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Gu X.,Chinese University of Hong Kong | Li K.,Chinese University of Hong Kong | Laybutt D.R.,Garvan Institute of Medical Research | He M.-L.,Chinese University of Hong Kong | And 5 more authors.
Life Sciences | Year: 2010

Aims: In this study we investigated whether attenuation of endoplasmic reticulum stress (ER stress) could protect HepG2 cells from free fatty acid (FFA)-induced apoptosis. Main methods: Human liver cell line HepG2 cells were exposed to Sodium Palmitate (Pa) or Sodium Oleate (Ol). Apoptosis and ER stress of HepG2 cells were analyzed with flow cytometry, real-time RT-PCR and Western Blotting. An expression plasmid encoding for the ER chaperone immunoglobulin heavy chain-binding protein (Bip) was transfected into HepG2 cells to attenuate ER stress. Small interfering RNA siCHOP was used to knockdown the expression of C/EBP Homologous Protein (CHOP) in HepG2. Key findings: Pa led to cytotoxicity and apoptosis in HepG2 cells in a dose-dependent pattern and also induced ER stress indicated by increased phosphorylation of eIF2α, upregulation of IRE1α and CHOP. Bip expression levels were slightly down regulated after Pa treatment. The unsaturated fatty acid, Ol, induced neither apoptosis nor ER stress in HepG2 cells. Overexpression of Bip attenuated Pa-induced ER stress and led to a significant reduction in Pa-mediated apoptosis, indicating a requirement of ER stress for lipotoxicity in liver cells. siRNA-mediated reduction of CHOP did not protect against Pa-induced apoptosis. Significance: While ER stress makes a necessary contribution to palmitate cytotoxicity, inhibition of CHOP alone is not sufficient to prevent palmitate-induced apoptosis. Our findings could advance the detailed understanding on the mechanism of high fatty acid (FFA)-induced apoptosis. © 2010 Elsevier Inc.


Kong A.P.S.,Chinese University of Hong Kong | Yang X.,Chinese University of Hong Kong | Yang X.,Tianjin Medical University | So W.-Y.,Chinese University of Hong Kong | And 12 more authors.
BMC Medicine | Year: 2014

Background: Hyperglycemia is associated with increased risk of all-site cancer that may be mediated through activation of the renin-angiotensin-system (RAS) and 3-hydroxy-3-methyl-glutaryl-coenzyme-A-reductase (HMGCR) pathways. We examined the joint associations of optimal glycemic control (HbA1c <7%), RAS inhibitors and HMGCR inhibitors on cancer incidence in patients with type 2 diabetes. Methods: Patients with type 2 diabetes, with or without a history of cancer or prior exposure to RAS or HMGCR inhibitors at baseline were observed between 1996 and 2005. All patients underwent a comprehensive assessment at baseline and were followed until the censored date at 2005 or their death. Results: After a median follow-up period of 4.91 years (interquartile range, 2.81 to 6.98), 271 out of 6,103 patients developed all-site cancer. At baseline, patients with incident cancers were older, had longer disease duration of diabetes, higher alcohol and tobacco use, and higher systolic blood pressure and albuminuria, but lower triglyceride levels and estimated glomerular filtration rate (P <0.05). Patients who developed cancers during follow-up were less likely to have started using statins (22.5% versus 38.6%, P <0.001), fibrates (5.9% versus 10.2%, P = 0.02), metformin (63.8% versus 74.5%, P <0.001) or thiazolidinedione (0.7% versus 6.8%, P <0.001) than those who remained cancer-free. After adjusting for co-variables, new treatment with metformin (hazard ratio: 0.39; 95% confidence interval: 0.25, 0.61; P <0.001), thiazolidinedione (0.18; 0.04, 0.72; P = 0.015), sulphonylurea (0.44; 0.27, 0.73; P = 0.014), insulin (0.58; 0.38, 0.89; P = 0.01), statins (0.47; 0.31, 0.70; P <0.001) and RAS inhibitors (0.55; 0.39, 0.78; P <0.001) were associated with reduced cancer risk. Patients with all three risk factors of HbA1c ≥7%, non-use of RAS inhibitors and non-use of statins had four-fold adjusted higher risk of cancer than those without any risk factors (incidence per 1,000-person-years for no risk factors: 3.40 (0.07, 6.72); one risk factor: 6.34 (4.19, 8.50); two risk factors: 8.40 (6.60, 10.20); three risk factors: 13.08 (9.82, 16.34); P <0.001). Conclusions: Hyperglycemia may promote cancer growth that can be attenuated by optimal glycemic control and inhibition of the RAS and HMGCR pathways. © 2014 Kong et al.; licensee BioMed Central Ltd.


