Association of technologically assisted integrated care with clinical outcomes in type 2 diabetes in Hong Kong using the prospective JADE Program: A retrospective cohort analysis.

BACKGROUND: Diabetes outcomes are influenced by host factors, settings, and care processes. We examined the association of data-driven integrated care assisted by information and communications technology (ICT) with clinical outcomes in type 2 diabetes in public and private healthcare settings. METHODS AND FINDINGS: The web-based Joint Asia Diabetes Evaluation (JADE) platform provides a protocol to guide data collection for issuing a personalized JADE report including risk categories (1-4, low-high), 5-year probabilities of cardiovascular-renal events, and trends and targets of 4 risk factors with tailored decision support. The JADE program is a prospective cohort study implemented in a naturalistic environment where patients underwent nurse-led structured evaluation (blood/urine/eye/feet) in public and private outpatient clinics and diabetes centers in Hong Kong. We retrospectively analyzed the data of 16,624 Han Chinese patients with type 2 diabetes who were enrolled in 2007-2015. In the public setting, the non-JADE group (n = 3,587) underwent structured evaluation for risk factors and complications only, while the JADE (n = 9,601) group received a JADE report with group empowerment by nurses. In a community-based, nurse-led, university-affiliated diabetes center (UDC), the JADE-Personalized (JADE-P) group (n = 3,436) received a JADE report, personalized empowerment, and annual telephone reminder for reevaluation and engagement. The primary composite outcome was time to the first occurrence of cardiovascular-renal diseases, all-site cancer, and/or death, based on hospitalization data censored on 30 June 2017. During 94,311 person-years of follow-up in 2007-2017, 7,779 primary events occurred. Compared with the JADE group (136.22 cases per 1,000 patient-years [95% CI 132.35-140.18]), the non-JADE group had higher (145.32 [95% CI 138.68-152.20]; P = 0.020) while the JADE-P group had lower event rates (70.94 [95% CI 67.12-74.91]; P < 0.001). The adjusted hazard ratios (aHRs) for the primary composite outcome were 1.22 (95% CI 1.15-1.30) and 0.70 (95% CI 0.66-0.75), respectively, independent of risk profiles, education levels, drug usage, self-care, and comorbidities at baseline. We reported consistent results in propensity-score-matched analyses and after accounting for loss to follow-up. Potential limitations include its nonrandomized design that precludes causal inference, residual confounding, and participation bias. CONCLUSIONS: ICT-assisted integrated care was associated with a reduction in clinical events, including death in type 2 diabetes in public and private healthcare settings.

Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes.

We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.

Predictive role of multilocus genetic polymorphisms in cardiovascular disease and inflammation-related genes on chronic kidney disease in Type 2 diabetes--an 8-year prospective cohort analysis of 1163 patients.

BACKGROUND: Chinese diabetic patients are at greater risk of developing chronic kidney disease (CKD) than Caucasian counterparts. In this hypothesis-generating study, we examined the independent and joint effects of multiple genetic variants on CKD in a prospective Chinese cohort of Type 2 diabetic patients. METHODS: Seventy-seven single-nucleotide polymorphisms (SNPs) of 54 candidate genes for cardiorenal diseases and inflammation were genotyped in 1163 patients with no past history of CKD at baseline. CKD was defined as the first estimated glomerular filtration rate <60 mL/min/1.73 m(2) or the first hospitalization with a diagnosis of renal disease. RESULTS: In Cox-regression analysis, 15 SNPs of 13 genes were associated with incident CKD. After correction for multiple comparisons, 6 SNPs including PON1 55Met, PON2 311Cys CETP-629C, ITGA2 873A, LTA 26Asn and LTA 252Gly remained independently associated with CKD, with respective hazard ratios (95% confidence interval):2.6 (1.4-4.8, P = 0.002), 1.5 (1.2-1.9, P = 0.003), 1.4 (1.1-1.7, P = 0.001), 2.2 (1.3-3.7, P = 0.002), 1.6 (1.1-2.2, P = 0.008) and 1.5 (1.1-2.1, P = 0.019). Analysis of joint effect of the six SNPs showed stepwise increase in risk of CKD with the accumulation of risk alleles and weighted genetic risk score (P(trend) = 8.9 × 10(-7) and 4.0 × 10(-5), respectively). CONCLUSIONS: In Type 2 diabetes, there are independent and joint effects of multiple genetic variants on risk of CKD. Risk associations with PON1, PON2, CETP, ITGA2 and LTA genetic polymorphisms underline the importance of lipid metabolism, haemostasis and inflammation in the development of CKD in patients with Type 2 diabetes.

