Chien-Hsing Lee

Publications of Chien-Hsing Lee

• The growth arrest-specific 6 (Gas6) gene polymorphism c.834+7G>A is associated with type 2 diabetes.

  Authors: Chien-Hsing Lee, Nain-Feng Chu, Yi-Shing Shieh, Yi-Jen Hung

  Diabetes research and clinical practice. 09/2011; 95(2):201-6.

  The plasma protein growth arrest-specific 6 (Gas6) is important to the inflammatory process and involved in the development of diabetic renal and vascular complications. Recently, Gas6 protein alsoThe plasma protein growth arrest-specific 6 (Gas6) is important to the inflammatory process and involved in the development of diabetic renal and vascular complications. Recently, Gas6 protein also represents a novel independent risk factor of type 2 diabetes. We further investigated the association of c.843+7G>A Gas6 polymorphism and type 2 diabetes. 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. All subjects were genotyped for c.843+7G>A Gas6 polymorphism. Plasma Gas6 concentrations were significantly lower among patients with type 2 diabetes compared to subjects with IGT and NGT. Subjects with Gas6 c.843+7AA genotype had higher Gas6 levels and lower glucose values than GG genotype. The AA genotype and A allele were less frequent in patients with type 2 diabetes compared with NGT subjects. In univariate analysis, the AA genotype was found to be associated with a decreased risk for type 2 diabetes. Moreover, the association was even stronger after adjustment for established diabetes risk factors. The Gas6 c.843+7AA genotype and A allele are less prevalent in type 2 diabetes, which may have a protective role for type 2 diabetes.

• Axl Is a Prognostic Marker in Oral Squamous Cell Carcinoma.

  Authors: Chien-Hsing Lee, Ching-Yu Yen, Shyun-Yeu Liu, Chi-Kang Chen, Chi-Fu Chiang, Shine-Gwo Shiah, Pei-Hsuan Chen, Yi-Shing Shieh

  Annals of surgical oncology. 08/2011;

  BACKGROUND: Overexpression of the receptor tyrosine kinase Axl is implicated in several diseases. The present study was conducted to determine the biologic and clinical significance of Axl in oralBACKGROUND: Overexpression of the receptor tyrosine kinase Axl is implicated in several diseases. The present study was conducted to determine the biologic and clinical significance of Axl in oral squamous cell carcinoma (OSCC). METHODS: The expression of Axl was examined in a panel of OSCC cell lines. Activation of Axl by Gas6 treatment and silencing of Axl via Axl shRNA were used to examine the effect of Axl on OSCC cell line. Expression of Axl in cancer tissues were examined by immunohistochemical staining. The associations between Axl expression and clinicopathologic features and prognosis were analyzed. RESULTS: Varied Axl expression was noted in OSCC cell lines. Compared with control cells, modulated Axl signal affected epithelial-mesenchymal gene expression and cell invasion and migration. The immunoreactivity of Axl was low in normal epithelium, and a progressively increased positive percentage was noted, from normal/hyperplastic epithelium (10.9%) to dysplasia (30.8%) to cancer tissue (54.5%). Axl expression correlated with lymph node status (P = .001) and clinical stage (P = .014) of OSCC. Patients with high expression of Axl showed poor prognosis compared with those with low Axl expression patients (P < .001). In multivariate prognostic analysis according to the Cox proportional hazard regression model, Axl expression remained as an independent prognostic factor (P = .037; CI, 1.042-3.839). CONCLUSIONS: Our data indicated that Axl signal promotes OSCC carcinogenesis and progression. The expression of Axl is a valuable marker for OSCC aggressiveness and clinical outcome.

• Intratumoral macrophage counts correlate with tumor progression in colorectal cancer.

  Authors: Jung-Cheng Kang, Jin-Shuen Chen, Chien-Hsing Lee, Jao-Jen Chang, Yi-Shing Shieh

  Journal of surgical oncology. 09/2010; 102(3):242-8.

