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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.

Background: Body mass index (BMI) is associated with death in a V-shaped manner in general populations but it is unknown whether BMI or other risk factors also exhibit V-shaped relationships with death in type 2 diabetic patients., Methods: A prospective cohort of 7534 Chinese, type 2 diabetic patients enrolled since 1995 were censored on 30 July 2005. Spline Cox regression analysis with a stepwise algorithm (p < 0.05) was used to select predictors. Hazard ratio (HR) curves were used to explore the relationships, which were confirmed by standard Cox models., Results: 763 patients died during the 5.5 years of follow-up. BMI, high-density lipoprotein cholesterol (HDL-C) and white blood cell (WBC) count were related to all-cause mortality in a V-shaped manner. The nadirs of the risk curves were at 26 kg/m(2) for BMI, 1.15 mmol/L for HDL-C and 6.25 x 10(9) counts/L for WBC. The multivariate hazard ratio of BMI away from 26.0 kg/m(2) was 1.08; HDL-C, 1.06 per mmol/L for values less than the nadir and 6.97 per mmol/L for greater than the nadir; and WBC, 1.16 per 10(9) count/L for less than 6.25 x 10(9) and 1.47 for greater than the nadir. Respiratory and neoplastic deaths were the major contributors to the increased death in patients with low or high BMI. Neoplastic death was the major contributor to the increased death in those with low WBC. Genitourinary death was the major contributor to the increased death in those with low and high HDL-C., Conclusion: BMI, HDL-C and WBC are associated with death in a V-shaped manner in type 2 diabetic patients., (Copyright (c) 2008 John Wiley & Sons, Ltd.)

Background: Glycated haemoglobin (HbA1c), blood pressure and body mass index (BMI) are risk factors for albuminuria, the latter in turn can lead to hyperlipidaemia. We used novel statistical analyses to examine how albuminuria and chronic kidney disease (CKD) may influence the effects of other risk factors on coronary heart disease (CHD)., Methods: A prospective cohort of 7067 Chinese type 2 diabetic patients without history of CHD enrolled since 1995 were censored on July 30th, 2005. Cox proportional hazard regression with restricted cubic spline was used to auto-select predictors. Hazard ratio plots were used to examine the risk of CHD. Based on these plots, non-linear risk factors were categorised and the categorised variables were refitted into various Cox models in a stepwise manner to confirm the findings., Results: Age, male gender, duration of diabetes, spot urinary albumin: creatinine ratio, estimated glomerular filtration rate, total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and current smoking status were risk factors of CHD. Linear association between TC and CHD was observed only in patients with albuminuria. Although in general, increased HDL-C was associated with decreased risk of CHD, full-range HDL-C was associated with CHD in an A-shaped manner with a zenith at 1.1 mmol/L. Albuminuria and CKD were the main contributors for the paradoxically positive association between HDL-C and CHD for HDL-C values less than 1.1 mmol/L., Conclusion: In type 2 diabetes, albuminuria plays a linking role between conventional risk factors and CHD. The onset of CKD changes risk associations between lipids and CHD.

Background: To examine the risk of developing impaired glucose regulation (IGR), diabetes mellitus (DM) and metabolic syndrome (MetS) in Chinese women with history of gestational diabetes., Methods: 203 Chinese women enrolled in a previous study were followed up at a median of 8 (range 7-10) years of whom 136 had normal glucose tolerance (NGT) and 68 had gestational diabetes mellitus (GDM) and gestational impaired glucose tolerance (GIGT)., Results: In women with a history of gestational diabetes (n = 4), GIGT (n = 63) and NGT (n = 136), 2 (50%), 19 (30.2%) and 21 (15.4%) developed IGR while 2 (50%), 4 (6.3%), 3 (2.2%) developed DM respectively. Most women developed IGR (86%, n = 36) or DM (78%, n = 7) were undiagnosed. MetS occurred in 16 (7.9%) women with similar rates between those with and those without a history of gestational diabetes (7.5% vs 8.1%; p = 0.85). History of gestational diabetes [OR: 3.8 (95% CI 1.9-7.8)] and body mass index (BMI) >/= 23 kg/m(2) [OR: 3.4 (95% CI 1.7-6.8)] at first antenatal visit were predictors for IGR or DM. Family history of DM [OR: 5.0 (95% CI 1.5-16.4)] and BMI >/= 23 kg/m(2) [OR: 28.3 (95% CI 3.6-223)] at first antenatal visit were predictors for MetS., Conclusions: Chinese women with a history of gestational diabetes have a high risk of IGR or DM. Overweight at the first antenatal visit is a common risk factor for IGR, DM and MetS. A prior history of gestational diabetes was predictive of IGR and DM while a positive family history of DM was predictive of MetS.

