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1.  Correlation of Circulating Acid-Labile Subunit Levels with Insulin Sensitivity and Serum LDL Cholesterol in Patients with Type 2 Diabetes: Findings from a Prospective Study with Rosiglitazone 
PPAR Research  2014;2014:917823.
Silencing of acid-labile subunit (ALS) improved glucose metabolism in animal models. The aim of this study is to evaluate the effects of rosiglitazone (RSG) on ALS levels in individuals with type 2 diabetes. A randomized, double-blind, placebo-controlled trial was conducted. Subjects with type 2 diabetes mellitus were randomly distributed to an RSG-treated (n = 30) or a placebo (n = 31) group. Patients were evaluated prior to treatment at baseline and at 12 and 24 weeks after treatment. At baseline, ALS levels were negatively associated with low-density lipoprotein cholesterol (LDLc) levels and homeostatic model assessment version 2 insulin sensitivity (HOMA2-%S). Over 24 weeks, there was a significantly greater reduction in ALS levels in the nonobese RSG-treated individuals than placebo-treated group. The effect of RSG on ALS was not significant in obese individuals. Fasting plasma glucose and hemoglobin A1c were reduced, but total cholesterol and LDLc were increased, in patients on RSG. Change in ALS levels predicted changes in total cholesterol and HOMA2-%S over time. This study suggested a BMI-dependent effect of RSG treatment on ALS levels. Reduction of ALS by RSG increases the risk of atherosclerosis in individuals with type 2 diabetes.
PMCID: PMC4055636  PMID: 24966876
3.  Evaluating Self-Management Behaviors of Diabetic Patients in a Telehealthcare Program: Longitudinal Study Over 18 Months 
Self-management is an important skill for patients with diabetes, and it involves frequent monitoring of glucose levels and behavior modification. Techniques to enhance the behavior changes of diabetic patients have been developed, such as diabetes self-management education and telehealthcare. Although the patients are engaged in self-management activities, barriers to behavior changes remain and additional work is necessary to address the impact of electronic media and telehealthcare on patient self-care behaviors.
The aims of this study were to (1) explore the behaviors of diabetic patients interacting with online applications, (2) determine the impact of a telehealthcare program among 7 self-care behaviors of the patients, and (3) determine the changes in glycosylated hemoglobin (HbA1c) levels.
A telehealthcare program was conducted to assist the patients with 7 self-care activities. The telehealthcare program lasted for 18 months and included the use of a third-generation mobile telecommunications glucometer, an online diabetes self-management system, and a teleconsultant service. We analyzed the data of 59 patients who participated in the telehealthcare program and 103 who did not. The behavioral assessments and the HbA1c data were collected and statistically analyzed to determine whether the telehealthcare services had an impact on the patients. We divided the 18-month period into 3 6-month intervals and analyzed the parameters of patients assisted by the telehealthcare service at different time points. We also compared the results of those who were assisted by the telehealthcare service with those who were not.
There was a significant difference in monitoring blood glucose between the beginning and the end of the patient participation (P=.046) and between the overall period and the end of patient participation (P<.001). Five behaviors were significantly different between the intervention and control patients: being active (P<.001), healthy eating (P<.001), taking medication (P<.001), healthy coping (P=.02), and problem solving (P<.001). Monitoring of blood glucose was significantly different (P=.02) during the 6-12 month stage of patient participation between the intervention and control patients. A significant difference between the beginning and the 6-12 month stage of patient participation was observed for the mean value of HbA1c level (P=.02), and the differences between the overall HbA1c variability and the variability of each 6-month interval was also significant.
Telehealthcare had a positive effect on diabetic patients. This study had enhanced blood glucose monitoring, and the patients in the program showed improvements in glycemic control. The self-care behaviors affect patient outcomes, and the changes of behavior require time to show the effects.
PMCID: PMC3869106  PMID: 24323283
Internet; diabetes mellitus; telemedicine; self-care; online systems; personal health record; patient access to records
4.  Roux-en-Y Gastric Bypass versus Intensive Medical Management for the Control of Type 2 Diabetes, Hypertension and Hyperlipidemia: An International, Multicenter, Randomized Trial 
Guideline directed care for diabetes calls for control of glycemia, blood pressure and cholesterol (composite goal). Most patients treated medically do not reach this goal.