  The role of intratumoral tumor-associated macrophages (TAMs) in colorectal cancer (CRC) is not clear. We aim to examine the relationships of TAMs and the clinicopathologic features of CRC and theThe role of intratumoral tumor-associated macrophages (TAMs) in colorectal cancer (CRC) is not clear. We aim to examine the relationships of TAMs and the clinicopathologic features of CRC and the expression of matrix metalloproteinases (MMP)-2 and MMP-9. Immunohistochemical staining of CD68, MMP-2, and MMP-9 was determined in tissue samples from CRC patients. To test the biological effect of macrophages on tumor cells, cancer cells were cocultured with macrophages and function change of cancer cells were examined. Intratumoral TAM count correlated with depth of invasion (P = 0.048), lymph node metastasis (P < 0.0001), and staging (P < 0.0001) of CRC. MMP-2 and MMP-9 expression was significantly associated with lymph node metastasis and staging. A significant association between intratumoral TAM counts and MMP-2 (P < 0.0001) and MMP-9 (P < 0.0001) expression was noted. When cocultured with macrophages, cancer cells increased their invasiveness and migration and elevated MMP-2 and MMP-9 secretion. Intratumoral TAMs cause cancer cells to have a more aggressive behavior, and this may be due to an upregulation of tumor cell-derived MMP-2 and MMP-9. Examination of intratumoral TAMs can serve as a progressive marker for CRC patients.

• Plasma protein growth arrest-specific 6 levels are associated with altered glucose tolerance, inflammation, and endothelial dysfunction.

  Authors: Yi-Jen Hung, Chien-Hsing Lee, Nain-Feng Chu, Yi-Shing Shieh

  Diabetes care. 08/2010; 33(8):1840-4.

  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 determinePlasma 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)-alpha, 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-alpha, 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.

• Epidermal growth factor receptor regulates beta-catenin location, stability, and transcriptional activity in oral cancer.

  Authors: Chien-Hsing Lee, Hsing-Wen Hung, Pei-Hsin Hung, Yi-Shing Shieh

  Molecular cancer. 03/2010; 9:64.

  Many cancerous cells accumulate beta-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of beta-catenin in the nuclei of oral cancerMany cancerous cells accumulate beta-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of beta-catenin in the nuclei of oral cancer cells. We used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of beta-catenin and GSK-3beta, association of beta-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, beta-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of beta-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of beta-catenin (tyrosine) and GSK-3beta(Ser-(9), resulting in a loss of beta-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates beta-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of beta-catenin in oral cancer. EGFR signaling regulates beta-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of beta-catenin under EGFR activation is a malignancy marker of oral cancer.

• Loss of SFRP1 expression is associated with aberrant beta-catenin distribution and tumor progression in mucoepidermoid carcinoma of salivary glands.

  Authors: Chien-Hsing Lee, Yi-Jen Hung, Chih-Yuan Lin, Pei-Hsin Hung, Hsing-Wen Hung, Yi-Shing Shieh

  Annals of surgical oncology. 02/2010; 17(8):2237-46.

  Cytoplasmic and nuclear accumulation of beta-catenin in mucoepidermoid carcinoma (MEC) is frequently noted, but the mechanism is unknown. The methylation status of adenomatous polyposis coli (APC)Cytoplasmic and nuclear accumulation of beta-catenin in mucoepidermoid carcinoma (MEC) is frequently noted, but the mechanism is unknown. The methylation status of adenomatous polyposis coli (APC) and secreted frizzled-related proteins (SFRPs) was examined by methylation-specific polymerase chain reaction (MSP) assay. The association of SFRP1, beta-catenin, and cyclin D1 expression in MEC was evaluated by immunohistochemical staining. A high percentage of methylation in APC and the SFRP genes was found in MEC compared with adjacent normal tissues, in which SFRP1 (58.6%) was the most frequent methylated gene. Moreover, abundant expression of SFRP1 was noted in normal tissues, whereas reduced SFRP1 expression was detected in 71.7% (33/46) of MECs. There was significant association between methylation and reduced expression of SFRP1. Cytoplasmic/nuclear (C/N) beta-catenin and high cyclin D1 expression were found in 13/55 (23.6%) and 36/55 (65.5%) of cases, respectively. There was significant correlation between C/N beta-catenin expression and reduced SFRP1 expression (P = 0.009). In addition, SFRP1 and beta-catenin expression correlated with tumor malignancy index such as tumor grade and stage. Overall patient survival was significantly worse in patients with reduced SFRP1 and C/N beta-catenin expression (P = 0.009 and P = 0.002, respectively). Methylation of the SFRP1 gene was the major cause of reduced SFRP1 expression. Reduced SFRP1 led to C/N accumulation of beta-catenin and was associated with tumor malignancy. Therefore, examination of SFRP1 expression and beta-catenin location could be useful predictors of tumor progression and prognosis in patients with MEC.

