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1.  Antidepressant Effects on Insulin Sensitivity and Proinflammatory Cytokines in the Depressed Males 
Mediators of Inflammation  2010;2010:573594.
Growing evidence suggests that mood disorder is associated with insulin resistance and inflammation. Thus the effects of antidepressants on insulin sensitivity and proinflammatory responses will be a crucial issue for depression treatment. In this study, we enrolled 43 non-diabetic young depressed males and adapted standard testing procedures to assess glucose metabolism during 4-week hospitalization. Before and after the 4-week antidepressant treatment, participants underwent oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIGT). Insulin sensitivity (SI), glucose effectiveness (SG), acute insulin response, and disposition index (DI) were estimated using the minimal model method. The plasma levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and adiponectin were measured. The Hamilton depression rating scale (HAM-D) total scores were reduced significantly during the course of treatment. There were no significant changes in the parameters of SI, SG, and DI. Compared to drug naïve status, the level of plasma IL-6 was significantly elevated (0.77 to 1.30 pg/ml; P = .001) after antidepressant therapy. However, the concentrations of CRP, TNF-α, and adiponectin showed no differences during the course of treatment. The results suggest that antidepressants may promote stimulatory effect on the IL-6 production in the early stage of antidepressant treatment.
PMCID: PMC2872762  PMID: 20490354
2.  Aggravation of Hypertriglyceridemia and Acute Pancreatitis in a Bipolar Patient Treated with Quetiapine 
Yonsei Medical Journal  2014;55(3):831-833.
Pancreatitis is a very rare adverse effect of quetiapine treatment, with only 5 cases of quetiapine-associated pancreatitis reported in the English literature to date. Herein, we report one patient who developed severe hypertriglyceridemia (>1000 mg/dL) after quetiapine administration, resulting in acute pancreatitis. An analysis of the underlying pathogenic mechanisms and a review of relevant literature are also presented. Clinicians should be aware of the potentially life-threatening metabolic disturbances and/or pancreatitis associated with quetiapine therapy.
PMCID: PMC3990081  PMID: 24719155
Quetiapine; hypertriglyceridemia; pancreatitis
3.  High glucose induces human endothelial dysfunction through an Axl-dependent mechanism 
The receptor tyrosine kinase Axl and its ligand growth arrest-specific protein 6 (Gas6) are involved in the diabetic vascular disease. The aim of this study was to explore the role of Gas6/Axl system in high glucose (HG)-induced endothelial dysfunction.
We investigated the effect of various glucose concentrations on Axl signaling in human microvascular endothelial cells (HMEC-1 s).
Human plasma Gas6 value inversely correlated with glucose status, endothelial markers. HG decreased Gas6/Axl expression and increased intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expression in HMEC-1 s. HG significantly decreased HMEC-1 s cell viability and tube formation and promoted monocyte-EC adhesion. Down-regulation of Akt phosphorylation was found in HG culture. Axl transfection significantly reversed HG-induced Akt phosphorylation, VCAM-1 expression and endothelial dysfunction. We also found additive changes in Axl-shRNA-infected HMEC-1 cells in HG culture. Furthermore, Axl overexpression in HMEC-1 s significantly reversed HG-induced vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) expression. In addition, significantly lower Axl and VEGFR2 expression in arteries were found in diabetic patients as compared with non-diabetic patients.
This study demonstrates that HG can alter Gas6/Axl signaling and may through Akt and VEGF/VEGFR2 downstream molecules and suggests that Gas6/Axl may involve in HG-induced EC dysfunction.
PMCID: PMC3941696  PMID: 24572151
Diabetes; Endothelial cell; Gas6/Axl
4.  Urine Annexin A1 as an Index for Glomerular Injury in Patients 
Disease Markers  2014;2014:854163.
Background. We recently demonstrated high urine levels of annexin A1 (ANXA1) protein in a mouse Adriamycin-induced glomerulopathy (ADG) model. Objective. To establish ANXA1 as a potential biomarker for glomerular injury in patients. Methods. A time-course study in the mouse ADG model, followed by renal tissues and urine samples from patients with various types of glomerular disorders for ANXA1. Results. Urinary ANXA1 protein was (1) detectable in both the ADG model and in patients except those with minimal change disease (MCD); (2) positively correlated with renal lesions in patients; and (3) early detectable in diabetes patients with normoalbuminuria. Conclusions. ANXA1 is a universal biomarker that is helpful in the early diagnosis, prognostic prediction, and outcome monitoring of glomerular injury. Measurement of urinary ANXA1 protein levels can help in differentiating MCD from other types of glomerular disorders.