Determine the efficacy and safety of Roux-en-Y gastric bypass (RYGB) added to lifestyle modification and intensive medical management (LS/IMM) to achieve control of all 3 endpoints.
Two-arm unblinded randomized clinical trial with 120 participants. The primary endpoint of the composite outcome was assessed at 12 months. The study began in April 2008 and completed one year follow-up in all participants in December 2012.
Four academic teaching hospitals in the U.S. and Taiwan, involving five operating surgeons.
Inclusion criteria for the Diabetes Surgery Study (DSS) included HbA1c ≥ 8.0%, BMI 30.0-39.9 kg/m2, diagnosis and treatment of type 2 diabetes for at least six months, and stimulated C peptide > 1.0 ng/ml.
All patients received lifestyle intervention modeled after the Look AHEAD study. Medications for hyperglycemia, hypertension, and dyslipidemia were prescribed according to protocol. RYGB techniques were standardized.
Main Outcome Measure
Attainment of a composite goal: HbA1c < 7.0%, LDL-C < 100 mg/dl, and SBP < 130 mmHg.
One hundred and twenty participants were randomized with equal probability into LS/IMM or RYGB (60 in each group). Baseline characteristics were similar between groups. Mean BMI was 34.6 kg/m2 (95% CI 29.2 to 40.8 kg/m2) with 71 (59%; 95% CI 50% to 68%) participants having BMI < 35 kg/m2, and mean HbA1c was 9.6% (95% CI 9.4% to 9.8%). At 12 months the followup rate was 95%, and 11 (19%) in the LS/IMM group and 28 (49%) in the RYGB group achieved the primary endpoint (OR = 4.8, 95% CI 1.9 to 11.6). RYGB participants required 3.1 fewer medications than LS/IMM (4.8 versus 1.7, 95% CI -3.6 to -2.3). Weight loss was 7.9% LS/IMM vs. 26.1% RYGB (difference 18.2% 95% CI 14.2% to 20.7%). Regression analyses indicate that achieving the composite endpoint was primarily attributable to weight loss. There were 22 serious adverse events in the RYGB group, including one cardiovascular event, and 15 in the LS/IMM group. There were 4 peri-operative complications and 6 late postoperative complications in the RYGB group. Nutritional deficiency of iron, vitamin B12 and albumin were observed more frequently with RYGB.
In mild to moderately obese patients with type 2 diabetes addition of RYGB to LS/IMM resulted in greater likelihood of achieving the composite treatment goal. RYGB participants required fewer medications but had more complications.
PMCID: PMC3954742  PMID: 23736733
5.  Insulin Resistance: Regression and Clustering 
PLoS ONE  2014;9(6):e94129.
In this paper we try to define insulin resistance (IR) precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI) or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ), a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT). We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with “main effects” is not satisfactory, but prediction that includes interactions may be.
PMCID: PMC4041565  PMID: 24887437
6.  Measurement of Waist Circumference 
Diabetes Care  2013;36(6):1660-1666.
Waist circumference (WC) is used to define central obesity. This study aimed to compare the performance of two recommended locations of WC measurement.
A cohort of 1,898 subjects who were without diabetes from 2006 to 2012 were followed for a median of 31 months (Taiwan Lifestyle Study). The WC-IC, recommended by the National Cholesterol Education Program Third Adult Treatment Panel, was measured at the superior border of the iliac crest, and the WC-mid, recommended by World Health Organization and International Diabetes Federation, was measured midway between the lowest ribs and the iliac crest. The abdominal subcutaneous fat area (SFA) and visceral fat area (VFA) were assessed by computed tomography.
There was greater difference between WC-IC and WC-mid measurements in women than in men (P < 0.001). Both WC-IC and WC-mid correlated significantly with BMI, VFA, and SFA (all P < 0.001). WC-mid was better correlated to VFA than WC-IC, particularly in women, and it correlated more strongly to blood pressure, plasma glucose, hemoglobin A1c, triglyceride levels, HDL cholesterol, and C-reactive protein (all P < 0.05). The association of WC-mid with hypertension, diabetes, and metabolic syndrome was slightly better than that of WC-IC (area under the receiver operator curve 0.7 vs. 0.69, 0.71 vs. 0.68, and 0.75 vs. 0.7, respectively; all age-adjusted P < 0.05). With 90 cm (male)/80 cm (female) as criteria for central obesity, WC-mid, but not WC-IC, predicted the incidence of diabetes development (age-adjusted P = 0.003).