Renin-angiotensin system activation in renal adipogenesis.

The kidney is one of the major organs involved in whole-body homeostasis while chronic renal impairment usually leads to fat redistribution and hyperlipidemia. The aim of this study was to elucidate the role of tissue renal renin-angiotensin system (RAS) components, lipogenic peroxisome proliferator-activated receptor-gamma (PPARgamma), and cytokine TNF-alpha in the development of ectopic adipogenesis and lipid deposition. Adult male Sprague-Dawley rats were randomized into three groups: untreated uninephrectomized (UNX) rats, UNX rats treated with an angiotensin-converting enzyme inhibitor (ACEI), lisinopril, and sham-operated rats. All animals were euthanized at 10 mo postoperation. The untreated UNX rats showed increased protein expression of renin, angiotensinogen, PPARgamma, and the angiotensin II type 2 receptor (AT2R) but reduced protein expression of AT1R and TNF-alpha in their remnant kidneys. Immunofluorescence staining revealed increased reactivity of angiotensinogen and angiotensin I/II in renal tubular cells and adipocytes of the untreated UNX rats. ACEI treatment largely prevented these disorders in association with restored normolipidemia and normalized renal adipogenesis and lipid deposition. These findings support the notion that tissue RAS, PPARgamma, and TNF-alpha collectively play an important role in the renal adipogenesis and lipid metabolism.

Lipid control and use of lipid-regulating drugs for prevention of cardiovascular events in Chinese type 2 diabetic patients: a prospective cohort study.

BACKGROUND: Dyslipidaemia is an important but modifiable risk factor of cardiovascular disease (CVD) in type 2 diabetes. Yet, the effectiveness of lipid regulating drugs in Asians is lacking. We examined the effects of lipid control and treatment with lipid regulating drugs on new onset of CVD in Chinese type 2 diabetic patients. METHODS: In this prospective cohort consisting of 4521 type 2 diabetic patients without history of CVD and naïve for lipid regulating treatment recruited consecutively from 1996 to 2005, 371 developed CVD after a median follow-up of 4.9 years. We used Cox proportional hazard regression to obtain the hazard ratios (HR) of lipids and use of lipid regulating drugs for risk of CVD. RESULTS: The multivariate-adjusted HR (95% confidence interval) of CVD in patients with high LDL-cholesterol (≥ 3.0 mmol/L) was 1.36 (1.08 - 1.71), compared with lower values. Using the whole range value of HDL-cholesterol, the risk of CVD was reduced by 41% with every 1 mmol/L increase in HDL-cholesterol. Plasma triglyceride did not predict CVD. Statins use was associated with lower CVD risk [HR = 0.66 (0.50 - 0.88)]. In sub-cohort analysis, statins use was associated with a HR of 0.60 (0.44 - 0.82) in patients with high LDL-cholesterol (≥ 3.0 mmol/L) and 0.49 (0.28 - 0.88) in patients with low HDL-cholesterol. In patients with LDL-cholesterol < 3.0 mmol/L, use of fibrate was associated with HR of 0.34 (0.12 - 1.00). Only statins were effective in reducing incident CVD in patients with metabolic syndrome [(HR = 0.58(0.42 - 0.80)]. CONCLUSIONS: In Chinese type 2 diabetic patients, high LDL-cholesterol and low HDL-cholesterol predicted incident CVD. Overall, patients treated with statins had 40-50% risk reduction in CVD compared to non-users.

From design to implementation--the Joint Asia Diabetes Evaluation (JADE) program: a descriptive report of an electronic web-based diabetes management program.

