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author:("Lee, Wei-jeti")
1.  Gastrointestinal metabolic surgery for the treatment of type 2 diabetes mellitus 
World Journal of Gastroenterology : WJG  2014;20(39):14315-14328.
Medical therapy for type 2 diabetes mellitus is ineffective in the long term due to the progressive nature of the disease, which requires increasing medication doses and polypharmacy. Conversely, bariatric surgery has emerged as a cost-effective strategy for obese diabetic individuals; it has low complication rates and results in durable weight loss, glycemic control and improvements in the quality of life, obesity-related co-morbidity and overall survival. The finding that glucose homeostasis can be achieved with a weight loss-independent mechanism immediately after bariatric surgery, especially gastric bypass, has led to the paradigm of metabolic surgery. However, the primary focus of metabolic surgery is the alteration of the physio-anatomy of the gastrointestinal tract to achieve glycemic control, metabolic control and cardio-metabolic risk reduction. To date, metabolic surgery is still not well defined, as it is used most frequently for less obese patients with poorly controlled diabetes. The mechanism of glycemic control is still incompletely understood. Published research findings on metabolic surgery are promising, but many aspects still need to be defined. This paper examines the proposed mechanism of diabetes remission, the efficacy of different types of metabolic procedures, the durability of glucose control, and the risks and complications associated with this procedure. We propose a tailored approach for the selection of the ideal metabolic procedure for different groups of patients, considering the indications and prognostic factors for diabetes remission.
PMCID: PMC4202361  PMID: 25339819
Metabolic surgery; Gastrointestinal surgery; Type-2 diabetes mellitus; Glucolipotoxicity; Efficacy; Prognostic factor
2.  Impairment of gastrointestinal quality of life in severely obese patients 
AIM: To investigate the common gastro-intestinal symptoms and quality of life in severely obese subjects.
METHODS: We prospectively recruited 340 severely obese patients [mean age 30.5 ± 7.8 years; mean body mass index (BMI) 42.9 ± 6.1 kg/m2] and 340 healthy persons (mean BMI 23.1 ± 3.8 kg/m2) matched in sex, age, marriage and education. The quality of life was studied using a specific gastrointestinal quality of life index (GIQLI) questionnaire. The 36 items and four functional domains of the GIQLI were compared and analyzed between the groups. The possible correlation of GIQLI scores with specific clinical variables in severely obese patients was assessed by measuring Pearson’s coefficient of correlation.
RESULTS: The mean GIQLI score of severely obese patients was lower than the normal control group (108.5 ± 17.1 vs 123.2 ± 14.8, P < 0.01). Severely obese patients had decreased scores in the domains of general health, including physical (17.3 ± 6.0 vs 22.4 ± 3.1, P < 0.01), emotional (12.6 ± 4.3 vs 16.6 ± 3.1, P < 0.01) and social function (14.7 ± 3.9 vs 17.9 ± 2.5, P < 0.01), and in the domain of gastrointestinal symptoms (63.9 ± 6.7 vs 66.3 ± 7.2, P < 0.05). A significantly decreased score was found in nine items, and there was an increased score in one out of the 19 items in the domain of symptoms of the GIQLI questionnaire. The decreased score in the domain of symptoms was correlated with increasing glycosylated hemoglobin (HbA1c) levels.
CONCLUSION: Severe obesity resulted in a significant impairment of the quality of life and caused specific gastrointestinal symptoms compared with normal controls. The development of gastrointestinal symptoms is correlated increasing HbA1c, suggesting that a poor control of hyperglycemia might be the etiology.
PMCID: PMC4051947  PMID: 24944498
Severe obesity; Quality of life; Gastro-intestinal symptoms; Glycosylated hemoglobin
3.  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
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.  Gender, Body Mass Index, and PPARγ Polymorphism Are Good Indicators in Hyperuricemia Prediction for Han Chinese 
Hyperuricemia is closely associated with obesity and metabolic abnormalities, which is also an independent risk factor for cardiovascular diseases. The PPARγ gene, which is linked to obesity and metabolic abnormalities in Han Chinese, might be considered a top candidate gene that is involved in hyperuricemia. This study recruited 457 participants, aged 20–40 years old, to investigate the associations of the PPARγ gene and metabolic parameters with hyperuricemia. Three tag-single nucleotide polymorphisms, rs2292101, rs4684846, and rs1822825, of the PPARγ gene were selected to explore their association with hyperuricemia. Risk genotypes on rs1822825 of the PPARγ gene exhibited statistical significance with hyperuricemia (odds ratio: 1.9; 95% confidence interval: 1.05–3.57). Although gender, body mass index (BMI), serum total cholesterol concentration, or protein intake per day were statistically associated with hyperuricemia, the combination of BMI, gender, and rs1822825, rather than that of age, serum lipid profile, blood pressure, and protein intake per day, satisfied the predictability for hyperuricemia (sensitivity: 69.3%; specificity: 83.7%) in Taiwan-born obese Han Chinese. BMI, gender, and the rs1822825 polymorphism in the PPARγ gene appeared good biomarkers in hyperuricemia; therefore, these powerful indicators may be included in the prediction of hyperuricemia to increase the accuracy of the analysis.
PMCID: PMC3525899  PMID: 23237621
6.  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
7.  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
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.  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

Results 1-9 (9)