Yang X.,Prince of Wales Hospital | Ma R.C.W.,Prince of Wales Hospital | So W.Y.,Prince of Wales Hospital | Yu L.W.L.,Prince of Wales Hospital | And 9 more authors.
Cancer | Year: 2011

BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have increased cancer risks. The authors reported nonlinear associations of cancer with triglyceride and other lipids in T2DM. Crosstalk between lipid metabolism and the renin-angiotensin system may increase cancer risk via activation of insulin-like growth factor-1 pathway in T2DM. In this analysis, the authors explored associations of cancer risk with high/low triglyceride in T2DM and possible modifying effects of statins on this risk association, if any. METHODS: A consecutive cohort of 5166 Chinese patients with T2DM, free of cancer at enrollment and not using statins at or before enrollment, was analyzed using Cox models. Biological interactions were estimated using relative excess risk because of interaction, attributable proportion because of interaction, and synergy index. Relative excess risk because of interaction >0, attributable proportion because of interaction >0, or synergy index >1 indicates biological interaction. RESULTS: During 5.25 years of follow-up (median), 4.7% (n = 243) patients developed cancer. Triglyceride <1.70 mmol/L was associated with increased cancer risk in the entire cohort and in statin nonusers, but not in statin users. Patients with triglyceride <1.70 mmol/L plus nonuse of statins during follow-up had 2.74-fold increased cancer risk compared with their counterparts with either triglyceride ≥1.70 mmol/L or use of statins or both. There was significant interaction between triglyceride <1.70 mmol/L and nonuse of statins (relative excess risk because of interaction, 0.99; 95% confidence interval [CI], 0.07-1.90 and attributable proportion because of interaction, 0.36; 95% CI, 0.02-0.70). CONCLUSIONS: In Chinese T2DM patients, triglyceride <1.70 mmol/L might be associated with increased cancer risk, which was attenuated in the presence of use of statins. © 2010 American Cancer Society.


Ma R.C.W.,Hong Kong Institute of Diabetes and Obesity | Ma R.C.W.,Chinese University of Hong Kong | Lin X.,CAS Shanghai Institutes for Biological Sciences | Jia W.,Shanghai JiaoTong University
The Lancet Global Health | Year: 2014

The prevalence of diabetes in China has increased substantially over recent decades, with more than 100 million people estimated to be affected by the disease presently. During this period there has been an increase in the rates of obesity and a reduction in physical activity. Many of the changes in lifestyle and diet are a result of increased economic development and urbanisation. In addition to an increasingly westernised diet, the traditional Chinese diet also plays a part, with the quantity and quality of rice intake linked to the risk of type 2 diabetes. Familial factors including inherited genetic variants are important, although differences in the genetic architecture suggest a different combination of genetic variants could be most relevant in Chinese when compared with Europeans. Recent advances have also emphasised the role of early life factors in the epidemic of diabetes and non-communicable diseases: maternal undernutrition, maternal obesity, and gestational diabetes are all linked to increased risk of diabetes in offspring. A mismatch between developmentally programmed biology and the modern environment is relevant for countries like China where there has been rapid economic transformation. Multisectoral efforts to address the risks will be needed at different stages throughout the lifecourse to reduce the burden of diabetes. © 2014 Elsevier Ltd.


Fan R.,Chinese University of Hong Kong | Kang Z.,Chinese University of Hong Kong | He L.,Chinese University of Hong Kong | Chan J.,Chinese University of Hong Kong | And 3 more authors.
PLoS ONE | Year: 2011

Aims: Type 2 diabetes is highly prevalent in the elderly population. Glucagon like Peptide-1 mimetic such as exendin-4 augments post-prandial insulin secretion. However, the potential influence of aging on the therapeutic effects of this peptide has not been well studied. In this study, we examined the glucose regulatory effects of exendin-4 in mice with different ages. Methods: We treated 3-month and 20 to 22-month old C57/DBA mice with 10 nM/kg exendin-4 for 10 days with measurements of blood glucose and body weight. We performed OGTT and ITT to evaluate the glucose response and insulin sensitivity. Islet morphology and beta cell mass were measured by immuno-staining and beta cell proliferation was evaluated by BrdU incorporation and PCNA staining. Real-time PCR and western blot were used to measure protein changes in the liver tissue after exendin-4 treatment. Results: Exendin-4 treatment improved glycemic control in both 3-month and 20 to 22-month old mice. In both groups of mice, the blood glucose lowering effect was independent of beta cell function as indicated by unchanged beta cell proliferation, insulin secretion or beta cell mass. Moreover, we found that exendin-4 treatment increased hepatic AKT and FOXO1 phosphorylation and inhibited glucose-6-phosphotase (G6P) and Phosphoenolpyruvate carboxykinase (PEPCK) expression in young mice, but this effect was attenuated in aging mice while the insulin sensitivity showed no change in the young group but significantly improved in aging mice. Conclusion: Based on these data, we conclude that the glucose lowering effect of exendin-4 in normal non-diabetic mice was not blunted by aging. We further showed that although there was slight difference in the glucose modulating mechanism of exendin-4 therapy in young and aged mice, the improved glucose control seemed uncorrelated with increased beta cell mass or insulin secretion. © 2011 Fan et al.