BACKGROUND: The Joint Asia Diabetes Evaluation (JADE) Program is a web-based program incorporating a comprehensive risk engine, care protocols, and clinical decision support to improve ambulatory diabetes care. METHODS: The JADE Program uses information technology to facilitate healthcare professionals to create a diabetes registry and to deliver an evidence-based care and education protocol tailored to patients' risk profiles. With written informed consent from participating patients and care providers, all data are anonymized and stored in a databank to establish an Asian Diabetes Database for research and publication purpose. RESULTS: The JADE electronic portal (e-portal: http://www.jade-adf.org) is implemented as a Java application using the Apache web server, the mySQL database and the Cocoon framework. The JADE e-portal comprises a risk engine which predicts 5-year probability of major clinical events based on parameters collected during an annual comprehensive assessment. Based on this risk stratification, the JADE e-portal recommends a care protocol tailored to these risk levels with decision support triggered by various risk factors. Apart from establishing a registry for quality assurance and data tracking, the JADE e-portal also displays trends of risk factor control at each visit to promote doctor-patient dialogues and to empower both parties to make informed decisions. CONCLUSIONS: The JADE Program is a prototype using information technology to facilitate implementation of a comprehensive care model, as recommended by the International Diabetes Federation. It also enables health care teams to record, manage, track and analyze the clinical course and outcomes of people with diabetes.

Genetic variants of the protein kinase C-beta 1 gene and development of end-stage renal disease in patients with type 2 diabetes.

CONTEXT: Protein kinase C-beta (PKC-beta) is a cell-signaling intermediate implicated in development of diabetic complications. OBJECTIVE: To examine the risk association of PKC-beta 1 gene (PRKCB1) polymorphisms and end-stage renal disease (ESRD) in an 8-year prospective cohort of Chinese patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS: We genotyped 18 common tag single-nucleotide polymorphisms (SNPs) that span the PRKCB1 gene (r(2) = 0.80) in 1172 Chinese patients (recruited 1995-1998) without renal disease at baseline. A validation cohort included an additional 1049 patients with early-onset diabetes who were free of renal disease at baseline and were recruited after 1998. MAIN OUTCOME MEASURES: Associations of PRKCB1 polymorphisms under additive, dominant, and recessive genetic models with new onset of ESRD (defined as estimated glomerular filtration rate <15 mL/min/1.73 m(2) or dialysis or renal-related death) were assessed by Cox proportional hazard regression, adjusted for all conventional risk factors including use of medications. RESULTS: After a mean (SD) of 7.9 (1.9) years, 90 patients (7.7%) progressed to ESRD. Four common SNPs were associated with ESRD (P < .05). The closely linked T allele at rs3760106 and G allele rs2575390 (r(2) = 0.98) showed the strongest association with ESRD (hazard ratio [HR], 2.25; 95% confidence interval [CI], 1.31-3.87; P = .003, and HR, 2.26; 95% CI, 1.31-3.88; P = .003, respectively). Four common variants predicted ESRD in separate models. The HR for ESRD increased with increasing number of risk alleles (P < .001) in the joint effect analysis. The adjusted risk for ESRD was 6.04 (95% CI, 2.00-18.31) for patients with 4 risk alleles compared with patients with 0 or 1 risk allele. Incidence was 4.4 per 1000 person-years (95% CI, 0.5-8.2) among individuals with 0 or 1 risk allele compared with 20.0 per 1000 person-years (95% CI, 8.8-31.1) in those carrying 4 risk alleles (6.9% of the cohort). These results were validated in a separate prospective cohort of young-onset diabetic patients. Of 1049 patients in the validation cohort, 151 (14.3%) developed chronic kidney disease (CKD) during follow-up, and there were significant associations between both the T allele of rs3760106 and the G allele of rs2575390 and development of CKD (HR, 1.68; 95% CI, 1.10-2.57; P = .02, and HR, 1.62; 95% CI, 1.07-2.47; P = .02, respectively). CONCLUSION: Genetic variants in the PRKCB1 gene were independently associated with development of ESRD in Chinese patients with type 2 diabetes.

Lack of benefits for prevention of cardiovascular disease with aspirin therapy in type 2 diabetic patients--a longitudinal observational study.