PMCID: PMC3925619  PMID: 24591769
5.  Interleukin-6 Receptor Gene 48892 A/C Polymorphism Is Associated with Metabolic Syndrome in Female Taiwanese Adolescents 
Background: This study was to evaluate the relationship between the interleukin-6 receptor (IL-6R) 48892 A/C single-nucleotide polymorphism (SNP) (rs8192284) and the metabolic syndrome (MetS) and its components among young adolescents in Taiwan. Methods: We enrolled 925 adolescents (451 boys and 474 girls). Modified National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III) criteria were applied to define MetS (with age- and gender-specific 90th percentile cutoff point of variables). Subjects had three or more of the following cardiometabolic abnormalities that occur in MetS: high blood pressure, high fasting glucose, high triglyceride (TG), low high-density lipoprotein cholesterol (HDL-C), and obesity. The characteristics of the MetS components associated with different alleles and genotypes of the IL-6R rs8192284 SNP were compared. Results: Frequencies of alleles and genotypes of the IL-6R 48892 polymorphism were similar in both sexes. Boys with C-alleles had borderline lower TG levels than A-allele carriers (66.0±30.1 vs. 70.3±34.6 mg/dL, p=0.07). However, girls with C-alleles had higher waist circumference (WC) (68.0±7.9 vs. 67.0±7.7 cm) and lower HDL-C levels (50.7±11.1 vs. 52.2±11.7 g/dL) than A-allele carriers (p=0.05). The prevalence of MetS and its components, high WC and low HDL-C level, were higher in female C-allele carriers (all p<0.05) but not in boys. The odds ratios for high WC, low HDL-C levels, and MetS for female C-allele carriers were 1.54 (95% confidence interval [CI]: 1.01–2.34), 1.49 (95% CI: 1.01–2.18), and 2.19–2.39 (95% CI: 1.15–4.51), respectively, when compared with A-allele carriers. Conclusions: The IL-6R 48892 A/C polymorphism is associated with high TG and WC, and low HDL-C levels in adolescents. Additionally, there is a gender difference in the incidence of MetS, indicating a possible gene–gender interaction of the IL-6R 48892 A/C polymorphism in MetS among Taiwanese adolescents.
PMCID: PMC3501111  PMID: 23094986
6.  Plasma Concentrations Predict Aortic Expression of Growth-Arrest-Specific Protein 6 in Patients Undergoing Coronary Artery Bypass Grafting 
PLoS ONE  2013;8(11):e79452.
The tyrosine kinase receptor Axl is expressed in the vasculature, and growth arrest-specific protein 6 (Gas6) is its ligand. Plasma Gas6 levels have been shown to be associated with endothelial dysfunction markers and cardiovascular events. We set out to determine the plasma Gas6 levels in patients undergoing coronary artery bypass grafting (CABG) and investigate the expression of Gas6 and Axl in the aorta.
Methods and Results
Immunoassays were used to investigate plasma Gas6 levels in CABG patients (n = 19) and control subjects (n = 20). The expression of Gas6 and Axl in the injured aorta were examined by reverse transcription-polymerase chain reactions, real-time reverse transcription-polymerase chain reactions, western blotting, and immunohistochemical staining. Plasma Gas6 levels were significantly lower in CABG patients than in matched control subjects. In CABG patients, plasma Gas6 levels were negatively correlated with fasting glucose, E-selectin, and vascular cell adhesion molecule-1 levels. The levels predicted the operative mortality rate and were positively correlated with plasma soluble Axl (sAxl) levels and Gas6 expression in the aorta. Moreover, Gas6 expression was positively correlated with Axl expression in the aorta.
We concluded that plasma Gas6 is associated with fasting glucose, endothelial dysfunction markers, sAxl values, and vascular Gas6 expression in CABG patients, and it predicts the operative mortality of these patients. These findings suggest that the Gas6/Axl system is crucial in vascular biology.
PMCID: PMC3827360  PMID: 24236135
7.  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
8.  Common ALDH2 genetic variants predict development of hypertension in the SAPPHIRe prospective cohort: Gene-environmental interaction with alcohol consumption 
Genetic variants near/within the ALDH2 gene encoding the mitochondrial aldehyde dehydrogenase 2 have been associated with blood pressure and hypertension in several case–control association studies in East Asian populations.
Three common tag single nucleotide polymorphisms (tagSNP) in the ALDH2 gene were genotyped in 1,134 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. We examined whether the ALDH2 SNP genotypes predicted the development of hypertension in the prospective SAPPHIRe cohort.