WC-mid is a better measurement to define central obesity than WC-IC, particularly in women.
PMCID: PMC3661855  PMID: 23275359
7.  Different angiotensin receptor blockers and incidence of diabetes: a nationwide population-based cohort study 
Angiotensin receptor blockers (ARBs) have been shown to exert various peroxisome proliferator-activated receptor gamma (PPARγ) binding activities and insulin-sensitizing effects. The objective of this study was to investigate the association of different ARBs with new-onset diabetes mellitus.
In the respective cohort, a total of 492,530 subjects who initiated ARB treatment between January 2004 and December 2009 were identified from Taiwan National Health Insurance Database. The primary outcome was newly diagnosed diabetes, defined as at least one hospital admission or two or more outpatient visits within a year with an ICD-9-CM code 250. Cox proportional regression was used to estimate the risk of diabetes associated with each ARB, using losartan as the reference.
A total of 65,358 incident diabetes cases were identified out of 1,771,173 person-years. Olmesartan initiators had a small but significantly increased risk of developing diabetes after adjusting for baseline characteristics and mean daily dose (hazard ratio [HR], 1.07; 95% confidence interval [CI], 1.03-1.12). After excluding those followed for less than one year, the increase in diabetes risk are more pronounced (HR, 1.09; 95% CI, 1.05-1.14). This association was consistent across all subgroup analyses. Similar results were observed when a more strict definition of diabetes combining both diabetes diagnosis and anti-diabetic treatment was used. On the other hand, there was no difference in diabetes risk between telmisartan and losartan.
Among all ARBs, olmesartan might be associated with a slightly increased risk of diabetes mellitus. Our data suggest differential diabetes risks associated with ARBs beyond a class effect.
PMCID: PMC4039330  PMID: 24886542
Angiotensin receptor antagonists; Diabetes mellitus; Cohort studies
9.  Validation of Type 2 Diabetes Risk Variants Identified by Genome-Wide Association Studies in Han Chinese Population: A Replication Study and Meta-Analysis 
PLoS ONE  2014;9(4):e95045.
Several genome-wide association studies (GWAS) involving European populations have successfully identified risk genetic variants associated with type 2 diabetes mellitus (T2DM). However, the effects conferred by these variants in Han Chinese population have not yet been fully elucidated.
We analyzed the effects of 24 risk genetic variants with reported associations from European GWAS in 3,040 Han Chinese subjects in Taiwan (including 1,520 T2DM cases and 1,520 controls). The discriminative power of the prediction models with and without genotype scores was compared. We further meta-analyzed the association of these variants with T2DM by pooling all candidate-gene association studies conducted in Han Chinese.
Five risk variants in IGF2BP2 (rs4402960, rs1470579), CDKAL1 (rs10946398), SLC30A8 (rs13266634), and HHEX (rs1111875) genes were nominally associated with T2DM in our samples. The odds ratio was 2.22 (95% confidence interval, 1.81-2.73, P<0.0001) for subjects with the highest genetic score quartile (score>34) as compared with subjects with the lowest quartile (score<29). The incoporation of genotype score into the predictive model increased the C-statistics from 0.627 to 0.657 (P<0.0001). These estimates are very close to those observed in European populations. Gene-environment interaction analysis showed a significant interaction between rs13266634 in SLC30A8 gene and age on T2DM risk (P<0.0001). Further meta-analysis pooling 20 studies in Han Chinese confirmed the association of 10 genetic variants in IGF2BP2, CDKAL1, JAZF1, SCL30A8, HHEX, TCF7L2, EXT2, and FTO genes with T2DM. The effect sizes conferred by these risk variants in Han Chinese were similar to those observed in Europeans but the allele frequencies differ substantially between two populations.
We confirmed the association of 10 variants identified by European GWAS with T2DM in Han Chinese population. The incorporation of genotype scores into the prediction model led to a small but significant improvement in T2DM prediction.
