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BACKGROUND Noninvasive stress tests for the diagnosis of significant coronary arterial stenosis requiring intervention are not perfect. We investigated whether plasma metabolome during the oral glucose tolerance test (OGTT) can improve the diagnosis. METHODS A total of 117 subjects with positive stress test results who received coronary angiography were recruited. After excluding subjects with a history of myocardial infarction and subjects who did not receive OGTT, the 18 subjects without significant stenosis were selected as controls. Another 18 age- and sex-matched subjects with significant stenosis were selected as cases. Plasma metabolome from samples obtained in fasting, 30 and 120 min after OGTT was measured using liquid chromatography combined with time-of-flight mass spectrometry. RESULTS We found five metabolites which can identify patients with significant stenosis independent to clinical risk factors, including diabetes, hypertension, hypercholesterolaemia, smoking and history of percutaneous coronary intervention (all P

Summary Background A recent genome-wide association study for type 2 diabetes in Han Chinese identified several novel genetic variants. We investigated their associations with quantitative measures to explore the mechanism by which these variants influence glucose homoeostasis. We also examined whether these variants predict progression to diabetes in a large prospective family based Chinese cohort. Methods Five single nucleotide polymorphisms (SNPs) near the protein tyrosine phosphatase, receptor type, D (PTPRD), SRR, MAF/WWOX, and KCNQ1 genes were genotyped in 1138 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance study. Results At baseline, the risk-conferring rs7192960 C allele near the MAF/WWOX genes was associated with lower homoeostasis model assessment of β-cell (HOMA-β) (P = 0·01) and second-phase insulin response in oral glucose tolerance test (OGTT) (P = 0·04). The risk-conferring rs2237897 C alleles in the KCNQ1 gene were associated with higher fasting glucose (P = 0·009), lower HOMA-β (P = 0·03), and lower first-phase insulin response in OGTT (P = 0·03). Over an average follow-up period of 5·43 years, participants with the risk-conferring rs17584499 TT genotype in the PTPRD gene were more likely to progress from nondiabetes to diabetes than were noncarriers (hazard ratio: 8·82, P = 4 × 10−5). The risk-conferring T allele in the PTPRD gene was associated with greater increase in homoeostasis model assessment of insulin resistance (HOMA-IR) (P = 0·04) over time. PTPRD gene expression in human adipose tissues was negatively associated with fasting insulin levels and HOMA-IR. Conclusion Genetic variants near the KCNQ1 and MAF/WWOX genes are associated with reduced insulin secretion. The PTPRD genetic variant appears to be associated with progression to diabetes in Han Chinese, most likely through increased insulin resistance.

Summary Background The association between haemoglobin A1c (HbA1c) levels and subclinical atherosclerosis in carotid arteries in Chinese populations is unknown. Aim, design and methods The objective of this study was to investigate this relationship and evaluate the ability of HbA1c levels to predict carotid atherosclerosis in a Chinese population. This was a cross-sectional study, which included 541 subjects without known diabetes (Taiwan Lifestyle Study). About 67 (9·2%) subjects were newly diagnosed with diabetes during the study. Carotid intima–media thickness (IMT) and the presence of carotid plaques were determined using ultrasonography. Results The HbA1c level in all subjects was positively correlated with carotid IMT (β = 0·018, P = 0·03) after being adjusted for age, gender, smoking, low-density lipoprotein cholesterol level, hypertension and body mass index. HbA1c level was higher in subjects with plaques in carotid arteries (P = 0·01). There was a positive and linear relationship between HbA1c levels and the probability of having plaques, thickened carotid IMT or both (P for all comparisons