BACKGROUND: The risk-benefit ratio of aspirin therapy in prevention of cardiovascular disease (CVD) remains contentious, especially in type 2 diabetes. This study examined the benefit and harm of low-dose aspirin (daily dose < 300 mg) in patients with type 2 diabetes. METHODS: This is a longitudinal observational study with primary and secondary prevention cohorts based on history of CVD at enrollment. We compared the occurrence of primary composite (non-fatal myocardial infarction or stroke and vascular death) and secondary endpoints (upper GI bleeding and haemorrhagic stroke) between aspirin users and non-users between January 1995 and July 2005. RESULTS: Of the 6,454 patients (mean follow-up: median [IQR]: 4.7 [4.4] years), usage of aspirin was 18% (n = 1,034) in the primary prevention cohort (n = 5731) and 81% (n = 585) in the secondary prevention cohort (n = 723). After adjustment for covariates, in the primary prevention cohort, aspirin use was associated with a hazard-ratio of 2.07 (95% CI: 1.66, 2.59, p < 0.001) for primary endpoint. There was no difference in CVD event rate in the secondary prevention cohort. Overall, aspirin use was associated with a hazard-ratio of 2.2 (1.53, 3.15, p < 0.001) of GI bleeding and 1.71 (1.00, 2.95, p = 0.051) of haemorrhagic stroke. The absolute risk of aspirin-related GI bleeding was 10.7 events per 1,000 person-years of treatment. CONCLUSION: In Chinese type 2 diabetic patients, low dose aspirin was associated with a paradoxical increase in CVD risk in primary prevention and did not confer benefits in secondary prevention. In addition, the risk of GI bleeding in aspirin users was rather high.

Expression and subcellular targeting of human insulin-like growth factor binding protein-3 in transgenic tobacco plants.

Human insulin-like growth factor binding protein-3 (hIGFBP-3) is a multifunctional protein which has high affinity for insulin-like growth factor-I (IGF-I). It combines with IGF-I to form a tertiary complex in circulation, thus regulating the activity of IGF-I. Furthermore, recombinant hIGFBP-3 (rhIGFBP-3) has been found to negatively regulate cell proliferation and induce apoptosis. In this study, we have established an efficient plant bioreactor platform for mass production of rhIGFBP-3. Different expression constructs, driven by the seed-specific phaseolin promoter, were designed and transformed into tobacco plant via Agrobacterium. To enhance protein expression level, the signal peptide (SP) and the C-terminal tetrapeptide AFVY of phaseolin were used to direct rhIGFBP-3 to protein storage vacuole (PSV) in tobacco seed for stable accumulation. Western blot analysis showed that rhIGFBP-3 was successfully synthesized in transgenic tobacco seeds, with the highest protein expression of 800 mug/g dry weight. The localization of rhIGFBP-3 in PSV was also evident by confocal immunofluorescence microscopy. Our results indicated that protein sorting sequences could benefit the expression level of rhIGFBP-3 and it is feasible to use plant as "bio-factory" to produce therapeutic recombinant proteins in large quantity.

Apolipoprotein E polymorphism and expression in type 2 diabetic patients with nephropathy: clinicopathological correlation.

BACKGROUND: Diabetic nephropathy represents a heterogeneous group of renal pathologies that may be associated with genetic susceptibility. There have been clinical reports on the risk association of diabetic nephropathy with an apolipoprotein E (ApoE) exon 4 polymorphism although its correlations with renal histopathological changes have not been explored. METHODS: A total of 213 adult autopsies with type 2 diabetes and 111 non-diabetic control cases were analysed. Genomic DNA samples were obtained from spleen tissues. The ApoE genotype was determined by PCR-LDR analysis. Histopathological examination of kidney sections was performed in a subset of 51 diabetic and 111 control cases. ApoE protein expression in diabetic carriers with similar clinical status was examined by immunohistochemical staining. RESULTS: In type 2 diabetes, epsilon2 carriers (P = 0.04; odds ratio = 5.42; 95% CI: 1.10-26.8) and epsilon3/epsilon4 (P = 0.04; odds ratio = 22.5; 95% CI: 1.11-454.90) genotype carriers were more likely to have glomerular hypertrophy than were epsilon3/epsilon3 carriers. The epsilon2 carriers showed an increase in glomerular ApoE protein expression. A correlation between ApoE genotype and nodular glomerulosclerosis was not found. CONCLUSIONS: Our findings confirm the risk association of the ApoE polymorphism with diabetic nephropathy in clinical studies and is the first study demonstrating the correlations between ApoE genotypes, protein expression and structural changes in diabetic nephropathy.

Effect of interactions between C peptide levels and insulin treatment on clinical outcomes among patients with type 2 diabetes mellitus.