PMCID: PMC3988150  PMID: 24736664
10.  Acetylation of yeast AMP-Activated Protein Kinase Controls Intrinsic Aging Independently of Caloric Restriction 
Cell  2011;146(6):969-979.
(De)acetylation of histone and non-histone proteins is an important post-translational modification affecting many cellular processes. Here we report that NuA4 acetylation of Sip2, one of three regulatory β subunits of Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. We used mutations at four acetylation sites, K12, 16, 17 and 256, to study acetyl-Sip2 function. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), ultimately leads to slower growth but extends replicative lifespan. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a novel protein acetylation- phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging and extends replicative lifespan in yeast.
PMCID: PMC3176974  PMID: 21906795
11.  Hemoglobin A1c for the diagnosis of diabetes: To replace or to guide oral glucose tolerance tests? 
Aims/Introduction:  To evaluate if hemoglobin A1c (A1C) can replace the use of the oral glucose tolerance test (OGTT) to diagnose diabetes in Chinese patients.
Materials and Methods:  Subjects without pre‐existing diabetes were included in this community‐based study. Each participant received a 75‐g OGTT and A1C tests.
Results:  A total of 1362 subjects, 512 men and 850 women, aged 18–88 years, were enrolled. The prevalence of diabetes was 7.4 and 7.3% by OGTT and by A1C ≥ 6.5% criteria, respectively. The optimal A1C cut‐off for diabetes defined by OGTT was 6.1%. The performance of A1C ≥ 6.1% to find diabetes by OGTT was poor, with a kappa 0.50, sensitivity 80% and specificity 91%. Using current criteria of fasting plasma glucose (FPG) < 5.56 mmol/L to exclude and ≥7 mmol/L to diagnose diabetes (FPG criterion), the sensitivity, specificity and OGTT required were 77.2, 100 and 13.5%, respectively. Using A1C < 5.9% to exclude and ≥7.0% to diagnose diabetes (A1C criterion), the sensitivity, specificity and OGTT required were 89.1, 99.8 and 26.5%, respectively. However, using FPG < 5.56 mmol/L and A1C < 6.1% to exclude, and A1C ≥ 7.0% to diagnose diabetes (A1C plus FPG criterion), the sensitivity, specificity and OGTT required were 85.2, 100 and 18.9%, respectively.
Conclusions:  To screen for diabetes, the A1C criterion is more sensitive than the FPG criterion, with more OGTT needed. The A1C plus FPG criterion reduced the number of OGTT needed with acceptable sensitivity. A1C can guide, but cannot replace, OGTT to diagnose diabetes. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2011.00181.x, 2011)
PMCID: PMC4014947  PMID: 24843574
Diagnosis; Hemoglobin A1c; Oral glucose tolerance test
12.  Serum Vascular Adhesion Protein-1 Predicts 10-Year Cardiovascular and Cancer Mortality in Individuals With Type 2 Diabetes 
Diabetes  2011;60(3):993-999.
Vascular adhesion protein-1 (VAP-1) participates in inflammation and catalyzes the breakdown of amines to produce aldehyde, hydrogen peroxide, and ammonia. Serum VAP-1 correlates positively with both acute hyperglycemia and diabetes. We conducted a cohort study to evaluate whether serum VAP-1 predicts 10-year survival in type 2 diabetic patients.
Between July 1996 and June 2003, we enrolled 661 type 2 diabetic subjects at National Taiwan University Hospital. Serum VAP-1 in the samples obtained at enrollment was measured by time-resolved immunofluorometric assay. The vital status of all subjects was ascertained by linking their data with computerized death certificates in Taiwan.
The medium follow-up period was 10.4 years. Subjects with serum VAP-1 in the highest tertile had a hazard ratio (HR) of 2.19 (95% CI 1.17–4.11) for all-cause mortality adjusted for age, sex, smoking, history of cardiovascular disease, obesity, hypertension, hemoglobin A1c, diabetes duration, total cholesterol, use of statins, abnormal ankle-brachial index, estimated glomerular filtration rate (eGFR), and proteinuria. The adjusted HRs for logarithmically transformed serum VAP-1 were 5.83 (95% CI 1.17–28.97) for cardiovascular mortality, 6.32 (95% CI 1.25–32.00) for mortality from cardiovascular and diabetic causes, and 17.24 (95% CI 4.57–65.07) for cancer mortality. There were four variables, including age, serum VAP-1, proteinuria, and eGFR, which could enhance mortality prediction significantly.