• Epidermal growth factor receptor regulates β-catenin location, stability, and transcriptional activity in oral cancer

  Authors: Chien-Hsing Lee, Hsing-Wen Hung, Pei-Hsin Hung, Yi-Shing Shieh

  Molecular Cancer. 01/2010;

  Abstract Background Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in theAbstract Background Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells. Results We used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of β-catenin and GSK-3β, association of β-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, β-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of β-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of β-catenin (tyrosine) and GSK-3β(Ser-(9), resulting in a loss of β-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates β-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of β-catenin in oral cancer. Conclusions EGFR signaling regulates β-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of β-catenin under EGFR activation is a malignancy marker of oral cancer.

• Association between white blood cell count and components of metabolic syndrome.

  Authors: Chung-Ze Wu, Jiunn D Lin, Jer-Chuan Li, Shi-Wen Kuo, Chang-Hsun Hsieh, Wei-Chen Lian, Chien-Hsing Lee, Hsiang-Lin Wan, Yi-Jen Hung, Dee Pei

  Pediatrics international : official journal of the Japan Pediatric Society. 03/2009; 51(1):14-8.

  BACKGROUND: Components of metabolic syndrome (MetS) were found to be associated with several inflammatory factors including white blood cell count (WBCC), which is an easily available test inBACKGROUND: Components of metabolic syndrome (MetS) were found to be associated with several inflammatory factors including white blood cell count (WBCC), which is an easily available test in clinical practice. In the present study, the relationships between WBCC and MetS components were investigated in children. METHODS: A total of 288 Taiwanese children, under 10 years old, with normal WBCC, were enrolled in the study. They were divided into quartiles according to WBCC (lowest, WBCC1; highest, WBCC4). The mean values of each MetS component for every group were compared in boys and girls separately. Multivariate linear regression between the WBCC and the MetS components after adjusting for age and body mass index (BMI) were also evaluated. RESULTS: In group comparison, only the high-density lipoprotein-cholesterol (HDL-C) was found to be significantly lower in WBCC4 in boys. Other components were not different. After multivariate linear regression, WBCC was negatively correlated to HDL-C and positively to BMI in boys. Although not significant, similar relationships were also observed in girls. Interestingly, borderline positive correlation was noted between triglyceride (TG) and WBCC in girls. CONCLUSION: BMI was positively and HDL-C was negatively related to WBCC in boys. A similar trend could also be observed in girls but without significance. Borderline significant correlation between TG and WBCC was noted in girls. These findings suggest that cardiovascular risks might commence even in childhood. Early detection of children with these abnormalities may help to prevent cardiovascular disease and diabetes in adolescence or even adulthood.

• Identifying subjects with insulin resistance by using the modified criteria of metabolic syndrome.

  Authors: Chang-Hsun Hsieh, Dee Pei, Yi-Jen Hung, Shi-Wen Kuo, Chih-Tseung He, Chien-Hsing Lee, Chung-Ze Wu

  Journal of Korean medical science. 07/2008; 23(3):465-9.

  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 inThe 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.

• Correlation between white blood cell count and metabolic syndrome in adolescence.

  Authors: Chang-Hsun Hsieh, Dee Pei, Shi-Wen Kuo, Cheng-Yu Chen, Shih-Li Tsai, Chun-Lung Lai, Chien-Hsing Lee, Chung-Ze Wu, Yi-Jen Hung, Ming-Chen Hsieh

  Pediatrics international : official journal of the Japan Pediatric Society. 12/2007; 49(6):827-32.

  BACKGROUND: Metabolic syndrome (MetS) is associated with increased risk for diabetes and coronary heart disease. Data suggest that MetS starts even in children. Thus, it is important to understandBACKGROUND: Metabolic syndrome (MetS) is associated with increased risk for diabetes and coronary heart disease. Data suggest that MetS starts even in children. Thus, it is important to understand the role of MetS and the risks related to it. Furthermore, white blood cell count (WBCC) is available in routine examination and it has been proved to be related to risks of MetS. METHODS: A total of 1657 subjects aged 14-19 years were enrolled, with normal WBCC (< or =10 x 10(9) cells/L). The subjects were divided into four quartiles according to WBCC (WBCC1-4, from the lowest to highest WBCC) in both genders. RESULTS: The female subjects had significantly lower systolic blood pressure, fasting plasma glucose (FPG), triglyceride (TG), body mass index (BMI) and higher high-density lipoprotein-cholesterol (HDL-C) than the male subjects. When comparing the risks of the quartiles of WBCC, WBCC4 had significant higher BMI than WBCC1 and WBCC2 in both genders; and lower HDL-C than WBCC3 in male subjects. On multiple regression WBCC was positively related with BMI and TG and negatively related to HDL-C in male subjects. In female subjects only BMI was positively correlated with WBCC. Subjects with MetS did not have significant higher WBCC than those without MetS. CONCLUSIONS: In adolescents with normal WBCC, BMI is significantly related to the levels of WBCC and is the earliest component of MetS to be noted in adolescents. Elevated TG and decreased HDL-C could also be important markers for future risk factors only in male subjects.