Summary objective The significance of the association of amino terminal polymorphisms in β2-adrenoreceptor (ADRB2) with obesity and type 2 diabetes is controversial and differs among ethnic groups. In this study, the association of ADRB2 with risk and age of onset of type 2 diabetes has been examined in a Taiwanese population. design The study design is a case–control study to investigate the impact of the two amino acid polymorphisms in ADRB2. patients and measurements This study includes 130 patients with type 2 diabetes [female : male = 1 : 1, age: 52·4 ± 10·0 years; body mass index (BMI): 24·2 ± 2·9 kg/m2; mean ± SD] and 130 controlled subjects matched for gender, age and BMI with normal glucose tolerance (female : male = 1 : 1, age: 51·7 ± 10·6 years; BMI: 23·9 ± 2·7 kg/m2). The Arg16Gly and Gln27Glu polymorphisms of ADRB2 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) assays. The genotypic and allelic frequencies between two groups were compared and the relationship between the genotypes and clinical phenotypes was examined. results A difference in genotypic frequency in the Arg16Gly polymorphism was noted between groups in this gender-, age- and BMI-matched case–control study (P = 0·039). Multivariate regression analysis revealed that the Arg16Gly polymorphism was the only independent factor for development of type 2 diabetes (P = 0·021). In addition, we utilized the log-rank test to compare the differences in age of onset between wild-type and nonwild-type polymorphisms. The Arg16Gly polymorphism was independently associated with age of onset in type 2 diabetes (P = 0·017). There was no difference in the Gln27Glu polymorphism between diabetic and control groups in this study. conclusions In a Taiwanese population, homozygosity of Arg16 in the ADRB2 gene was associated with a higher frequency (odds ratio 1·87, 95% confidence interval 1·34–2·40) for development of type 2 diabetes. Moreover, this polymorphism was also associated with an earlier onset of type 2 diabetes. However, the Glu27Gln polymorphism had no impact on either BMI or type 2 diabetes in a Taiwanese population.

Objective As type 2 diabetes results from an imbalance between insulin sensitivity and beta cell function, either or both may worsen with age. However, existing data are controversial on the effect of ageing on both insulin sensitivity and beta cell function. Subjects and design We enrolled 149 healthy, glucose tolerant and normotensive Caucasians (age 35 +/- 1 years, body mass index 26.07 +/- 0.44 kg/m2, waist-hip ratio 0.842 +/- 0.009 cm/cm, mean +/- standard error). A cross-sectional study was designed to examine the impact of age on insulin sensitivity and beta cell function. Their beta cell function (percentage B [%B]) and insulin sensitivity (percentage S [%S]) were estimated using the homeostasis model assessment. Results Simple regression analysis revealed that %B declined with age (P = 0.008) while no relation was found between %S and age (P = 0.769). A stepwise regression analysis revealed that body mass index and diastolic blood pressure explained 14.7% of variation in %S, while age, waist-hip ratio, gender, and systolic blood pressure had no influence on %S. Age, body mass index and diastolic blood pressure together accounted for 21.7% of variation in %B, with age being an independent variable. Conclusions In the present study, we showed that beta cell function declined with age at a rate of about 1% per year. In contrast, insulin sensitivity was not affected by ageing. Our observations suggest that the age-related decline in glucose tolerance is primarily related to the loss of beta-cell function.

OBJECTIVE Vitamin D and its receptor have been suggested to play a role in the pathogenesis of type 1 diabetes mellitus. We have therefore studied the influence of vitamin D receptor (VDR) gene polymorphisms on susceptibility to type 1 diabetes, and rates of glutamic acid decarboxylase (GAD65) autoantibody and islet cell autoantibody (ICA512) positivity. SUBJECTS AND MEASUREMENTS One hundred and fifty-seven type 1 diabetic patients and 248 unrelated normal controls were recruited for this study. Genomic DNA was extracted from peripheral blood leucocytes. All type 1 diabetic patients and controls were genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP), for three restriction sites in the VDR gene, BsmI, ApaI and TaqI. The χ2 test was used to compare the frequency of the VDR gene polymorphisms in patients and normal controls. The association of VDR gene polymorphisms in type 1 diabetes with the presence of GAD65 and ICA512 autoantibodieswere also examined using the χ2 test. RESULTS The allele frequency of the BsmI and ApaI polymorphisms, but not TaqI polymorphism, differed between patients and controls (BsmI P = 0.015; ApaI P = 0.018; TaqI P = 0.266). However, after correction for the three different polymorphisms tested, only the BsmI was significant (pc = 0.045). CONCLUSIONS Vitamin D receptor gene polymorphisms were associated with type 1 diabetes in a Taiwanese population. However, functional studies are needed to establish the role of the vitamin D receptor in the pathogenesis of type 1 diabetes mellitus.