Serum VAP-1 can predict 10-year all-cause mortality, cardiovascular mortality, and cancer mortality independently in type 2 diabetic subjects. Serum VAP-1 is a novel biomarker that improves risk prediction over and above established risk factors.
PMCID: PMC3046860  PMID: 21282368
14.  Predicting the Glycemic Response to Gastric Bypass Surgery in Patients With Type 2 Diabetes 
Diabetes Care  2012;36(1):20-26.
To find clinically meaningful preoperative predictors of diabetes remission and conversely inadequate glycemic control after gastric bypass surgery. Predicting the improvement in glycemic control in those with type 2 diabetes after bariatric surgery may help in patient selection.
Preoperative details of 154 ethnic Chinese subjects with type 2 diabetes were examined for their influence on glycemic outcomes at 1 year after gastric bypass. Remission was defined as HbA1c ≤6%. Analysis involved binary logistic regression to identify predictors and provide regression equations and receiver operating characteristic curves to determine clinically useful cutoff values.
Remission was achieved in 107 subjects (69.5%) at 12 months. Diabetes duration <4 years, body mass >35 kg/m2, and fasting C-peptide concentration >2.9 ng/mL provided three independent preoperative predictors and three clinically useful cutoffs. The regression equation classification plot derived from continuous data correctly assigned 84% of participants. A combination of two or three of these predictors allows a sensitivity of 82% and specificity of 87% for remission. Duration of diabetes (with different cutoff points) and C-peptide also predicted those cases in which HbA1c ≤7% was not attained. Percentage weight loss after surgery was also predictive of remission and of less satisfactory outcomes.
The glycemic response to gastric bypass is related to BMI, duration of diabetes, fasting C-peptide (influenced by insulin resistance and residual β-cell function), and weight loss. These data support and refine previous findings in non-Asian populations. Specific ethnic and procedural regression equations and cutoff points may vary.
PMCID: PMC3526207  PMID: 23033249
15.  Cross-Sectional Validation of Diabetes Risk Scores for Predicting Diabetes, Metabolic Syndrome, and Chronic Kidney Disease in Taiwanese 
Diabetes Care  2009;32(12):2294-2296.
To validate the performance of current diabetes risk scores (DRSs) based on simple clinical information in detecting type 2 diabetes, metabolic syndrome (MetSyn), and chronic kidney disease (CKD).
The performance of 10 DRSs was evaluated in a cross-sectional population screening of 2,759 Taiwanese subjects.
All DRSs significantly correlated with measures of insulin resistance, estimated glomerular filtration rate, and urine albumin excretion. The prevalence of screening-detected diabetes (SDM), MetSyn, and CKD increased with higher DRSs. For prediction of SDM, the Cambridge DRS by Griffin et al. and the Finnish DRS outperformed other DRSs in terms of discriminative power and model fit. For prediction of MetSyn and CKD, the Atherosclerosis Risk in Community Study score by Schmidt et al. outperformed other DRSs.
Risk scores based on simple clinical information are useful to identify individuals at high risk for diabetes, MetSyn, and CKD in different ethnic populations.
PMCID: PMC2782993  PMID: 19755627
16.  The role of oxidative stress in the pathogenesis of type 2 diabetes: from molecular mechanism to clinical implication 
A surplus of food supply has evoked a worldwide increase in incidence of type 2 diabetes. This trend will have a significant impact on the life span of people living in modern societies. In contrast, reduced calorie intake has significant impact on preventing type 2 diabetes and increasing longevity. Increased production of reactive oxygen species (ROS), resulting in oxidative stress, has long been proposed as a unifying mechanism linking nutrient excess and diabetes. This review describes the updated mechanism by which oxidative stress provoked by nutrient excess contributes to the development of insulin resistance and pancreatic betacell failure. However, despite the promising results in cellular and animal models, major clinical trials have failed to demonstrate beneficial effect of antioxidants on the prevention of type 2 diabetes or the degree of glycemic control in individuals with diabetes. Emerging evidence shows that ROS also function as an insulin-signaling molecule in normal physiology and casts doubt on the potential beneficial effect of antioxidants. The gap between basic research and clinical outcomes heightens the importance for elucidating the precise molecular mechanisms by which cellular redox status affects insulin signaling.