Background: It remains unclear whether hyperglycaemia as measured by HbA(1c) is a significant risk factor for stroke in patients with type 2 diabetes mellitus (T2DM)., Methods: A case-control study nested in a prospective cohort with 1 : 3 controls matched on age, gender, systolic blood pressure and low-density lipoprotein cholesterol (LDL-C) was conducted. The case group included 105 patients who developed incident stroke during 2.88 years (SD: 1.59) of follow-up of 4150 T2DM patients and 299 matched patients without incident stroke, used as the control group. Stratified Cox proportional hazard regression was used to obtain hazard ratio (HR)., Results: Median age was 71 years (IQR: 9.0 for the case and 10.0 for the control). HbA(1c) was significantly higher in the cases than in the controls (median 8.0% [IQR: 2.0] versus 7.2% [2.1], p < 0.0001). After controlling for smoker status, haematocrit, drug treatments and other covariates, 1% increase in HbA(1c) was associated with 1.49 (95% CI: 1.18-1.88, p = 0.0008) folds risk of occurrence of incident stroke. Patients with a history of coronary heart disease (CHD) were also at increased risk of stroke (HR: 8.25, 95% CI: 2.22-30.73, p = 0.0016). Smoker status and haematocrit were marginally significant predictors of incident stroke. Every adjusted month using lipid-lowering drugs was significantly associated with reduced risk of incident stroke (HR: 0.95, 95% CI: 0.90-0.99, p = 0.0199). Similar analysis using ACEI or ARB as a drug group was marginally significant (p = 0.0555)., Conclusion: Chronic hyperglycaemia is a risk factor of stroke in Chinese patients with T2DM., ((c) 2007 John Wiley & Sons, Ltd.)

Objective: Thyrotoxic periodic paralysis (TTP) has been associated with genetic variations in the gene encoding the alpha 1 subunit of the L-type calcium channel (CACNA1S). Mutations in CACNA1S are known to account for the majority of cases of familial hypokalaemic periodic paralysis (HOKPP). In this study we have examined 48 genetic polymorphisms in the CACNA1S gene and genotyped a tagging set of representative polymorphisms to determine the role of this gene in TPP., Design and Patients: A genetic association study was carried out with 98 TPP patients and 162 male thyrotoxic controls. Among 47 polymorphisms evaluated for linkage disequilibrium (LD) and the spectrum of haplotypes in the Chinese population, 31 were selected as tagging single-nucleotide polymorphisms (SNPs) for genotyping the whole sample. A new genotyping protocol was used to analyse an insertion/deletion (I/D) polymorphism., Results: We studied the LD among 47 polymorphisms in the CACNA1S gene, which comprised a set of high-density markers with an average of one SNP every 2 kb. Subsequently, 31 tagSNPs were genotyped for all the samples. The gene is composed of three LD blocks. With this block structure, we were confident that variations of the gene were comprehensively covered by the tagSNPs. No significant association was found between the polymorphisms and TPP., Conclusion: We established the LD structure of this calcium channel subunit gene (CACNA1S) for the first time. However, its genetic variations are not associated with TPP in Chinese patients.