We report a 28-year-old young male with MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes) presenting with two previous episodes of stroke-like manifestation, lactic acidosis and mitochondrial cardiomyopathy. He was also affected with insulin-dependent diabetes mellitus (IDDM), as diagnosed by the experience of diabetic ketoacidosis (DKA), and dependence on insulin therapy. On admission, the serum lactate level was found to be increased to 5.4 mmol/l, and plasma glucose level to 7.9 mmol/l with haemoglobin A1c 8.4%, while he was using insulin 26-30 units per day. Physical examination revealed a short stature male of height of 150 cm and weight of 49 kg. Mild mental retardation with bilateral sensorineural hearing impairment was observed. After glucagon stimulation, C-peptide levels rose from 0.46 nmol/l to 0.53 nmol/l, indicative of impaired insulin secretion. Anti-glutamate decarboxylase (anti-GAD) antibody was positive. In addition, human leucocyte associated antigen (HLA) typing showed DR3 and DR4, suggesting the strong contribution of autoimmunity to the pathogenesis of IDDM in this patient. Moreover, the result of a treadmill exercise test was positive due to inferior wall myocardial ischaemia. Cardiac catheterization and endomyocardial biopsy disclosed a normal coronary angiogram and confirmed the diagnosis of mitochondrial cardiomyopathy. Molecular genetic analysis of his family revealed a sporadic occurrence of mitochondrial DNA (mtDNA) mutation at base pair (bp) 3243. The degree of heteroplasmy of mtDNA mutation from a total of 19 passages of skin-derived fibroblasts from this patient showed a slightly downward trend. This extremely rare case of sporadic MELAS syndrome with autoimmune IDDM harbouring mtDNA mutation highlights the possible pathogenetic role of mtDNA mutations in autoimmune disease.

OBJECTIVE Anti-GAD65 antibody has been studied widely in patients with insulin-dependent diabetes mellitus (IDDM) in many different populations. However, the prevalence of GAD65 autoantibody has not been assessed in Taiwanese patients with IDDM. We therefore characterized GAD65 antibody and investigated the effect of HLA-DR phenotypes on GAD65 autoimmunity and other clinical characteristics in Taiwanese subjects with IDDM. SUBJECTS AND MEASUREMENTS Two hundred and twenty-five patients (male 102, female 123) with IDDM were recruited. The diagnostic criteria for IDDM were age of onset before 30 years, presence of diabetic ketoacidosis, and insulin-dependency within 3 years of onset. We employed a radioligand method to detect GAD65 antibody. HLA-DR typing was performed by the PCR-SSO techniques. Plasma C-peptide and antithyroid microsomal antibody were also measured. RESULTS The prevalence of GAD65 antibody according to duration of disease were 50/91 (54.9%), 37/95 (38.9%), 8/24 (33%), and 3/15 (20%) among the groups of duration ≤5, 6–10, 11–15, and >15 years, respectively (p = 0.0011). There were no significant differences between GAD(+) and GAD(−) patients in age of onset (11.5 ± 6.5 and 11.6 ± 13.4 years, respectively), gender distribution (male:female 39:59 and 58:69, respectively) and percentage with residual β cell function (38.8% and 29.1%, respectively). Multiple regression analysis revealed that duration of IDDM correlated inversely with residual β cell function. Earlier onset of IDDM correlated with a loss of β cell function and a HLA-DR phenotype containing DR3/4, DR3/3 or DR3/9. CONCLUSIONS Prevalence of GAD65 autoantibody among Taiwanese subjects with IDDM was negatively correlated with duration of disease. Different determinants in the HLA-DR locus contributed to the clinical onset of IDDM but not to GAD autoimmunity.

OBJECTIVE Elevated YKL-40 concentrations have been observed in both coronary heart disease (CHD) and diabetes. Thus, YKL-40 may play a role in pathogenesis of CHD in patients with diabetes. We evaluated whether plasma YKL-40 concentration can predict all-cause and cardiovascular mortality in individuals with type 2 diabetes. DESIGN This is a prospective, observational study. PATIENTS A total of 628 subjects with type 2 diabetes were recruited between July 1996 and June 2003. MEASUREMENTS Plasma YKL-40 concentrations were measured via enzyme-linked immunosorbent assay (ELISA). The cohort was followed up until 31 December 2008, when vital status and causes of death were obtained. Survival analysis and concordance statistics were performed. All-cause and cardiovascular mortalities were documented. RESULTS There were 153 (24·36%) mortalities, including 48 participants (7·64%) who died from cardiovascular diseases (CVDs). Participants with higher plasma YKL-40 (defined with a level above the median of 87·5 μg/l) had an increased risk of mortality. After adjusting for confounding variables, the hazard ratios (HR) for all-cause and cardiovascular mortality in participants with higher plasma YKL-40 were 1·97 (95% CI, 1·31-2·95, P < 0·01) and 2·45 (95% CI, 1·11-5·37, P < 0·05). The results remained similar after adjustment for age. Concordance statistics revealed that plasma YKL-40 concentration significantly increases the predictive power for both all-cause and cardiovascular mortality in different models. CONCLUSIONS Plasma YKL-40 concentration is an independent predictor of 10-year all-cause and cardiovascular mortality in subjects with type 2 diabetes. Further investigations on the role of YKL-40 in the pathogenesis of CVD are required to elucidate the underlying mechanisms.