PMCID: PMC2892404  PMID: 20589170
Reactive oxygen species; type 2 diabetes; insulin resistance; pancreatic beta-cell
17.  Common Variation in the Fat Mass and Obesity-Associated (FTO) Gene Confers Risk of Obesity and Modulates BMI in the Chinese Population 
Diabetes  2008;57(8):2245-2252.
OBJECTIVE— Genetic variants in the fat mass and obesity-associated (FTO) gene have been linked with obesity and type 2 diabetes in European populations. We aimed to test the role of FTO genetic variants in obesity and type 2 diabetes in the Chinese population.
RESEARCH DESIGN AND METHODS— We genotyped 19 single-nucleotide polymorphisms (SNPs) spanning from the 3′ end of the neighboring RPGRIP1L gene to the 5′ flanking region of the FTO gene. We analyzed their associations with obesity (638 case and 1,610 control subjects), type 2 diabetes (759 case and 784 control subjects), and obesity-related traits in nondiabetic subjects.
RESULTS— Among the 19 SNPs, the rs9939609 A allele was strongly associated with obesity (P = 7.0 × 10−4) and BMI (P = 0.0024) in the Chinese population. The odds ratio for obesity was 2.60 (95% CI 1.24–5.46) (P = 0.011) for the AA genotype and 1.32 (1.05–1.66) (P = 0.018) for the AT genotype compared with the TT genotype. Each additional copy of the rs9936609 A allele was associated with a BMI increase of ∼0.37 kg/m2. The rs9939609 A allele was substantially less common in the Chinese population than in the European population (12.6 vs. 45%). We did not find significant associations of the 19 SNPs with type 2 diabetes or other obesity-related traits.
CONCLUSIONS— Genetic variation in the FTO gene is strongly associated with obesity and BMI in the Chinese population. The risk variant is less common in the Chinese population, but its effect size on BMI is comparable with that in the European population.
PMCID: PMC2494679  PMID: 18487448
18.  Breast-Feeding and Childhood-Onset Type 1 Diabetes 
Diabetes Care  2012;35(11):2215-2225.
To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.
Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies.
Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64–0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75–1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81–1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78–1.00). These associations were all subject to marked heterogeneity (I2 = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75–0.99), and heterogeneity was reduced (I2 = 0%). Adjustments for potential confounders altered these estimates very little.
The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.
PMCID: PMC3476923  PMID: 22837371
19.  Trans-ethnic fine mapping identifies a novel independent locus at the 3′ end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population 
Diabetologia  2013;56:2619-2628.
Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.
A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression.
We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10−12 for KCNQ1; p = 5.0 × 10−8 for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3′ end of CDKAL1.
These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-3047-1) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3825282  PMID: 24013783
Ethnic difference; Genetic association; Type 2 diabetes
20.  Deficiency of NPGPx, an oxidative stress sensor, leads to obesity in mice and human 
EMBO Molecular Medicine  2013;5(8):1165-1179.
Elevated oxidative stress is closely associated with obesity. Emerging evidence shows that instead of being a consequence of obesity, oxidative stress may also contribute to fat formation. Nonselenocysteine-containing phospholipid hydroperoxide glutathione peroxidase (NPGPx) is a conserved oxidative stress sensor/transducer and deficiency of NPGPx causes accumulation of reactive oxygen species (ROS). In this communication, we show that NPGPx was highly expressed in preadipocytes of adipose tissue. Deficiency of NPGPx promoted preadipocytes to differentiate to adipocytes via ROS-dependent dimerization of protein kinase A regulatory subunits and activation of CCAAT/enhancer-binding protein beta (C/EBPβ). This enhanced adipogenesis was alleviated by antioxidant N-acetylcysteine (NAC). Consistently, NPGPx-deficient mice exhibited markedly increased fat mass and adipocyte hypertrophy, while treatment with NAC ablated these phenotypes. Furthermore, single nucleotide polymorphisms (SNPs) in human NPGPx gene, which correlated with lower NPGPx expression level in adipose tissue, were associated with higher body mass index (BMI) in several independent human populations. These results indicate that NPGPx protects against fat accumulation in mice and human via modulating ROS, and highlight the importance of targeting redox homeostasis in obesity management.