Over an average follow-up period of 5.7 years, carriers homozygous for the rs2238152 T allele in the ALDH2 gene were more likely to progress to hypertension than were non-carriers (hazard ratio [HR], 2.88, 95% confidence interval [CI], 1.06-7.84, P = 0.03), corresponding to a population attributable risk of ~7.1%. The risk associated with the rs2238152 T allele were strongest in heavy/moderate alcohol drinkers and was reduced in non-drinkers, indicating an interaction between ALDH2 genetic variants and alcohol intake on the risk of hypertension (P for interaction = 0.04). The risk allele was associated with significantly lower ALDH2 gene expression levels in human adipose tissue.
ALDH2 genetic variants were associated with progression to hypertension in a prospective Chinese cohort. The association was modified by alcohol consumption.
PMCID: PMC3476438  PMID: 22839215
ALDH2; Hypertension; SNP; Chinese
9.  Plasma Protein Growth Arrest–Specific 6 Levels Are Associated With Altered Glucose Tolerance, Inflammation, and Endothelial Dysfunction 
Diabetes Care  2010;33(8):1840-1844.
Plasma protein growth arrest–specific 6 (Gas6) is important to the inflammatory process and is involved in the development of diabetic renal and vascular complications. We set out to determine whether plasma Gas6 levels are associated with altered glucose tolerance, insulin sensitivity, inflammation, and endothelial dysfunction.
A total of 278 adults, including 96 with normal glucose tolerance (NGT), 82 with impaired glucose tolerance (IGT), and 100 with type 2 diabetes were recruited. Plasma Gas6 concentration and biochemical, proinflammatory, and endothelial variables were determined. Insulin sensitivity was examined by homeostasis model assessment.
Plasma Gas6 concentration was significantly lower among patients with type 2 diabetes compared with subjects with NGT (P < 0.001). The plasma Gas6 value was inversely correlated with fasting glucose, tumor necrosis factor (TNF)-α, interleukin (IL)-6, and vascular cell adhesion molecule (VCAM)-1. In multivariate logistic regression analysis, after adjustment for established diabetes risk factors, higher plasma Gas6 concentrations were significantly associated with a decreased risk of type 2 diabetes. Moreover, the association became slightly stronger after further adjustment for TNF-α, IL-6, high-sensitive C-reactive protein, E-selectin, intercellular adhesion molecule-1, and VCAM-1.
Plasma Gas6 is associated with altered glucose tolerance, inflammation, and endothelial dysfunction. It also may represent a novel independent risk factor of type 2 diabetes and a potential surrogate marker of inflammation and endothelial dysfunction.
PMCID: PMC2909074  PMID: 20504897
10.  Pilot study of an association between a common variant in the non-muscle myosin heavy chain 9 (MYH9) gene and type 2 diabetic nephropathy in a Taiwanese population 
Nowadays diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). Recent studies have demonstrated that the myosin, heavy chain 9, non-muscle (MYH9) gene is associated with ESRD in African Americans. In this study, we tested the hypothesis that a common single nucleotide polymorphism rs16996677 in the MYH9 gene may contribute to the etiology of DN in type 2 diabetes (T2D) in a Taiwanese population with T2D. There were 180 T2D patients diagnosed with DN and 178 age- and sex-similar T2D without DN controls. Single locus analyses showed no significant main effects of MYH9 rs16996677 on the risk of DN in T2D. The results suggest that the rs16996677 SNP in MYH9 may not contribute to the risk of DN in T2D in Taiwanese T2D patients.
PMCID: PMC3681160  PMID: 23776349
diabetic nephropathy; end-stage renal disease; single nucleotide polymorphisms; type 2 diabetes
11.  Identifying Subjects with Insulin Resistance by Using the Modified Criteria of Metabolic Syndrome 
Journal of Korean Medical Science  2008;23(3):465-469.
The objectives of this cohort analysis were to explore the relationship between insulin resistance (IR) and the criteria for metabolic syndrome (MetS) and to evaluate the ability to detect IR in subjects fulfilling those criteria. We enrolled 511 healthy subjects (218 men and 283 women) and measured their blood pressure (BP), body mass index, high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and fasting plasma glucose levels. Insulin suppression testing was done to measure insulin sensitivity as the steady-state plasma glucose (SSPG) value. Subjects with an SSPG value within the top 25% were considered to have IR. The commonest abnormality was a low HDL-C level, followed by high BP. The sensitivity to detect IR in subjects with MetS was about 47%, with a positive predictive value of about 64.8%, which has higher in men than in women. In general, the addition of components to the criteria for MetS increased the predictive value for IR. The most common combination of components in subjects with MetS and IR were obesity, high BP, and low HDL-C levels. All of the components were positive except for HDL-C, which was negatively correlated with SSPG. The correlation was strongest for obesity, followed by high TG values. In subjects with MetS, sensitivity for IR was low. However, body mass index and TG values were associated with IR and may be important markers for IR in subjects with MetS.