• Both slow-release and regular-form metformin improve glycemic control without altering plasma visfatin level in patients with type 2 diabetes mellitus.

  Authors: Chang-Hsun Hsieh, Chih-Tseung He, Chien-Hsing Lee, Ling-Yi Wu, Yi-Jen Hung

  Metabolism: clinical and experimental. 09/2007; 56(8):1087-92.

  Both slow-release (SR) and regular-release (RR) metformin were effective in the treatment of type 2 diabetes mellitus. We compare the efficacy, safety, and effects on serum adipocytokines andBoth slow-release (SR) and regular-release (RR) metformin were effective in the treatment of type 2 diabetes mellitus. We compare the efficacy, safety, and effects on serum adipocytokines and inflammatory markers of both regimens in patients with type 2 diabetes mellitus. A prospective, randomized, double-blind study enrolled 55 patients with type 2 diabetes mellitus, which were randomly assigned to receive either metformin SR or RR (at a maximal dosage of 2000 mg/d for 12 weeks). Glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose, adipocytokines, C-reactive protein, and insulin resistance and pancreatic beta-cell function were measured before and after treatment. Significant decreases (P<.001) in mean HbA1c and fasting plasma glucose levels were observed in each group. However, the mean changes in HbA1c from baseline to end point in the 2 groups were not significantly different. Changes in metabolic parameters were similar except that a decreased total cholesterol level was observed in the metformin RR group. Neither regimen treatment had any influence on insulin resistance, but metformin RR improved beta-cell function. Neither regimen had an effect on serum adipocytokines or inflammatory markers. Once-daily metformin SR was as safe and effective as metformin RR in type 2 diabetic patients. Neither dosage form affected serum adipocytokines and inflammatory markers.

• Impaired glucose tolerance and impaired fasting glucose share similar underlying pathophysiologies.

  Authors: Jiunn-Diann Lin, Hsiang-Lin Wan, Jer-Chuan Li, Chung-Ze Wu, Shi-Wen Kuo, Chang-Hsun Hsieh, Wei-Chen Lian, Chien-Hsing Lee, Mei-Teng Kao, Dee Pei

  The Tohoku journal of experimental medicine. 08/2007; 212(4):349-57.

  Both impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are pre-diabetic states. IGT was defined as having normal fasting plasma glucose (< 6.1 mmol/l) and abnormal 2-hrBoth impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are pre-diabetic states. IGT was defined as having normal fasting plasma glucose (< 6.1 mmol/l) and abnormal 2-hr post-challenge plasma glucose. IFG was defined as having abnormal fasting plasma and normal 2-hr post-challenge plasma glucose (< 7.8 mmol/l). To explore whether these two abnormalities share similar underlying pathophysiologies, we evaluated risk factors of IGT and IFT using the models of factor analysis. The present study included 107 subjects with IGT and 52 with IFG. An oral glucose tolerance test and insulin suppression test, which could quantify insulin resistance, were performed on separate days. The risk factors include waist-to-hip ratio (WHR), triglycerides, high-density lipoprotein (HDL)-cholesterol, blood pressure, and fasting plasma glucose, which are associated with metabolic syndrome and insulin resistance. Factor analysis is a commonly used statistical method that could reduce a large number of risk factors into smaller numbers of groups, also called dimension. Accordingly, the complicated data could be interpreted more easily, since the related risk factors are grouped in one dimension. The results showed that the risk factors of IGT and IFG have similar grouping patterns. Triglyceride, insulin resistance, and HDL-cholesterol were grouped in one dimension (the lipid dimension), while WHR, mean blood pressure and fasting plasma glucose were grouped in another dimension (the metabolic dimension). In conclusion, except for WHR, the grouping patterns of the components in both IGT and IFG were nearly identical. These results suggest that IGT and IFG may share similar pathophysiologies.