Ma R.C.W.,Hong Kong Institute of Diabetes and Obesity | Ma R.C.W.,International Diabetes Federation | Lin X.,CAS Shanghai Institutes for Biological Sciences | Jia W.,Shanghai JiaoTong University
The Lancet Diabetes and Endocrinology | Year: 2014

The prevalence of diabetes in China has increased substantially over recent decades, with more than 100 million people estimated to be affected by the disease presently. During this period there has been an increase in the rates of obesity and a reduction in physical activity. Many of the changes in lifestyle and diet are a result of increased economic development and urbanisation. In addition to an increasingly westernised diet, the traditional Chinese diet also plays a part, with the quantity and quality of rice intake linked to the risk of type 2 diabetes. Familial factors including inherited genetic variants are important, although differences in the genetic architecture suggest a different combination of genetic variants could be most relevant in Chinese when compared with Europeans. Recent advances have also emphasised the role of early life factors in the epidemic of diabetes and non-communicable diseases: maternal undernutrition, maternal obesity, and gestational diabetes are all linked to increased risk of diabetes in offspring. A mismatch between developmentally programmed biology and the modern environment is relevant for countries like China where there has been rapid economic transformation. Multisectoral efforts to address the risks will be needed at different stages throughout the lifecourse to reduce the burden of diabetes. © 2014 Elsevier Ltd.


Zhou J.-W.,Chinese University of Hong Kong | Tsui S.K.W.,Chinese University of Hong Kong | Ng M.C.Y.,Wake forest University | Geng H.,Chinese University of Hong Kong | And 10 more authors.
PLoS ONE | Year: 2011

This study aimed at substantiating the associations of the apolipoproein M gene (APOM) with type 2 diabetes (T2D) as well as with metabolic traits in Hong Kong Chinese. In addition, APOM gene function was further characterized to elucidate its activity in cholesterol metabolism. Seventeen APOM SNPs documented in the NCBI database were genotyped. Five SNPs were confirmed in our study cohort of 1234 T2D and 606 control participants. Three of the five SNPs rs707921(C+1871A), rs707922(G+1837T) and rs805264(G+203A) were in linkage disequilibrium (LD). We chose rs707922 to tag this LD region for down stream association analyses and characterized the function of this SNP at molecular level. No association between APOM and T2D susceptibility was detected in our Hong Kong Chinese cohort. Interestingly, the C allele of rs805297 was significantly associated with T2D duration of longer than 10 years (OR = 1.245, p = 0.015). The rs707922 TT genotype was significantly associated with elevated plasma total- and LDL- cholesterol levels (p = 0.006 and p = 0.009, respectively) in T2D patients. Molecular analyses of rs707922 lead to the discoveries of a novel transcript APOM5 as well as the cryptic nature of exon 5 of the gene. Ectopic expression of APOM5 transcript confirmed rs707922 allele-dependent activity of the transcript in modifying cholesterol homeostasis in vitro. In conclusion, the results here did not support APOM as a T2D susceptibility gene in Hong Kong Chinese. However, in T2D patients, a subset of APOM SNPs was associated with disease duration and metabolic traits. Further molecular analysis proved the functional activity of rs707922 in APOM expression and in regulation of cellular cholesterol content. © 2011 Zhou et al.