A recent genome-wide association study for type 2 diabetes in Han Chinese identified several novel genetic variants. We investigated their associations with quantitative measures to explore the mechanism by which these variants influence glucose homoeostasis. We also examined whether these variants predict progression to diabetes in a large prospective family based Chinese cohort. Five single nucleotide polymorphisms (SNPs) near the protein tyrosine phosphatase, receptor type, D (PTPRD), SRR, MAF/WWOX, and KCNQ1 genes were genotyped in 1138 subjects of Chinese origin from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance study. At baseline, the risk-conferring rs7192960 C allele near the MAF/WWOX genes was associated with lower homoeostasis model assessment of β-cell (HOMA-β) (P = 0·01) and second-phase insulin response in oral glucose tolerance test (OGTT) (P = 0·04). The risk-conferring rs2237897 C alleles in the KCNQ1 gene were associated with higher fasting glucose (P = 0·009), lower HOMA-β (P = 0·03), and lower first-phase insulin response in OGTT (P = 0·03). Over an average follow-up period of 5·43 years, participants with the risk-conferring rs17584499 TT genotype in the PTPRD gene were more likely to progress from nondiabetes to diabetes than were noncarriers (hazard ratio: 8·82, P = 4 × 10(-5) ). The risk-conferring T allele in the PTPRD gene was associated with greater increase in homoeostasis model assessment of insulin resistance (HOMA-IR) (P = 0·04) over time. PTPRD gene expression in human adipose tissues was negatively associated with fasting insulin levels and HOMA-IR. Genetic variants near the KCNQ1 and MAF/WWOX genes are associated with reduced insulin secretion. The PTPRD genetic variant appears to be associated with progression to diabetes in Han Chinese, most likely through increased insulin resistance.

The association between haemoglobin A1c (HbA1c) levels and subclinical atherosclerosis in carotid arteries in Chinese populations is unknown. AIM, DESIGN AND METHODS: The objective of this study was to investigate this relationship and evaluate the ability of HbA1c levels to predict carotid atherosclerosis in a Chinese population. This was a cross-sectional study, which included 541 subjects without known diabetes (Taiwan Lifestyle Study). About 67 (9·2%) subjects were newly diagnosed with diabetes during the study. Carotid intima-media thickness (IMT) and the presence of carotid plaques were determined using ultrasonography.The HbA1c level in all subjects was positively correlated with carotid IMT (β = 0·018, P = 0·03) after being adjusted for age, gender, smoking, low-density lipoprotein cholesterol level, hypertension and body mass index. HbA1c level was higher in subjects with plaques in carotid arteries (P = 0·01). There was a positive and linear relationship between HbA1c levels and the probability of having plaques, thickened carotid IMT or both (P for all comparisons,0·05). The ability of HbA1c levels to predict thickened carotid IMT or the presence of plaques was only modest {the optimal cutoff of HbA1c level [5·7%] was determined from the receiver operating characteristic (ROC) curve (sensitivity = 67%, specificity = 61%) and the area under the ROC curve [0·666]}.Thus, HbA1c level is associated with subclinical atherosclerosis in carotid arteries in a Chinese population. The relationship is linear without an inflection point. However, HbA1c criterion is not a useful marker for the identification of subclinical atherosclerosis.

Summary Objective Infiltration of the retro-ocular space by inflammatory cells, accumulation of glycosaminoglycans, and the overabundance of orbital adipose tissue are characteristic findings in Graves’ ophthalmopathy (GO). The cause of macrophage infiltration in the orbital adipose tissue of patients with GO remains to be elucidated. Design Immunohistochemistry of orbital adipose tissues with anti-CD68 was used for determining macrophage infiltration pattern and cell counts. Quantitative real-time PCR was used for analysing mRNA expression. Correlation of macrophage infiltration with the duration of GO and mRNA expression were also determined. Patients Fifteen subjects with GO who underwent orbital decompression were recruited. Six patients without thyroid history who underwent elective orbital surgery were enrolled as controls. Measurements Histological distribution of macrophages, macrophage cell counts, CD68 and monocyte chemoattractant protein-1 (MCP-1) mRNA levels, and duration of GO. Results We demonstrated that macrophage infiltration in orbital fat from patients with GO was higher than controls (P = 0·005). The infiltration of macrophages was located primarily around blood vessels and between mature adipocytes. Macrophage infiltration did not attenuate in GO of long duration. We also found that the expression of MCP-1 was higher in GO orbital fat than that in the orbital fat of controls (P = 0·047) and the infiltration of macrophages in adipose tissue from patients with GO was positively correlated with expression of MCP-1 mRNA (r = 0·546, P = 0·035). Conclusion Macrophage infiltration may play an important role in the pathogenesis of GO via over-expression of MCP-1.