BACKGROUND: A recently halted clinical trial showed that intensive treatment of type 2 diabetes mellitus was associated with increased mortality. Given the phenotypic heterogeneity of diabetes, therapy targeted at insulin status may maximize benefits and minimize harm. METHODS: In this longitudinal cohort study, we followed 503 patients with type 2 diabetes who were free of cardiovascular disease from 1996 until data on mortality and cardiovascular outcomes were censored in 2005. Phenotype-targeted therapy was defined as use of insulin therapy in patients with a fasting plasma C peptide level of 0.2 nmol/L or less and no insulin therapy in patients with higher C peptide levels. RESULTS: The mean age of the cohort was 54.4 (standard deviation 13.1) years, and 56% were women. The mean duration of diabetes was 4.6 years (range 0-35.9 years). Of the 503 patients, 110 (21.9%) had a low C peptide level and 111 (22.1%) were given insulin. Based on their C peptide status, 338 patients (67.2%) received phenotype-targeted therapy (non-insulin-treated, high C peptide level [n = 310] or insulin-treated, low C peptide level [n = 28]), and 165 patients (32.8%) received non-phenotype-targeted therapy (non-insulin-treated, low C peptide level [n = 82] or insulin-treated, high C peptide level [n = 83]). Compared with the insulin-treated, low-C-peptide referent group, the insulin-treated, high-C-peptide group was at a significantly higher risk of cardiovascular events (hazard ratio [HR] 2.85, p = 0.049) and death (HR 3.43, p = 0.043); the risk was not significantly higher in the other 2 groups. These differences were no longer significant after adjusting for age, sex and diabetes duration. INTERPRETATION: Patients with low C peptide levels who received insulin had the best clinical outcomes. Patients with normal to high C peptide levels who received insulin had the worst clinical outcomes. The results suggest that phenotype-targeted insulin therapy may be important in treating diabetes.

Development and validation of an all-cause mortality risk score in type 2 diabetes.

BACKGROUND: Diabetes reduces life expectancy by 10 to 12 years, but whether death can be predicted in type 2 diabetes mellitus remains uncertain. METHODS: A prospective cohort of 7583 type 2 diabetic patients enrolled since 1995 were censored on July 30, 2005, or after 6 years of follow-up, whichever came first. A restricted cubic spline model was used to check data linearity and to develop linear-transforming formulas. Data were randomly assigned to a training data set and to a test data set. A Cox model was used to develop risk scores in the test data set. Calibration and discrimination were assessed in the test data set. RESULTS: A total of 619 patients died during a median follow-up period of 5.51 years, resulting in a mortality rate of 18.69 per 1000 person-years. Age, sex, peripheral arterial disease, cancer history, insulin use, blood hemoglobin levels, linear-transformed body mass index, random spot urinary albumin-creatinine ratio, and estimated glomerular filtration rate at enrollment were predictors of all-cause death. A risk score for all-cause mortality was developed using these predictors. The predicted and observed death rates in the test data set were similar (P > .70). The area under the receiver operating characteristic curve was 0.85 for 5 years of follow-up. Using the risk score in ranking cause-specific deaths, the area under the receiver operating characteristic curve was 0.95 for genitourinary death, 0.85 for circulatory death, 0.85 for respiratory death, and 0.71 for neoplasm death. CONCLUSIONS: Death in type 2 diabetes mellitus can be predicted using a risk score consisting of commonly measured clinical and biochemical variables. Further validation is needed before clinical use.

Protein kinase Czeta mediates insulin-induced glucose transport through actin remodeling in L6 muscle cells.

Protein kinase C (PKC) zeta has been implicated in insulin-induced glucose uptake in skeletal muscle cell, although the underlying mechanism remains unknown. In this study, we investigated the effect of PKCzeta on actin remodeling and glucose transport in differentiated rat L6 muscle cells expressing myc-tagged glucose transporter 4 (GLUT4). On insulin stimulation, PKCzeta translocated from low-density microsomes to plasma membrane accompanied by increase in GLUT4 translocation and glucose uptake. Z-scan confocal microscopy revealed a spatial colocalization of relocated PKCzeta with the small GTPase Rac-1, actin, and GLUT4 after insulin stimulation. The insulin-mediated colocalization, PKCzeta distribution, GLUT4 translocation, and glucose uptake were inhibited by wortmannin and cell-permeable PKCzeta pseudosubstrate peptide. In stable transfected cells, overexpression of PKCzeta caused an insulin-like effect on actin remodeling accompanied by a 2.1-fold increase in GLUT4 translocation and 1.7-fold increase in glucose uptake in the absence of insulin. The effects of PKCzeta overexpression were abolished by cell-permeable PKCzeta pseudosubstrate peptide, but not wortmannin. Transient transfection of constitutively active Rac-1 recruited PKCzeta to new structures resembling actin remodeling, whereas dominant negative Rac-1 prevented the insulin-mediated PKCzeta translocation. Together, these results suggest that PKCzeta mediates insulin effect on glucose transport through actin remodeling in muscle cells.