Objective: We sought to develop stroke risk equations for Chinese patients with type 2 diabetes in Hong Kong., Research Design and Methods: A total of 7,209 Hong Kong Chinese type 2 diabetic patients without a history of stroke at baseline were analyzed. The data were randomly and evenly divided into the training subsample and the test subsample. In the training subsample, stepwise Cox models were used to develop the risk equation. Validation of the U.K. Prospective Diabetes Study (UKPDS) stroke risk engine and the current stroke equation was performed in the test dataset. The life-table method was used to check calibration, and the area under the receiver operating characteristic curve (aROC) was used to check discrimination., Results: A total of 372 patients developed incident stroke during a median of 5.37 years (interquartile range 2.88-7.78) of follow-up. Age, A1C, spot urine albumin-to-creatinine ratio (ACR), and history of coronary heart disease (CHD) were independent predictors. The performance of the UKPDS stroke engine was suboptimal in our cohort. The newly developed risk equation defined by these four predictors had adequate performance in the test subsample. The predicted stroke-free probability by the current equation was within the 95% CI of the observed probability. The aROC was 0.77 for predicting stroke within 5 years. The risk score was computed as follows: 0.0634 x age (years) + 0.0897 x A1C + 0.5314 x log(10) (ACR) (mg/mmol) + 0.5636 x history of CHD (1 if yes). The 5-year stroke probability can be calculated by: 1 - 0.9707(EXP (Risk Score - 4.5674))., Conclusions: Although the risk equation performed reasonably well in Chinese type 2 diabetic patients, external validation is required in other populations.

Despite the high cardiovascular risk of diabetic patients, there is a paucity of data on isolated systolic hypertension (ISH) in diabetic patients. In this cross-sectional study, we examined the risk of ISH and its associated factors in Chinese type 2 diabetic patients. Isolated systolic hypertension was defined as systolic blood pressure (SBP) > or =140 mm Hg and diastolic blood pressure (DBP) <90 mm Hg. The mean value of two BP measurements taken 1 min apart was used. There were 1048 type 2 diabetic patients recruited from the Prince of Wales Hospital Diabetes Clinic. Another 1043 age- and sex-matched non-diabetic subjects were recruited from the community. The mean age of the 2091 subjects was 40.6 +/- 7.6 years (median: 40 years, range: 16-69 years). Diabetic patients had an increased risk of ISH compared to non-diabetic subjects (7.6% vs. 3.4%, p < 0.001) with an odd ratio of 2.38. On multivariate analysis, age, body mass index, total cholesterol and duration of diabetes in diabetic subjects while age and waist-hip ratio (WHR) in non-diabetic subjects were independently associated with ISH. In conclusion, Chinese type 2 diabetic patients had increased risk to develop ISH than non-diabetic subjects. Age, obesity, lipid and duration of diabetes were independent associated with ISH. These findings suggest that control of body weight and metabolic profile might have beneficial effects on ISH.

Objective: Previous studies have reported associations between two apolipoprotein A-I (apoA-I) gene MspI polymorphisms (G-75A and C83T) and high density lipoprotein (HDL)-cholesterol and/or apoA-I levels, but have not investigated the relationship with obesity., Methods: We determined the distribution of these polymorphisms in 482 early-onset (< or = 40 years) Type 2 Chinese diabetics and 167 Chinese selected healthy controls., Results: The -75A and 83T allele frequencies were similar in the diabetic and healthy subjects. In the healthy control subjects, HDL-cholesterol levels were significantly higher in the AA homozygotes than in the GG/GA carriers (1.74 +/- 0.58 vs. 1.45 +/- 0.58 mmol/l, P<0.001). Furthermore, analyses showed a significant relationship between increasing HDL-cholesterol tertiles and the AA genotype frequency in the selected healthy subjects (3.6, 8.9 and 16.1%, P=0.026). For the C83T polymorphism, healthy male CT carriers had higher HDL-cholesterol levels than CC homozygotes (1.71 +/- 0.57 vs. 1.25 +/- 0.30 mmol/l, P=0.001), but this was not found in females. No relationship between these polymorphisms and lipid levels was found in the diabetics, who had a more adverse lipid profile than the selected controls. In the diabetics, but not the controls, in CT carriers compared to CC homozygotes there were lower levels of body mass index (BMI; 23.8 +/- 3.9 vs. 25.4 +/- 4.7 kg/m2, P=0.048) and waist-to-height ratio (0.49 +/- 0.06 vs. 0.52 +/- 0.07, P=0.023), and this relationship was supported by tertile analysis., Conclusions: The -75AA genotype was associated with higher HDL-cholesterol levels in the selected healthy, but not diabetic, subjects. The 83T allele was associated with greater indices of obesity in the diabetic patients, and with higher HDL-cholesterol in heterozygous healthy male subjects.