• Impact of clinical characteristics of individual metabolic syndrome on the severity of insulin resistance in Chinese adults.

  Authors: Chang-Hsun Hsieh, Yi-Jen Hung, Du-An Wu, Shi-Wen Kuo, Chien-Hsing Lee, Wayne Huey-Herng Sheu, Jer-Chuan Li, Kuan-Hung Yeh, Cheng-Yu Chen, Dee Pei

  Journal of Korean medical science. 03/2007; 22(1):74-80.

  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 accordingThe 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 HDLcholesterol 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.

• Insulin resistance & secretion in subjects with normal fasting plasma glucose.

  Authors: Chang-Hsun Hsieh, Yi-Jen Hung, Chung-Ze Wu, Shang-Sen Lee, Chien-Hsing Lee, Cheng-Yu Chen, Jur-Chuan Li, Shi-Wen Kuo, Ko-Lin Kuo, Dee Pei

  The Indian journal of medical research. 11/2006; 124(5):527-34.

  BACKGROUND & OBJECTIVES: Lowering the diagnostic threshold of normal fasting plasma glucose (FPG) from 6.1 to 5.56 mmol/l has been proposed by American Diabetes Association. As early detection ofBACKGROUND & OBJECTIVES: Lowering the diagnostic threshold of normal fasting plasma glucose (FPG) from 6.1 to 5.56 mmol/l has been proposed by American Diabetes Association. As early detection of subjects with risk of diabetes is important, it is crucial to understand the relationship between different levels of FPG, insulin resistance (IR) and insulin secretion. We measured IR and insulin secretion in subjects with different levels of FPG to investigate the relationship between FPG and IR and insulin secretion, and to see whether lowering the cut-off improves the sensitivity of impaired fasting glucose to predict diabetes. METHODS: Apparently healthy subjects (294) were enrolled and divided into 3 groups according to their FPG levels; group 1 (<5.56 mmol/l, n=129), group 2 (5.56-6.09 mmol/l, n=99) and group 3 (6.1-6.9 mmol/l, n=66). Steady state plasma glucose (SSPG) derived from insulin suppression test was used to quantify insulin resistance and 30 min insulinogenic index during an oral glucose tolerance test to measure acute insulin secretion. RESULTS: The blood pressure was higher in group 3 than group 2 and fasting plasma insulin and triglyceride were higher in group 3 than that in group 1. The insulinogenic index was higher in the group 1 than group 3 and the SSPG was significantly higher in group 3 compared to group 1. INTERPRETATION & CONCLUSION: Our study showed a trend of progressive deterioration of both insulin action and secretion with increasing FPG level. These are supportive evidences for lowering the FPG to 5.56 mmol/l as suggested by the ADA.

• The influence of chromium chloride-containing milk to glycemic control of patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled trial.

  Authors: Dee Pei, Chang-Hsun Hsieh, Yi-Jen Hung, Jer-Chuang Li, Chien-Hsing Lee, Shi-Wen Kuo

  Metabolism: clinical and experimental. 07/2006; 55(7):923-7.

  The aim of this study is to evaluate the effect and safety of chromium-containing milk powder in patients with type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial wasThe aim of this study is to evaluate the effect and safety of chromium-containing milk powder in patients with type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial was conducted in Taiwan. A total of 60 patients with type 2 diabetes mellitus, aged 30 to 75 years, and on a dose of gliclazide sulfonylurea agent (< or =160 mg/d) for at least 3 months were enrolled. Their glycosylated hemoglobin ranged from 7.5% to 12%, fasting plasma glucose (FPG) from 140 to 250 mg/dL, and body mass index from 20 to 35 kg/m(2). The subjects were divided into 2 groups, one group to receive chromium-containing milk powder (chromium 200 microg/20 g milk powder) and the other to receive placebo twice a day for 16 weeks. Frequently sampled intravenous glucose tolerance test (IVGTT) was performed before and after treatment. The chromium group demonstrated a lower FPG and fasting insulin (-38.1 +/- 9.2 vs 63 +/- 8. 5 mg/dL and -1.7 +/- 0.2 vs 1.9 +/- 0.3 microU/mL, respectively; P < .05), especially in male patients (-41 +/- 9.2 vs 85 +/- 11.7 mg/dL and -2.7 +/- 0.2 vs 3.1 +/- 0.3 microU/mL, respectively; P < .01), at the end of the study. Lower glycosylated hemoglobin was observed in chromium-treated male patients (-1.1 +/- 0. 5 vs 0.7 +/- 0. 2; P < .05). However, there were no significant changes in other metabolic parameters (lipid profiles including total cholesterol, triglyceride, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol), except improvement of insulin resistance (homeostasis model assessment for insulin resistance and insulin sensitivity index from frequently sampled intravenous glucose tolerance test) observed in male patients (-2.1 +/- 1.1 vs -0.41 +/- 1.12 and 0.18 +/- 0.11 vs -0.15 +/- 0. 2, respectively; P < .05). There were no adverse events in both groups, except for mild complaints in the chromium group on constipation (5%) and flatulence (5%). Intake of milk powder containing 400 microg/d of chromium for 16 weeks in subjects with type 2 diabetes mellitus resulted in lowering of FPG, fasting insulin, and improvement of metabolic control in male patients.

