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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.
doi:10.1155/2014/917823
PMCID: PMC4055636  PMID: 24966876
3.  Evaluating Self-Management Behaviors of Diabetic Patients in a Telehealthcare Program: Longitudinal Study Over 18 Months 
Background
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.
Objective
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.2196/jmir.2699
PMCID: PMC3869106  PMID: 24323283
Internet; diabetes mellitus; telemedicine; self-care; online systems; personal health record; patient access to records
5.  A meta-analysis of genome-wide association studies for adiponectin levels in East Asians identifies a novel locus near WDR11-FGFR2 
Human Molecular Genetics  2013;23(4):1108-1119.
Blood levels of adiponectin, an adipocyte-secreted protein correlated with metabolic and cardiovascular risks, are highly heritable. Genome-wide association (GWA) studies for adiponectin levels have identified 14 loci harboring variants associated with blood levels of adiponectin. To identify novel adiponectin-associated loci, particularly those of importance in East Asians, we conducted a meta-analysis of GWA studies for adiponectin in 7827 individuals, followed by two stages of replications in 4298 and 5954 additional individuals. We identified a novel adiponectin-associated locus on chromosome 10 near WDR11-FGFR2 (P = 3.0 × 10−14) and provided suggestive evidence for a locus on chromosome 12 near OR8S1-LALBA (P = 1.2 × 10−7). Of the adiponectin-associated loci previously described, we confirmed the association at CDH13 (P = 6.8 × 10−165), ADIPOQ (P = 1.8 × 10−22), PEPD (P = 3.6 × 10−12), CMIP (P = 2.1 × 10−10), ZNF664 (P = 2.3 × 10−7) and GPR109A (P = 7.4 × 10−6). Conditional analysis at ADIPOQ revealed a second signal with suggestive evidence of association only after conditioning on the lead SNP (Pinitial = 0.020; Pconditional = 7.0 × 10−7). We further confirmed the independence of two pairs of closely located loci (<2 Mb) on chromosome 16 at CMIP and CDH13, and on chromosome 12 at GPR109A and ZNF664. In addition, the newly identified signal near WDR11-FGFR2 exhibited evidence of association with triglycerides (P = 3.3 × 10−4), high density lipoprotein cholesterol (HDL-C, P = 4.9 × 10−4) and body mass index (BMI)-adjusted waist–hip ratio (P = 9.8 × 10−3). These findings improve our knowledge of the genetic basis of adiponectin variation, demonstrate the shared allelic architecture for adiponectin with lipids and central obesity and motivate further studies of underlying mechanisms.
doi:10.1093/hmg/ddt488
PMCID: PMC3900106  PMID: 24105470
6.  Acetylation of yeast AMP-Activated Protein Kinase Controls Intrinsic Aging Independently of Caloric Restriction 
Cell  2011;146(6):969-979.
SUMMARY
(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.
doi:10.1016/j.cell.2011.07.044
PMCID: PMC3176974  PMID: 21906795
7.  Hemoglobin A1c for the diagnosis of diabetes: To replace or to guide oral glucose tolerance tests? 
Abstract
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)
doi:10.1111/j.2040-1124.2011.00181.x
PMCID: PMC4014947  PMID: 24843574
Diagnosis; Hemoglobin A1c; Oral glucose tolerance test
8.  Serum Vascular Adhesion Protein-1 Predicts 10-Year Cardiovascular and Cancer Mortality in Individuals With Type 2 Diabetes 
Diabetes  2011;60(3):993-999.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/db10-0607
PMCID: PMC3046860  PMID: 21282368
10.  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.
OBJECTIVE
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).
RESEARCH DESIGN AND METHODS
The performance of 10 DRSs was evaluated in a cross-sectional population screening of 2,759 Taiwanese subjects.
RESULTS
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.
CONCLUSIONS
Risk scores based on simple clinical information are useful to identify individuals at high risk for diabetes, MetSyn, and CKD in different ethnic populations.
doi:10.2337/dc09-0694
PMCID: PMC2782993  PMID: 19755627
11.  Measurement of Visceral Fat: Should We Include Retroperitoneal Fat? 
PLoS ONE  2014;9(11):e112355.