The significance of the association of amino terminal polymorphisms in beta2-adrenoreceptor (ADRB2) with obesity and type 2 diabetes is controversial and differs among ethnic groups. In this study, the association of ADRB2 with risk and age of onset of type 2 diabetes has been examined in a Taiwanese population.The study design is a case-control study to investigate the impact of the two amino acid polymorphisms in ADRB2.This study includes 130 patients with type 2 diabetes [female : male = 1 : 1, age: 52.4 +/- 10.0 years; body mass index (BMI): 24.2 +/- 2.9 kg/m2; mean +/- SD] and 130 controlled subjects matched for gender, age and BMI with normal glucose tolerance (female : male = 1 : 1, age: 51.7 +/- 10.6 years; BMI: 23.9 +/- 2.7 kg/m2). The Arg16Gly and Gln27Glu polymorphisms of ADRB2 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assays. The genotypic and allelic frequencies between two groups were compared and the relationship between the genotypes and clinical phenotypes was examined.A difference in genotypic frequency in the Arg16Gly polymorphism was noted between groups in this gender-, age- and BMI-matched case-control study (P = 0.039). Multivariate regression analysis revealed that the Arg16Gly polymorphism was the only independent factor for development of type 2 diabetes (P = 0.021). In addition, we utilized the log-rank test to compare the differences in age of onset between wild-type and nonwild-type polymorphisms. The Arg16Gly polymorphism was independently associated with age of onset in type 2 diabetes (P = 0.017). There was no difference in the Gln27Glu polymorphism between diabetic and control groups in this study.In a Taiwanese population, homozygosity of Arg16 in the ADRB2 gene was associated with a higher frequency (odds ratio 1.87, 95% confidence interval 1.34-2.40) for development of type 2 diabetes. Moreover, this polymorphism was also associated with an earlier onset of type 2 diabetes. However, the Glu27Gln polymorphism had no impact on either BMI or type 2 diabetes in a Taiwanese population.

Objective Thyroid autoimmunity is frequently associated with insulin-dependent diabetes mellitus (IDDM). The genetic factors which contribute to thyroid autoimmunity and IDDM have been described but vary between different races. We have therefore investigated the effect of class II HLA genes at both loci and the HLA haplotypes on the presence of autoimmunity in patients with IDDM in Taiwan. Subjects and measurements Eighty-three patients with IDDM and 105 unrelated normal controls were recruited for the measurement of thyroid autoantibodies and for genotyping of HLA DRB1, DQA1 and DQB1 by polymerase chain reaction-based DNA typing techniques. Results Among 83 patients with IDDM, 23 (27.7%) were positive for antithyroid autoantibodies. Compared to those without thyroid autoimmunity, there was a female preponderance for IDDM with thyroid autoimmunity (female: male, 3:20 vs 29:31). Among the DR specificities, DR6 was associated with a weak protective effect against thyroid autoimmunity in IDDM patients. Upon detailed analysis of class II HLA haplotypes, the DRB1*0301/ DQA1*0501/DQB1*0201 haplotype was found to be associated with an increased risk of IDDM regardless of thyroid autoimmunity, while DRB1*0405/DQA1*0301/ DQB1*0401 was significantly increased only in the IDDM patients with thyroid autoimmunity. IDDM individuals with the HLA DRB1*0405/DQA1*0301/DQB1*0302 haplotype were not at risk of thyroid autoimmunity. Conclusions Our data indicated that there was a generalized genetic factor within or associated with the DRB1*0301/DQA1*0501/DQB1*0201 haplotype, and a more restricted effect with the DRB1*0405/DQA1*0301/DQB1*0401 haplotype which led to thyroid autoimmunity in patients with insulin-dependent diabetes mellitus.