• Rosiglitazone improves insulin sensitivity in nonobese subjects with impaired glucose tolerance: the role of adiponectin and C-reactive protein.

  Authors: Yi-Jen Hung, Shih-Hua Lin, Dee Pei, Shi-Wen Kuo, Chang-Hsun Hsieh, Chih-Tsueng He, Chien-Hsing Lee, Sandra Chyi Fan, Wayne Huey-Herng Sheu

  Metabolism: clinical and experimental. 05/2006; 55(4):439-44.

  To evaluate the effects of rosiglitazone (ROS) on serum adiponectin and C-reactive protein (CRP) in nonobese subjects with impaired glucose tolerance (IGT), we enrolled 21 patients with body massTo evaluate the effects of rosiglitazone (ROS) on serum adiponectin and C-reactive protein (CRP) in nonobese subjects with impaired glucose tolerance (IGT), we enrolled 21 patients with body mass index < or =24 kg/m(2) to receive ROS 4 mg daily for 12 weeks. Fifteen age-, sex-, and body mass index-matched healthy subjects were recruited as controls. A 75-g oral glucose tolerance test (OGTT), hemoglobin A(1c), fasting glucose, insulin, C-peptide, lipid profiles, adiponectin, and CRP levels were determined before initiation and at the end of the 12-week ROS treatment. Insulin resistance and beta-cell function were calculated using the homeostasis model assessment method (HOMA-IR and HOMA-beta, respectively). Compared with healthy controls, the ROS-treated subjects had significantly higher glycemic indices, HOMA-IR, CRP, and glucose and insulin concentrations in response to OGTT, and lower HOMA-beta level. After 12 weeks of ROS therapy, the results showed statistically significant changes from baseline in 2-hour plasma glucose during OGTT (9.4 +/- 0.3 vs 8.3 +/- 0.4 mmol/L, P < .05), HOMA-IR (2.6 +/- 0.2 vs 1.9 +/- 0.3, P < .05), HOMA-beta (63.4 +/- 12.5 vs 90.1 +/- 13.0, P < .05), and glucose and insulin concentrations during OGTT in nonobese subjects with IGT. In addition, elevation of serum adiponectin and decrease in CRP levels were significantly found after ROS treatment. Of 21 patients treated with ROS, 5 subjects were converted to normal (converter), 1 progressed to diabetes, and 15 remained in IGT status (nonconverter). There was a significant amelioration in HOMA-IR (-2.10 +/- 1.03 vs -0.07 +/- 0.33, P < .05) without significant changes in adiponectin and CRP levels in converter compared with nonconverter. We conclude that ROS effectively enhanced insulin sensitivity and beta-cell function to improve adiponectin and CRP levels in nonobese patients with IGT. The amelioration of insulin resistance may be a major determinant to predict the conversion of IGT independent of the changes in adiponectin and CRP.

• The effect of combination therapy with propylthiouracil and cholestyramine in the treatment of Graves' hyperthyroidism.

  Authors: Wen-Chin Tsai, Dee Pei, Tso-Fu Wang, Du-An Wu, Jer-Chuan Li, Cheng Lian Wei, Chien-Hsing Lee, Sheng-Pyng Chen, Shi-Wen Kuo

  Clinical endocrinology. 06/2005; 62(5):521-4.