PMCID: PMC2526525  PMID: 18583884
Insulin Resistance; Metabolic Syndrome; Obesity; Triglycerides
12.  Impact of Clinical Characteristics of Individual Metabolic Syndrome on the Severity of Insulin Resistance in Chinese Adults 
The impact the metabolic syndrome (MetS) components on the severity of insulin resistance (IR) has not been reported. We enrolled 564 subjects with MetS and they were divided into quartiles according to the level of each component; and an insulin suppression test was performed to measure IR. In males, steady state plasma glucose (SSPG) levels in the highest quartiles, corresponding to body mass index (BMI) and fasting plasma glucose (FPG), were higher than the other three quartiles and the highest quartiles, corresponding to the diastolic blood pressure and triglycerides, were higher than in the lowest two quartiles. In females, SSPG levels in the highest quartiles, corresponding to the BMI and triglycerides, were higher than in all other quartiles. No significant differences existed between genders, other than the mean SSPG levels in males were greater in the highest quartile corresponding to BMI than that in the highest quartile corresponding to HDL-cholesterol levels. The factor analysis identified two underlying factors (IR and blood pressure factors) among the MetS variables. The clustering of the SSPG, BMI, triglyceride and HDL-cholesterol was noted. Our data suggest that adiposity, higher FPG and triglyceride levels have stronger correlation with IR and subjects with the highest BMI have the highest IR.
PMCID: PMC2693573  PMID: 17297255
Adiposity; Factor Analysis, Statistical; Triglycerides; Metabolic Syndrome X; Insulin Resistance; Insulin Suppression Test
13.  Effect of GAS6 and AXL Gene Polymorphisms on Adiposity, Systemic Inflammation, and Insulin Resistance in Adolescents 
The present study was designed to explore the effects of GAS6 and AXL gene polymorphisms on adiposity, systemic inflammation, and insulin resistance in adolescents. After multistage sampling from the data of the Taipei Children Heart Study-III, we collected 358 boys and 369 girls with an average age of 13.3 years. We genotyped the adolescents' GAS6 rs8191973, GAS6 rs8191974, AXL rs4802113, and AXL rs2304232 polymorphisms. Significantly higher body mass index (BMI), waist circumference (WC), and hsCRP levels were found in boys with the GG genotype of GAS6 rs8191974 than A allele carriers; higher IL-6 and insulin levels and increased HOMA-IR were found in boys with the GG genotype of AXL rs2304232 than the A allele carriers. There was a significant difference in hsCRP levels of boys with the TT, TC, and CC genotypes of AXL rs4802113. Boys with both the GG genotype of GAS6 rs8191973 and the GG genotype of GAS6 rs8191974 exhibited higher BMI, WC, IL-6, and hsCRP levels than the boys carrying both the C allele of the GAS6 rs8191973 and the A allele of the GAS6 rs8191974. In conclusion, GAS6 and AXL polymorphisms are associated with adiposity, systemic inflammation, and insulin resistance in adolescents, especially in boys.
PMCID: PMC3948192  PMID: 24696684
14.  Soluble Form of Receptor for Advanced Glycation End Products Is Associated with Obesity and Metabolic Syndrome in Adolescents 
The aim of this cross-sectional study was to investigate the relationship between soluble form of receptor for advanced glycation end products (sRAGE), obesity, and metabolic syndrome (MetS) in adolescents. A total of 522 male and 561 female adolescents were enrolled into the final analyses. Anthropometric parameters, blood pressure, blood biochemistry, fasting insulin, and plasma sRAGE levels were measured. In males, sRAGE was significantly and inversely correlated with waist circumference (WC), body mass index (BMI), systolic blood pressure, triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and homeostasis model assessment-insulin resistance (HOMA-IR). Only WC and BMI were significantly and inversely correlated with sRAGE in females. Using linear regression analysis adjusting for age and gender, significant association was found between sRAGE and WC, BMI, TG, LDL-C, and HOMA-IR in adolescents of either gender (P < 0.05). This association was abolished when further adjusting BMI. In addition, sRAGE was significantly and inversely correlated with the increasing number of components of MetS in males (P for trend = 0.006) but not in females (P for trend = 0.422). In conclusion, plasma sRAGE is associated with obesity and MetS among adolescents. BMI may be the most important determinant of sRAGE levels in adolescents.
PMCID: PMC3918363  PMID: 24575131

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