Predicting values of lipids and white blood cell count for all-site cancer in type 2 diabetes.

Type 2 diabetic patients have increased cancer risk. We developed and validated an all-site cancer risk score in a prospective cohort of 7374 Chinese type 2 diabetic patients free of known history of cancer at enrolment, using split-half validation. Spline Cox model was used to detect common risk factors of cancer and to guide linear transformation of non-linear risk factors. After a median follow-up period of 5.45 years, 365 patients (4.95%) developed cancer. Body mass index (BMI; <24.0 or > or =27.6 kg/m2), triglyceride (> or =0.81 to <1.41 mmol/l), high-density lipoprotein cholesterol (<0.9 or > or =1.8 mmol/l), total cholesterol (<4.3 mmol/l) and white blood cell (WBC) count (<5.8x10(9) count per litre) were associated with increased cancer risks and exhibited non-linear relationships. We further linear transformed these terms for selection using backward Cox regression (P<0.05 for stay) in the training dataset. In the test dataset, calibration was checked using Hosmer-Lemeshow test and discrimination checked using area under receiver operating characteristic curve. In addition to age and current smoking, only linear-transformed total cholesterol and WBC count were selected. The risk score was 0.0488xage (years)-0.5810xtotal cholesterol (mmol/l, coded to 4.3 if >4.3)-0.3596xWBC count (10(9) counts/l, 5.8 if >5.8)+0.6390xcurrent smoking status (1 if yes). The 5-year probability of cancer was 1-0.9590(EXP(0.9382x(RISK SCORE+1.5903))). The predicted cancer probability was not significantly different from the observed cancer probability during the 5-year follow-up. The adjusted area under receiver operating characteristic curve was 0.712. In conclusion, BMI, lipids and WBC count have predicting values for cancer.

Fat redistribution and adipocyte transformation in uninephrectomized rats.

Dyslipidemia complicates renal function leading to disturbances of major homeostatic organs in the body. Here we examined the effect of chronic renal dysfunction induced by uninephrectomy on fat redistribution and lipid peroxidation in rats treated with an angiotensin-converting enzyme (ACE) inhibitor (lisinopril) for up to 10 months. Uninephrectomized rats developed fat redistribution and hypercholesterolemia typical of chronic renal failure when compared with sham-operated rats or lisinopril-treated uninephrectomized rats. The weight of the peri-renal fat was significantly less in the untreated compared to the lisinopril-treated uninephrectomized rats or those rats with a sham operation. We also found that there was a shift of heat-protecting unilocular adipocytes to heat-producing multilocular fat cells in the untreated uninephrectomized rats. Similarly in these rats we found a shift of subcutaneous and visceral fat to ectopic fat with excessive lipid accumulation and lipofuscin pigmentation. Lisinopril treatment prevented fat redistribution or transformation and lipid peroxidation. This study shows that ACE inhibition may prevent the fat anomalies associated with chronic renal dysfunction.

Development and validation of a total coronary heart disease risk score in type 2 diabetes mellitus.