  OBJECTIVE: The study aims to evaluate the efficacy of combination therapy with propylthiouracil (PTU) and cholestyramine in the treatment of Graves' hyperthyroidism. BACKGROUND: Thyroxine (T4) isOBJECTIVE: The study aims to evaluate the efficacy of combination therapy with propylthiouracil (PTU) and cholestyramine in the treatment of Graves' hyperthyroidism. BACKGROUND: Thyroxine (T4) is metabolized mainly in the liver by conjugation to glucuronides and sulphates that enter the enterohepatic circulation. Thyrotoxic patients have an abnormal increase in thyroid hormone in their enterohepatic circulation. Previous studies on combination therapy with methimazole and cholestyramine for Graves' hyperthyroidism have shown it to be an effective adjunctive treatment. In this study, we examined the efficacy of combination therapy with PTU and cholestyramine in the treatment of Graves' hyperthyroidism. METHODS: Thirty patients with newly diagnosed Graves' hyperthyroidism were randomly divided into two groups: group I (n = 15) received PTU 100 mg twice a day, propranolol 40 mg twice a day and cholestyramine 4 g twice a day for 4 weeks; group II (n = 15) received PTU 100 mg twice a day and propranolol 40 mg twice a day for 4 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), free thyroxine (FT4) and TRAb levels at baseline, and at the end of 2 and 4 weeks during the study period. RESULTS: There was no significant difference in baseline thyroid function parameters. At the end of 2 and 4 weeks of the study period, serum TT3 and FT4 levels of group I were significantly lower than those of group II. No significant differences in the TRAb level were found between the two groups. CONCLUSION: Cholestyramine contributed to a more rapid and complete decline in thyroid hormone levels in patients with Graves' hyperthyroidism. It was thus proved to be an effective and well-tolerated adjunctive therapy.

• The capability of glucose toxicity on severe type 2 diabetes.

  Authors: Chang-Hsun Hsieh, Yi-Jen Hung, Chih-Tseung He, Chien-Hsing Lee, Szu-Chun Hung, Yi-Kuan Wang, Shi-Wen Kuo, Dee Pei

  Endocrine research. 02/2005; 31(2):149-58.

  The underlying defects of type 2 diabetes are impaired insulin sensitivity and decreased beta-cell function. In poorly controlled type 2 diabetes, the 'glucose toxicity' further deteriorates theseThe underlying defects of type 2 diabetes are impaired insulin sensitivity and decreased beta-cell function. In poorly controlled type 2 diabetes, the 'glucose toxicity' further deteriorates these defects. The objective was to determine whether correction of glucose toxicity will lead to improve insulin sensitivity and beta-cell function in these severely affected patients. Twelve severe type 2 diabetic patients were enrolled. An intravenous glucose tolerance test was performed before and after treatment with insulin for 3 months. The insulin sensitivity, glucose sensitivity, and acute insulin response after glucose loading were calculated by a minimal model algorithm. The lipid profiles did not change significantly after insulin therapy, but the hemoglobin A1c, level improved significantly (12.2 +/- 2.2% to 9.2 +/- 1.9%; p = 0.001). The insulin sensitivity, glucose sensitivity, and acute insulin response did not change significantly with insulin therapy. Correction of hyperglycemia with 3-month insulin therapy may improve metabolic effect instead of insulin sensitivity, glucose sensitivity, and acute insulin response to glucose load in severe type 2 diabetic patients.

• The effect of testosterone supplement on insulin sensitivity, glucose effectiveness, and acute insulin response after glucose load in male type 2 diabetics.

  Authors: Chien-Hsing Lee, Shi-Wen Kuo, Yi-Jen Hung, Chang-Hsun Hsieh, Chih-Tsueng He, Tsao-Chin Yang, Wei-Cheng Lian, Sandra Chyi Fan, Dee Pei

  Endocrine research. 02/2005; 31(2):139-48.