Deficiency of the glutathione peroxidase NPGPx increases ROS levels in preadipocytes and promotes adipocyte differentiation via increasing oxidative stress and consequent increased fat mass and adipocyte hypertrophy.
PMCID: PMC3944459  PMID: 23828861
adipogenesis; C/EBPβ; N-acetylcysteine; NPGPx; oxidative stress
21.  Genetic Variation in the NOC Gene Is Associated with Body Mass Index in Chinese Subjects 
PLoS ONE  2013;8(7):e69622.
Circadian clock genes are critical regulators of energy homeostasis and metabolism. However, whether variation in the circadian genes is associated with metabolic phenotypes in humans remains to be explored. In this study, we systemically genotyped 20 tag single nucleotide polymorphisms (SNPs) in 8 candidate genes involved in circadian clock, including CLOCK, BMAL1(ARNTL), PER1, PER2, CRY1, CRY2, CSNK1E,, and NOC(CCRN4L) in 1,510 non-diabetic Chinese subjects in Taipei and Yunlin populations in Taiwan. Their associations with metabolic phenotypes were analyzed. We found that genetic variation in the NOC gene, rs9684900 was associated with body mass index (BMI) (P = 0.0016, Bonferroni corrected P = 0.032). Another variant, rs135764 in the CSNK1E gene was associated with fasting glucose (P = 0.0023, Bonferroni corrected P = 0.046). These associations were consistent in both Taipei and Yunlin populations. Significant epistatic and joint effects between SNPs on BMI and related phenotypes were observed. Furthermore, NOC mRNA levels in human abdominal adipose tissue were significantly increased in obese subjects compared to non-obese controls.
Genetic variation in the NOC gene is associated with BMI in Chinese subjects.
PMCID: PMC3724939  PMID: 23922759
22.  Meta-analysis of genome-wide association studies identifies 8 new loci for type 2 diabetes in East Asians 
Nature genetics  2011;44(1):67-72.
We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in East Asian populations. The first stage meta-analysis of eight T2D genome-wide association studies (6,952 cases and 11,865 controls) was followed by a second stage in silico replication analysis (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which were mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3. GLIS3, involved in pancreatic beta cell development and insulin gene expression1,2, is known for its association with fasting glucose levels3,4. The evidence of T2D association for PEPD5 and HNF4A6,7 has been detected in previous studies. KCNK16 may regulate glucose-dependent insulin secretion in the pancreas. These findings derived from East Asians provide new perspectives on the etiology of T2D.
PMCID: PMC3582398  PMID: 22158537
23.  Inference of Cross-Level Interaction between Genes and Contextual Factors in a Matched Case-Control Metabolic Syndrome Study: A Bayesian Approach 
PLoS ONE  2013;8(2):e56693.
Genes, environment, and the interaction between them are each known to play an important role in the risk for developing complex diseases such as metabolic syndrome. For environmental factors, most studies focused on the measurements observed at the individual level, and therefore can only consider the gene-environment interaction at the same individual scale. Indeed the group-level (called contextual) environmental variables, such as community factors and the degree of local area development, may modify the genetic effect as well. To examine such cross-level interaction between genes and contextual factors, a flexible statistical model quantifying the variability of the genetic effects across different categories of the contextual variable is in need. With a Bayesian generalized linear mixed-effects model with an unconditional likelihood, we investigate whether the individual genetic effect is modified by the group-level residential environment factor in a matched case-control metabolic syndrome study. Such cross-level interaction is evaluated by examining the heterogeneity in allelic effects under various contextual categories, based on posterior samples from Markov chain Monte Carlo methods. The Bayesian analysis indicates that the effect of rs1801282 on metabolic syndrome development is modified by the contextual environmental factor. That is, even among individuals with the same genetic component of PPARG_Pro12Ala, living in a residential area with low availability of exercise facilities may result in higher risk. The modification of the group-level environment factors on the individual genetic attributes can be essential, and this Bayesian model is able to provide a quantitative assessment for such cross-level interaction. The Bayesian inference based on the full likelihood is flexible with any phenotype, and easy to implement computationally. This model has a wide applicability and may help unravel the complexity in development of complex diseases.