There are no validated risk scores for predicting coronary heart disease (CHD) in Chinese patients with type 2 diabetes mellitus. This study aimed to validate the UKPDS risk engine and, if indicated, develop CHD risk scores. A total of 7,067 patients without CHD at baseline were analyzed. Data were randomly assigned to a training data set and a test data set. Cox models were used to develop risk scores to predict total CHD in the training data set. Calibration was assessed using the Hosmer-Lemeshow test, and discrimination was examined using the area under the receiver-operating characteristic curve in the test data set. During a median follow-up of 5.40 years, 4.97% of patients (n = 351) developed incident CHD. The UKPDS CHD risk engine overestimated the risk of CHD with suboptimal discrimination, and a new total CHD risk score was developed. The developed total CHD risk score was 0.0267 x age (years) - 0.3536 x sex (1 if female) + 0.4373 x current smoking status (1 if yes) + 0.0403 x duration of diabetes (years) - 0.4808 x Log(10) (estimated glomerular filtration rate [ml/min/1.73 m(2)]) + 0.1232 x Log(10) (1 + spot urinary albumin-creatinine ratio [mg/mmol]) + 0.2644 x non-high-density lipoprotein cholesterol (mmol/L). The 5-year probability of CHD = 1 - 0.9616(EXP(0.9440 x [RISK SCORE - 0.7082])). Predicted CHD probability was not significantly different from observed total CHD probability, and the adjusted area under the receiver-operating characteristic curve was 0.74 during 5 years of follow-up. In conclusion, the UKPDS CHD risk engine overestimated the risk of Chinese patients with type 2 diabetes mellitus and the newly developed total CHD risk score performed well in the test data set. External validations are required in other Chinese populations.

Topographical associations between islet endocrine cells and duct epithelial cells in the adult human pancreas.

OBJECTIVES: The pancreatic ducts, endocrine islets and exocrine acini are three functionally related components. From birth to adulthood, the islets and ducts are regarded as independent entities. The objective of this study is to investigate the topographical associations between the islet endocrine cells and duct epithelial cells in the adult human pancreas. MATERIALS AND METHODS: Panels of immunomarkers for the exocrine acinar cells (amylase), duct cells [cytokeratin 19 (CK19)], endocrine cells (chromogranin A, neurone specific enolase, synaptophysin) and islet hormones (glucagon, insulin, somatostatin, pancreatic polypeptide) were applied to sequential pancreatic tissue sections obtained from autopsy specimens of 10-nondiabetic human adults. Double immunofluorescent staining with CK19 and islet hormones was performed to confirm the islet to duct interrelationship. RESULTS: Sequential sectioning and immunostaining showed that 45% of the 172 islets examined appeared as single endocrine cell units or small clusters of < 10 endocrine cells on at least one plane of section. A topographical association was found between the islet endocrine cells and duct epithelial cells. Topographical associations with CK 19-stained duct cells occurred in 10.9% of the islet insulin-containing beta-cells and in 8.9% of the islet glucagon-producing alpha-cells. The frequency of topographical associations increased toward the more distally located duct systems. The CK19-stained duct cells and amylase-labelled acinar cells were less frequently in association with other islet hormone-producing cells. CONCLUSIONS: Topographical associations between islet endocrine cells and pancreatic duct cells are frequent in adult human pancreas. The islet-duct association suggests possible functional interactions between the two interrelated pancreatic compartments.

Development and validation of a risk score for hospitalization for heart failure in patients with Type 2 diabetes mellitus.

BACKGROUND: There are no risk scores available for predicting heart failure in Type 2 diabetes mellitus (T2DM). Based on the Hong Kong Diabetes Registry, this study aimed to develop and validate a risk score for predicting heart failure that needs hospitalisation in T2DM. METHODS: 7067 Hong Kong Chinese diabetes patients without history of heart failure, and without history and clinical evidence of coronary heart disease at baseline were analyzed. The subjects have been followed up for a median period of 5.5 years. Data were randomly and evenly assigned to a training dataset and a test dataset. Sex-stratified Cox proportional hazard regression was used to obtain predictors of HF-related hospitalization in the training dataset. Calibration was assessed using Hosmer-Lemeshow test and discrimination was examined using the area under receiver's operating characteristic curve (aROC) in the test dataset. RESULTS: During the follow-up, 274 patients developed heart failure event/s that needed hospitalisation. Age, body mass index (BMI), spot urinary albumin to creatinine ratio (ACR), HbA1c, blood haemoglobin (Hb) at baseline and coronary heart disease during follow-up were predictors of HF-related hospitalization in the training dataset. HF-related hospitalization risk score = 0.0709 x age (year) + 0.0627 x BMI (kg/m2) + 0.1363 x HbA1c(%) + 0.9915 x Log10(1+ACR) (mg/mmol) - 0.3606 x Blood Hb(g/dL) + 0.8161 x CHD during follow-up (1 if yes). The 5-year probability of heart failure = 1-S0(5)EXP{0.9744 x (Risk Score - 2.3961)}. Where S0(5) = 0.9888 if male and 0.9809 if female. The predicted and observed 5-year probabilities of HF-related hospitalization were similar (p > 0.20) and the adjusted aROC was 0.920 for 5 years of follow-up. CONCLUSION: The risk score had adequate performance. Further validations in other cohorts of patients with T2DM are needed before clinical use.