Objective
Whether retroperitoneal fat should be included in the measurement of visceral fat remains controversial. We compared the relationships of fat areas in peritoneal, retroperitoneal, and subcutaneous compartments to metabolic syndrome, adipokines, and incident hypertension and diabetes.
Methods
We enrolled 432 adult participants (153 men and 279 women) in a community-based cohort study. Computed tomography at the umbilicus level was used to measure the fat areas.
Results
Retroperitoneal fat correlated significantly with metabolic syndrome (adjusted odds ratio (OR), 5.651, p<0.05) and the number of metabolic abnormalities (p<0.05). Retroperitoneal fat area was significantly associated with blood pressure, plasma glycemic indices, lipid profile, C-reactive protein, adiponectin (r = −0.244, P<0.05), and leptin (r = 0.323, p<0.05), but not plasma renin or aldosterone concentrations. During the 2.94±0.84 years of follow-up, 32 participants developed incident hypertension. Retroperitoneal fat area (hazard ration (HR) 1.62, p = 0.003) and peritoneal fat area (HR 1.62, p = 0.009), but not subcutaneous fat area (p = 0.14) were associated with incident hypertension. Neither retroperitoneal fat area, peritoneal fat area, nor subcutaneous fat areas was associated with incident diabetes after adjustment.
Conclusions
Retroperitoneal fat is similar to peritoneal fat, but differs from subcutaneous fat, in terms of its relationship with metabolic syndrome and incident hypertension. Retroperitoneal fat area should be included in the measurement of visceral fat for cardio-metabolic studies in human.
doi:10.1371/journal.pone.0112355
PMCID: PMC4234414  PMID: 25401949
12.  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
13.  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.
doi:10.2337/db08-0377
PMCID: PMC2494679  PMID: 18487448
14.  Troglitazone and Δ2Troglitazone Enhance Adiponectin Expression in Monocytes/Macrophages through the AMP-Activated Protein Kinase Pathway 
Mediators of Inflammation  2014;2014:726068.
Accumulating evidence indicates that the regimen to increase adiponectin will provide a novel therapeutic strategy for inflammation and cardiovascular disorders. Here, we tested the effect of troglitazone (TG) and its newly synthesized derivative, 5-[4-(6-hydroxy-2,5,7,8-tetramethyl-chroman-2-yl-methoxy)-benzylidene]-2,4-thiazolidinedione (Δ2troglitazone, (Δ2TG)), on the adiponectin expression in monocytes/macrophages and the relative mechanisms. The expression of adiponectin was located in macrophages of atherosclerotic lesions from patients and cholesterol-fed rabbits. TG and Δ2TG enhanced adiponectin mRNA and protein expression in THP-1 cells by quantitative real-time PCR, Western blot, and immunocytochemistry. TG induced adiponectin mRNA expression through a PPARγ-dependent pathway whereas Δ2TG enhanced adiponectin mRNA expression through a PPARγ-independent pathway in THP-1 cells. Both TG and Δ2TG enhanced adiponectin mRNA expression through AMP-activated protein kinase (AMPK) activation. TG and Δ2TG decreased the adhesion of THP-1 cells to TNF-α-treated HUVECs and the inhibitory effect was abolished by specific antiadiponectin antibodies. TG- and Δ2TG-induced suppression on monocyte adhesion were inhibited by a selective AMPK inhibitor compound C. Our data suggest that the inhibitory effect of TG and Δ2TG on monocyte adhesion might be at least in part through de novo adiponectin expression and activation of an AMPK-dependent pathway, which might play an important role in anti-inflammation and antiatherosclerosis.