  Our understanding of the effect of androgens on insulin action and glucose metabolism is incomplete. Several different models and methods have been used to study androgen effects, with some studiesOur understanding of the effect of androgens on insulin action and glucose metabolism is incomplete. Several different models and methods have been used to study androgen effects, with some studies indicating that higher testosterone levels are associated with increased insulin resistance. In polycystic ovary syndrome, where high testosterone levels are frequently found, affected patients have a higher risk of diabetes. In contrast, increased insulin resistance was found in both hypergonadotropic and hypogonadotropic men with hypoandrogenism, patients with Klinefelter's syndrome and men with idiopathic gonadotropin deficiency. Insulin resistance is considered to be one of the cornerstones in the state that ultimately leads to clinically established type 2 diabetes mellitus. In addition, men with type 2 diabetes have relative hypogonadism. Therefore, supplementation with testosterone might play a role in improving both insulin resistance and hypogonadism. The study population consisted of 11 male patients with type 2 diabetes. Their mean age was 57.7 +/- 3.41 years, the body mass index (BMI) was 24.4 +/- 1.02 kg/m2, and the waist-to-hip ratio (W/H) was 0.91 +/- 0.05. The patients were all treated with oral hypoglycemic agents. The men received androgen injections every 3 weeks intramuscularly for 12 weeks. The injections were testosterone depot 100 mg/3 weeks. Insulin sensitivity, glucose effectiveness and area under acute insulin response were calculated from "minimal model" algorithms. There were no significant differences in the value of BMI, W/H ratios, plasma lipid concentrations, testosterone, homeostasis model assessment (HOMA) of insulin sensitivity, and beta-cell function, before and after supplementation of testosterone. Furthermore, the insulin sensitivity (SI) (1.04 +/- 0.25, 1.11 +/- 0.36 x 10(-5) min(-1/)pM; p = 0.43), glucose effectiveness (EG) (0.018 +/- 0.003, 0.017 +/- 0.002 min(-1); p = 0.29), and acute insulin response (AIR) after a glucose load (45.7 +/- 24.3, 50.1 +/- 32.5 pM; p = 0.45) did not change significantly after supplmentation with testosterone. In our study, there was no improvement of SI, EG, and AIR after 3 months of Testosterone Depot treatment in type 2 diabetes, but we believe that duration and dosage of the androgen therapy might play an important role in improving insulin sensitivity. The mechanisms by which testosterone causes insulin resistance is unknown, and larger studies on androgen treatment in type 2 diabetic patients are necessary.

• Rosiglitazone improves insulin sensitivity and glucose tolerance in subjects with impaired glucose tolerance.

  Authors: Yi-Jen Hung, Chang-Hsun Hsieh, Dee Pei, Shi-Wen Kuo, Jiunn-Tay Lee, Ling-Yi Wu, Chih-Tsueng He, Chien-Hsing Lee, Sandra Chyi Fan, Wayne Huey-Herng Sheu

  Clinical endocrinology. 02/2005; 62(1):85-91.

  OBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects withOBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects with impaired glucose tolerance (IGT). METHODS: Thirty patients with IGT (ages between 30 and 75 years and BMI (body mass index) < or = 27 kg/m2) were randomly assigned to receive either placebo (n = 15) or ROS (4 mg/day) (n = 15). All participants underwent a 75-g oral glucose tolerance test (OGTT), meal test, and frequently sampled intravenous glucose tolerance test (FSIGT) before and after the 12-week treatment. RESULTS: After 12 weeks of ROS treatment, there were significant increases in total cholesterol (TC) (4.25 +/- 0.22 vs 4.80 +/- 0.17 mmol/l, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (1.25 +/- 0.07 vs 1.43 +/- 0.06 mmol/l, P < 0.05), and low-density lipoprotein cholesterol (LDL-C) (2.70 +/- 0.15 vs 3.37 +/- 0.17 mmol/l, P < 0.05) without changes in triglyceride concentration, TC/HDL-C and LDL-C/HDL-C ratio. Although the acute insulin response (AIR) to intravenous glucose and disposition index (measured as the ability of pancreatic beta-cell compensation in the presence of insulin resistance) remained unchanged, the insulin sensitivity (SI) and glucose effectiveness (SG) were remarkably elevated (0.38 +/- 0.06 vs 0.54 +/- 0.09 x 10(-5) min(-1)/pmol, P < 0.05; 0.017 +/- 0.002 vs 0.021 +/- 0.001 min(-1), P < 0.05, respectively) in the ROS group. The glucose, insulin, and c-peptide areas under curve (AUC) in response to OGTT and the glucose and insulin AUC during meal were significantly ameliorated in the ROS group. Five out of 15 (33%) and two out of 15 (13%) subjects treated with ROS and placebo, respectively, reversed to normal response during OGTT (P < 0.05). CONCLUSION: Rosiglitazone treatment significantly improved insulin resistance and reduced postchallenge glucose and insulin concentrations in patients with impaired glucose tolerance without remarkable effects on beta-cell secretory function.