Objective: To determine whether clinical outcomes in patients with type 2 diabetes were improved by protocol-driven care in a Diabetes Centre compared with usual outpatient care., Study Design: Descriptive analysis of a prospective cohort., Patients and Methods: During a median 7-year observational period, 91 patients with type 2 diabetes and no cardiovascular or renal complications were monitored by a nurse and a diabetologist in a clinical trial setting according to a structured protocol. Another 81 patients with comparable clinical characteristics were monitored by generalists at the medical clinic in the same hospital. Clinical end points, defined as death and cardiovascular and renal events, were evaluated in 1997 by review of case records., Results: Patients receiving structured care had lower mortality (relative risk [RR] = 0.21; 95% confidence interval [CI] = 0.07, 0.65; P = .006) than the usual-care group, as well as a lower incidence of combined clinical end points (RR = 0.43; 95% CI = 0.22, 0.84; P = .01). In the usual-care group, patients who had no monitoring of glycosylated hemoglobin or plasma lipid levels during the entire observational period (8.6%) had a 14.6-fold (P < .01) and 15.7-fold (P < .01) increased risk of death and combined clinical end points, respectively, compared with those who had at least one measurement (60.5%)., Conclusion: Management by protocol-driven care model improved survival and clinical outcomes in patients with type 2 diabetes. Definitive studies are required to confirm these findings and compare the cost effectiveness of these care models.

The effect of biphosphonate therapy on bone mineral density (BMD) in patients with primary hyperparathyroidism (PHP) is unknown. Forty postmenopausal women (mean age, 70 yr) with PHP were randomized to receive alendronate 10 mg/d or placebo for 48 wk, followed by treatment withdrawal for 24 wk. The mean (+/-SD) changes in BMD at femoral neck (+4.17 +/- 6.01% vs. -0.25 +/- 3.3%; P = 0.011) and lumbar spine (+3.79 +/- 4.04% vs. 0.19 +/- 2.80%; P = 0.016) were significantly higher with alendronate at 48 wk. Serum calcium was reduced with alendronate but not placebo (-0.09 vs. +0.01 mmol/liter; P = 0.018). Serum bone-specific alkaline phosphatase activity was lower with alendronate from 12 wk onward and increased 24 wk after treatment withdrawal (21.1 +/- 12.8 to 7.3 +/- 4.9 IU/liter at 48 wk, and 15.0 +/- 14.8 IU/liter 24 wk after withdrawal; P = 0.002 for trend). Osteocalcin concentration decreased at 48 wk and increased 24 wk after alendronate withdrawal (P = 0.019 for trend of change over time) but not with placebo. Urinary N-telopeptide/creatinine ratio decreased with alendronate at 48 wk and increased 24 wk after treatment withdrawal (P = 0.008 for trend). N-telopeptide/creatinine ratio did not change with placebo. Alendronate improves BMD and reduces bone turnover markers in postmenopausal women with PHP.

Purpose: To review evidence-based management of nephropathy in patients with type 2 diabetes., Data Sources: A literature search (MEDLINE 1966 to 2000) was performed using the key word "diabetic nephropathy". Relevant book chapters were also reviewed., Study Selection: Well-controlled, prospective landmark studies and expert review articles on diabetic nephropathy were selected., Data Extraction: Data and conclusions from the selected articles that provide solid evidence to the optimal management of diabetic nephropathy were extracted and interpreted in light of our clinical research experience with many thousands of Hong Kong Chinese patients., Results: Hypertension, long diabetes duration, poor glycaemic control and central obesity are the most important risk factors. Microalbuminuria is a practical marker to predict overt nephropathy in type 2 diabetic patients. Risk factor modification, renal function monitoring and combined therapies are the current integrated approaches to manage patients with diabetic kidney disease. Optimal glycaemic control is the mainstay of treatment but effective antihypertensive therapy is also key to delaying the progression of diabetic nephropathy. Angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists have important renoprotective actions independent of their blood pressure lowering actions., Conclusions: Diabetic nephropathy is the leading cause of end-stage renal disease worldwide. Monitoring renal function and screening for microalbuminuria will allow the identification of patients with nephropathy at a very early stage for intervention. Tight glycaemic control and aggressive antihypertensive treatment as well as the use of renin-angiotensin system inhibitors should substantially delay the progression of nephropathy.