucleotide polymorphisms (SNPs) of KCNJ11 gene were significantly associated with the risk of T2DM in East Asian populations.

Rs4074134 near BDNF gene is associated with type 2 diabetes mellitus in Chinese Han population independently of body mass index.

Obesity and family history are the most important predictors for type 2 diabetes mellitus(T2DM) in the Chinese Han population. However, it is not known whether the genetic loci related to obesity are associated with the risk of developing T2DM in this population. The present case-control study evaluated the associations between five genetic loci for obesity and the pathogenesis of T2DM. The study included 1117 Chinese Han patients with T2DM, 1629 patients with pre-diabetes (impaired fasting glucose and impaired glucose tolerance, IFG/IGT) and 1113 control subjects residing in Beijing. Five genetic loci including rs2815752 near NEGR1, rs10938397 near GNPDA2, rs4074134 near BDNF, rs17782313 near MC4R and rs1084753 near KCTD15 were genotyped. The results showed an association between rs4074134-BDNF minor allele and T2DM irrespective of age, gender and body mass index (BMI) (OR = 0.87; 95%CI: 0.77–0.99, P = 0.04). This SNP was also associated with pre-diabetes (OR = 0.87; 95%CI: 0.77–0.97, P = 0.01) independently of age, gender and BMI. No associations were found between diabetes or pre-diabetes and any of the other SNP loci studied. Genotype–phenotype association analysis (adjusting for age and gender) showed rs4074134-BDNF to be associated with BMI, waist circumference, fasting and postprandial plasma glucose, fasting serum insulin, and HOMA-IR in subjects without T2DM. However, fasting and postprandial plasma glucose were the only significant factors after adjusting for BMI. These results suggest that the common variation of BDNF (rs4074134) is associated with T2DM independently of obesity in Chinese Han population. This variant also has an effect on plasma glucose concentration, BMI and insulin sensitivity.

Risk factors associated with the presence of diabetes in Chinese communities in Beijing.

OBJECTIVE To identify risk factors associated with the presence of diabetes. METHODS A diabetes survey was conducted in 2801 citizens aged 35-79 years living in 10 communities in Beijing, China. Participants were recruited by residents committees. 75g oral glucose tolerance test was performed to define diabetes according to the WHO 1999 criteria. Logistic regression analysis was used to estimate odds ratios (OR) for diabetes. RESULTS The prevalence of diabetes and impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) was 24.2% and 20.4% in men, respectively and 19.4% and 19.0% in women, respectively. The multivariate adjusted OR (95% CI) corresponding to a one standard deviation increase in age (year) was 1.52 (1.25,1.86), waist circumference (cm) 1.35 (1.12,1.63), serum triglycerides (mmol/L) 1.29 (1.09,1.54) and high density lipoprotein cholesterol (mmol/L) 0.74 (0.61,0.91) in men and 2.03 (1.77,2.33), 1.21 (1.06,1.38), 1.34 (1.21,1.49), 0.74 (0.66,0.84) in women, respectively. For diabetes family history they were 2.46 (1.66,3.65) in men and 2.39 (1.84,3.10) in women, and for hypertension 1.14 (0.77,1.68) in men and 1.54 (1.18,2.01) in women. There were no significant associations between the presence of diabetes and occupation, education level, household income, leisure time physical activities, current smoking and drinking status. CONCLUSIONS Age, diabetes family history, obesity, dyslipidemia and hypertension were all associated with the presence of diabetes in this study population.

Prevalence of Obesity and Its Influence on Achievement of Cardiometabolic Therapeutic Goals in Chinese Type 2 Diabetes Patients: An Analysis of the Nationwide, Cross-Sectional 3B Study

Background There are few data on the prevalence of obesity and its influence on achieving blood glucose, blood pressure, and blood lipid (3B) goals in Chinese type 2 diabetes outpatients. Methods Patient demographic data, anthropometric measurements, medications, and blood glucose and lipid profiles of 24,512 type 2 diabetes patients from a large, geographically diverse study (CCMR-3B) were analyzed. Using cut-points for body mass index (BMI) and waist circumference (WC) recommended by the Working Group on Obesity in China, overweight and obesity were defined as BMIs of 24–27.9kg/m2 and ≥28.0kg/m2. Central obesity was defined as a waist circumference ≥80cm in women and ≥85cm in men. The 3B therapeutic goals were HbA1c<7.0%, BP<140/90mmHg and LDL-C<2.6mmol/L. Results Overall, 43.0% of type 2 diabetes patients were overweight and 16.7% were obese; 13.3% of overweight and and10.1% of obese patients achieved all the 3B target goals. Overweight or obese patients were less likely to achieve 3B goals than those with normal BMIs. More than a half the overweight or obese patients (69.6%) were centrally obese. Patients with abdominal obesity were less likely to achieve cardiometabolic targets than those without abdominal obesity. In multivariate logistic regression analysis, female, higher BMI and waist circumference, smoking, drinking, sedentary lifestyle, and longer diabetes duration were significantly correlated with failure to achieve 3B control goals. Conclusions Obesity is highly prevalent and associated with poor 3B control in Chinese type 2 diabetes patients. In clinical practice, more attention and resources should focus on weight loss for such patients.

Association of serum ferritin levels with metabolic syndrome and insulin resistance in a Chinese population

AIMS Increased iron is associated with type 2 diabetes, dyslipidemia, and high blood pressure. Therefore, serum ferritin may be a suitable biomarker to detect metabolic syndrome (MetS). We investigated the relationship between serum ferritin, and the prevalence of MetS and insulin resistance (IR). METHODS This cross-sectional study assessed 2,786 Chinese participants, aged 25-75 years. MetS was defined using the 2006 International Diabetes Federation guidelines. IR was assessed with homeostasis model assessment estimated IR (HOMA-IR). Regression analysis was used to estimate the association between serum ferritin and the prevalence of MetS and IR. RESULTS MetS prevalence within each serum ferritin quartile (Q1-4) was 31.7%, 37.1%, 43.6%, and 55.4%, respectively in men (P<0.001), and 30.1%, 34.8%, 48.2%, and 66.9%, respectively in women (P<0.001). Increased serum ferritin correlated with the number of MetS components (P<0.001). The odds ratio for MetS in the ferritin Q4 group was 1.95 (1.39-2.73) for men and 1.66(1.12-2.47) for women, compared with Q1. Serum ferritin correlated positively with HOMA-IR in men (regression coefficient: 0.058, P=0.009) and women (regression coefficient: 0.082, P=0.001). CONCLUSION MetS prevalence increased with elevated serum ferritin levels, and serum ferritin levels were independently associated with MetS and IR.