Independent associations between low-density lipoprotein cholesterol and cancer among patients with type 2 diabetes mellitus.

BACKGROUND: The risk association between low-density lipoprotein (LDL) cholesterol and cancer remains controversial and largely unexplored for people not receiving statin therapy. METHODS: We examined the risk association between LDL cholesterol and cancer among patients with type 2 diabetes mellitus who were free of cancer at enrolment and whose statin use was known. We considered a variety of nonlinear relationships in our analysis. RESULTS: During a median follow-up period of 4.90 years, cancer developed in 270 (4.4%) of 6107 patients. Among the 3800 patients who did not receive statin therapy, the risk association between LDL cholesterol and cancer was represented by a V-shaped curve. Compared with patients whose LDL cholesterol was at least 2.80 mmol/L but less than 3.80 mmol/L, the risk of cancer, death from any cause or the composite outcome of cancer or death was greater among those with an LDL cholesterol level of less than 2.80 mmol/L (hazard ratio for cancer 1.74, 95% confidence interval [CI] 1.20-2.52) and those with an LDL cholesterol level of 3.80 mmol/L or greater (hazard ratio for cancer 1.87, 95% CI 1.29-2.71). Using 3.8 mmol/L as a reference point, we found that the hazard ratio for cancer for every millimole per litre absolute change in LDL cholesterol was 1.54 (95% CI 1.19-1.99) among patients not using statins; the hazard ratio was reduced to 1.24 (1.01-1.53) for the entire sample (statin users and those not using statins). These associations persisted after adjustment for covariates and exclusion of patients with less than 2.5 years of follow-up. INTERPRETATION: Among patients with type 2 diabetes, the association between LDL cholesterol and cancer was V-shaped, whereby both low and high levels of LDL cholesterol were associated with elevated risk of cancer.

Associations of overweight with insulin resistance, beta-cell function and inflammatory markers in Chinese adolescents.

BACKGROUND: Obesity is a growing global health problem. Obesity-associated inflammatory and metabolic consequences may vary in different ethnic populations, and data in Chinese adolescents are sparse. In this study, we analysed the clinical and biochemical factors associated with overweight and obesity in Chinese adolescents. METHODS: This is a cross-sectional cohort study with 2102 Chinese adolescents randomly selected from 14 secondary schools in Hong Kong. Clinical and biochemical parameters including inflammatory markers, among different groups stratified by degrees of obesity, were compared by multivariate logistic regression analysis. RESULTS: The median age was 16 yr (interquartile range: 14-17 yr) (45.6% boys and 54.4% girls). Among the boys, 16.5% were overweight and 6.8% were obese. The respective percentages in girls were 8.2 and 5.8%. Compared with the group with normal weight in both boys and girls, high systolic blood pressure (SBP), increased insulin resistance (by homoeostasis model assessment, HOMA-IR), elevated high-sensitivity C-reactive protein (hsCRP) level and low high-density lipoprotein cholesterol (HDL-C) level were independently associated with overweight/obesity. In boys, the respective odds ratio (95% CI) was 1.03 (1.01-1.05) for SBP, 21.0 (12.0-36.8) for HOMA-IR, 3.65 (2.10-6.35) for hsCRP and 0.24 (0.11-0.51) for HDL-C. In girls, the respective figures were 1.02 (1.00-1.04), 9.82 (5.65-17.1), 6.28 (3.12-12.6) and 0.18 (0.08-0.41). In girls, low-density lipoprotein cholesterol was also independently associated with overweight/obesity [1.56 (1.09-2.24)]. CONCLUSIONS: In Chinese adolescents, overweight/obesity is independently associated with SBP, insulin resistance, hsCRP and low HDL-C. Early intervention in overweight and obese adolescents may potentially retard the development of these cardiovascular risk factors.