Zhao H.,Chinese University of Hong Kong | Guan J.,Chinese University of Hong Kong | Lee H.-M.,Chinese University of Hong Kong | Sui Y.,Chinese University of Hong Kong | And 7 more authors.
Pancreas | Year: 2010

Objectives: The aim of this study was to examine correlations of the islet-specific microRNA-375 expression to islet amyloid formation and pancreatic islet damage in human type 2 diabetes. Methods: Autopsy pancreas samples from 40 type 2 diabetic and 15 nondiabetic patients were used to detect microRNA-375 expression using real-time quantitative polymerase chain reaction. Serial paraffin sections of the corresponding type 2 diabetic and nondiabetic cases were stained by immunofluorescence to evaluate for amylin expression, amyloid formation, and proportions of α and β cells. Results: Pancreatic microRNA-375 expression was increased in type 2 diabetic patients comparing with the nondiabetic patients (median, 4.02 for the diabetic patients vs 0.92 for the nondiabetic patients; P = 0.0001). The median was 6.14 for the diabetic patients with islet amyloid and 3.51 for islet amyloid-free diabetic patients. The expression level of microRNA-375 correlated positively with the frequency and the severity of islet amyloid formation and negatively with proportions of islet β-cells and amylin-positive area, and islet mitochondria density. Conclusions: Up-regulated microRNA-375 is associated with type 2 diabetes and pancreatic islet amyloid formation and β-cell deficit. microRNA-375 may serve as a biomarker for known and novel pathways in the pathogenesis of type 2 diabetes related to islet amyloid deposition and β-cell dysfunction. Copyright © 2010 by Lippincott Williams & Wilkins.


Gao W.G.,University of Helsinki | Gao W.G.,Finnish National Institute for Health and Welfare | Gao W.G.,Qingdao Endocrinology and Diabetes Hospital | Dong Y.H.,Qingdao Endocrinology and Diabetes Hospital | And 11 more authors.
Diabetic Medicine | Year: 2010

Aims: A diabetes risk score for screening undiagnosed diabetes was constructed and validated in Chinese adults. Methods: Two consecutive population-based diabetes surveys among Chinese adults aged 20-74 years were conducted in 2002 (n = 1986) and 2006 (n = 4336). Demographic and anthropometric measures were collected following similar procedures. Standard 2-h 75-g oral glucose tolerance tests (OGTTs) were performed to diagnose diabetes in both surveys. Fasting capillary plasma glucose (FCG) and glycated haemoglobin (HbA1c) were also measured together with the OGTTs on the same day of the 2006 survey. Beta coefficients estimated using logistic regression analysis derived from data of the 2002 survey were used to develop the risk assessment algorithm. The performance of the algorithm was validated in the study population of the 2006 survey. Results: Of all the variables tested, waist circumference, age and family history of diabetes were significant predictors of diabetes and were used to construct the risk assessment score. The score, ranging from 3 to 32, performed well when applied to the study population of the 2006 survey. The area under the receiver operating characteristic curve was 67.3% (95% CI, 64.9-69.7%) for the score, while it was 76.3% (73.5-79.0%) for FCG alone and 67.8% (64.9-70.8%) for HbA1c alone. At a cut-off point of 14, the sensitivity and specificity of the risk score were 84.2% (81.0-87.5%) and 39.8% (38.2-41.3%). Conclusions: The risk score based on age, waist circumference and family history of diabetes is efficient as a layperson-oriented diabetes screening tool for health promotion and for population-based screening programmes. © 2010 The Authors.


PubMed | Chinese University of Hong Kong, The Association for the Improvement of Mental Health Programmes and Hong Kong Institute of Diabetes and Obesity
Type: | Journal: BMC psychiatry | Year: 2015

The validity of the 20-item Center for Epidemiological Studies Depression (CES-D) scale for depression screening in Hong Kong Chinese patients with type 2 diabetes remains unknown. We aimed to validate CES-D, compare its psychometric properties with the 9-item Patient Health Questionnaire (PHQ-9), and explore whether one of the two is more suitable for depression screening in Chinese patients with type 2 diabetes.Between June 2010 and July 2011, 545 consecutive Chinese patients with type 2 diabetes who underwent structured comprehensive assessments completed the CES-D and PHQ-9. Forty patients were retested within 2-4 weeks by telephone interview and 97 patients were randomly selected to undergo the Mini International Neuropsychiatric Interview (MINI) by psychiatrists for clinical diagnosis of depression.The internal consistency (Cronbachs ) of CES-D was 0.85, with a test-retest correlation coefficient of 0.64. The area under the curve for CES-D compared to the clinical diagnosis of major depression was 0.85. A cut-off score of 21 for CES-D provided the optimal balance between sensitivity (78.3 %) and specificity (74.3 %) and identified 17.8 % (n = 97) of patients with depression. CES-D and PHQ-9 showed moderate agreement in depression screening (Cohens Kappa: 0.45). Compared to non-depressed patients, those who screened positive by PHQ-9 had a higher HbA1c whereas the glycemic differences were not significant when using CES-D.The CES-D is a valid screening tool for depression in Chinese type 2 diabetic patients although the PHQ-9 was more discriminative in identifying those with suboptimal glycemic control.

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