PMCID: PMC3577698  PMID: 23437214
24.  Plasma Adiponectin Levels Correlate Positively with an Increasing Number of Components of Frailty in Male Elders 
PLoS ONE  2013;8(2):e56250.
Frailty is an important geriatric syndrome. Adiponectin is an important adipokine that regulates energy homeostasis. The aim of this study is to investigate the relationship between plasma adiponectin levels and frailty in elders.
The demographic data, body weight, metabolic and inflammatory parameters, including plasma glucose, total cholesterol, triglyceride, tumor necrosis factor alpha (TNF-α), c-reactive protein (CRP) and adiponectin levels, were assessed. The frailty score was assessed using the Fried Frailty Index (FFI).
The mean (SD) age of the 168 participants [83 (49.4%) men and 85 (50.6%) women] was 76.86 (6.10) years. Judged by the FFI score, 42 (25%) elders were robust, 92 (54.7%) were pre-frail, and 34 (20.3%) were frail. The mean body mass index was 25.19 (3.42) kg/m2. The log-transformed mean (SD) plasma adiponectin (µg/mL) level was 1.00 (0.26). The log-transformed mean plasma adiponectin (µg/mL) levels were 0.93 (0.23) in the robust elders, 1.00 (0.27) in the pre-frail elders, and 1.10 (0.22) in the frail elders, and the differences between these values were statistically significant (p  = 0.012). Further analysis showed that plasma adiponectin levels rose progressively with an increasing number of components of frailty in all participants as a whole (p for trend  = 0.024) and males (p for trend  = 0.037), but not in females (p for trend  = 0.223).
Plasma adiponectin levels correlate positively with an increasing number of components of frailty in male elders. The difference between the sexes suggests that certain sex-specific mechanisms may exist to affect the association between adiponectin levels and frailty.
PMCID: PMC3571990  PMID: 23418545
25.  Prolonged Induction Activates Cebpα Independent Adipogenesis in NIH/3T3 Cells 
PLoS ONE  2013;8(1):e51459.
3T3-L1 cells are widely used to study adipogenesis and insulin response. Their adipogenic potential decreases with time in the culture. Expressing exogenous genes in 3T3-L1 cells can be challenging. This work tries to establish and characterize an alternative model of cultured adipocytes that is easier to work with than the 3T3-L1 cells.
Methodology/Principal Findings
Induced cells were identified as adipocytes based on the following three characteristics: (1) Accumulation of triglyceride droplets as demonstrated by oil red O stain. (2) Transport rate of 2-deoxyglucose increased after insulin stimulation. (3) Expression of fat specific genes such as Fabp4 (aP2), Slc2a4 (Glut4) and Pparg (PPARγ). Among the cell lines induced under different conditions in this study, only NIH/3T3 cells differentiated into adipocytes after prolonged incubation in 3T3-L1 induction medium containing 20% instead of 10% fetal bovine serum. Rosiglitazone added to the induction medium shortened the incubation period from 14 to 7 days. The PI3K/AKT pathway showed similar changes upon insulin stimulation in these two adipocytes. C/EBPα mRNA was barely detectable in NIH/3T3 adipocytes. NIH/3T3 adipocytes induced in the presence of rosiglitazone showed higher 2-deoxyglucose transport rate after insulin stimulation, expressed less Agt (angiotensinogen) and more PPARγ. Knockdown of C/EBPα using shRNA blocked 3T3-L1 but not NIH/3T3 cell differentiation. Mouse adipose tissues from various anatomical locations showed comparable levels of C/EBPα mRNA.
NIH/3T3 cells were capable of differentiating into adipocytes without genetic engineering. They were an adipocyte model that did not require the reciprocal activation between C/EBPα and PPARγ to differentiate. Future studies in the C/EBPα independent pathways leading to insulin responsiveness may reveal new targets to diabetes treatment.
PMCID: PMC3542373  PMID: 23326314

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