doi:10.1155/2014/726068
PMCID: PMC4189946  PMID: 25328285
15.  Genetic Variations in the Kir6.2 Subunit (KCNJ11) of Pancreatic ATP-Sensitive Potassium Channel Gene Are Associated with Insulin Response to Glucose Loading and Early Onset of Type 2 Diabetes in Childhood and Adolescence in Taiwan 
To investigate the role of E23K polymorphism of the KCNJ11 gene on early onset of type 2 diabetes in school-aged children/adolescents in Taiwan, we recruited 38 subjects with type 2 diabetes (ages 18.6 ± 6.6 years; body mass index percentiles 83.3 ± 15.4) and 69 normal controls (ages 17.3 ± 3.8 years; body mass index percentiles 56.7 ± 29.0) from a national surveillance for childhood/adolescent diabetes in Taiwan. We searched for the E23K polymorphism of the KCNJ11 gene. We found that type 2 diabetic subjects had higher carrier rate of E23K polymorphism of KCNJ11 gene than control subjects (P = 0.044). After adjusting for age, gender, body mass index percentiles, and fasting plasma insulin, the E23K polymorphism contributed to an increased risk for type 2 diabetes (P = 0.047). K23-allele-containing genotypes conferring increased plasma insulin level during OGTT in normal subjects. However, the diabetic subjects with the K23-allele-containing genotypes had lower fasting plasma insulin levels after adjustment of age and BMI percentiles. In conclusion, the E23K variant of the KCNJ11 gene conferred higher susceptibility to type 2 diabetes in children/adolescents. Furthermore, in normal glucose-tolerant children/adolescents, K23 allele carriers had a higher insulin response to oral glucose loading.
doi:10.1155/2014/983016
PMCID: PMC4189766  PMID: 25309595
16.  Roux-en-Y Gastric Bypass versus Intensive Medical Management for the Control of Type 2 Diabetes, Hypertension and Hyperlipidemia: An International, Multicenter, Randomized Trial 
Context
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.
Objective
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.
Design
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.
Setting
Four academic teaching hospitals in the U.S. and Taiwan, involving five operating surgeons.
Participants
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.
Interventions
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.
Results
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.
Conclusions
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.
doi:10.1001/jama.2013.5835
PMCID: PMC3954742  PMID: 23736733
17.  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.
doi:10.1371/journal.pone.0094129
PMCID: PMC4041565  PMID: 24887437
18.  Measurement of Waist Circumference 
Diabetes Care  2013;36(6):1660-1666.
OBJECTIVE
Waist circumference (WC) is used to define central obesity. This study aimed to compare the performance of two recommended locations of WC measurement.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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).
CONCLUSIONS
WC-mid is a better measurement to define central obesity than WC-IC, particularly in women.
doi:10.2337/dc12-1452
PMCID: PMC3661855  PMID: 23275359
19.  Different angiotensin receptor blockers and incidence of diabetes: a nationwide population-based cohort study 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1186/1475-2840-13-91
PMCID: PMC4039330  PMID: 24886542
Angiotensin receptor antagonists; Diabetes mellitus; Cohort studies
20.  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.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0095045
PMCID: PMC3988150  PMID: 24736664
21.  Predicting the Glycemic Response to Gastric Bypass Surgery in Patients With Type 2 Diabetes 
Diabetes Care  2012;36(1):20-26.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc12-0779
PMCID: PMC3526207  PMID: 23033249
22.  Breast-Feeding and Childhood-Onset Type 1 Diabetes 
Diabetes Care  2012;35(11):2215-2225.
OBJECTIVE
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.
RESEARCH DESIGN AND METHODS
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.
RESULTS
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.
CONCLUSIONS
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.
doi:10.2337/dc12-0438
PMCID: PMC3476923  PMID: 22837371
23.  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(12):2619-2628.
Aims/hypothesis
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.
Methods
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.
Results
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.
Conclusions/interpretation
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.
doi:10.1007/s00125-013-3047-1
PMCID: PMC3825282  PMID: 24013783
Ethnic difference; Genetic association; Type 2 diabetes
24.  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.
doi:10.1002/emmm.201302679
PMCID: PMC3944459  PMID: 23828861
adipogenesis; C/EBPβ; N-acetylcysteine; NPGPx; oxidative stress
25.  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.
Conclusion
Genetic variation in the NOC gene is associated with BMI in Chinese subjects.
doi:10.1371/journal.pone.0069622
PMCID: PMC3724939  PMID: 23922759

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