Boniface J. Lin

Abnormal Peripheral Microcirculation in Seemingly Normal Subjects Living in Blackfoot-Disease-Hyperendemic Villages in Taiwan

Blackfoot disease (BFD) is an endemic peripheral arterial disease confined to the southwestern coast of Taiwan. The cause of the disease has been ascribed to the high-arsenic artesian well water. The purpose of this study was to examine the possible association between the long-term exposure to artesian well water and the change in microvascular circulation in the absence of peripheral arterial insufficiency. A total of 45 men living in the BFD-hyperendemic villages and another 51 age- sex- body-mass index-matched men who lived in nonendemic villages nearby were recruited into this study. All subjects were free from peripheral vascular disease (resting ankle-brachial index > 1.00), clinical claudication, cigarette smoking, diabetes mellitus, hypertension, ischemic heart disease, cerebral infarction and obesity. Laser Doppler flowmetry was used to measure the peripheral microcirculation on the big toes both at 36 degrees C (basal perfusion, Pb) and after a hyperthermic test at 42 degrees C (Ph). The time required to reach Ph (T), and the average rate (R) of increase from Pb to Ph measured by (Ph-Pb)/T were also calculated. Results showed that those living in the BFD-hyperendemic area had a lower Pb [32.8 +/- 6.0 perfusion units (PU) vs. 67.0 +/- 4.3 PU, p < 0.001], a lower Ph (193.2 +/- 13.6 vs. 231.1 +/- 6.3 PU, p < 0.005), a longer T (3.04 +/- 0.19 vs. 1.31 +/- 0.08 min, p < 0.001) and a slower rate of increase from Pb to Ph (48.0 +/- 4.8 vs. 76.2 +/- 5.4 PU/min, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

QUANTITATIVE SENSORY TESTING AND RISK FACTORS OF DIABETIC SENSORY NEUROPATHY

Abstract The goal of this study was to identify risk factors for diabetic peripheral sensory neuropathy in type 2 diabetes mellitus in a Chinese population. Peripheral sensory neuropathy was detected by quantitative sensory testing (5.07/10 g monofilament, neurometer and 128-Hz Riedel Seiffert graduated tuning fork). Those who had two or more abnormal quantitative sensory testings were defined as having diabetic sensory neuropathy. Of the 558 non-insulin dependent diabetes mellitits subjects, 62 (11.1%) had peripheral neuropathy. In 59 (10.6%) detection was by monofilament testing, 45 (8.1%) by graduated tuning fork, and 189 (33.9%) by neurometer. In a multivariate logistic regression model, age and insulin therapy were significantly associated with peripheral neuropathy. Age, serum triglyceride, height, and fasting plasma glucose were independently associated with large fiber neuropathy. Our results confirm the previously identifed multiple risk factors of diabetic neuropathy. Different quantitative sensory testings detect different nerve fiber defects. The weak correlation between these tests indicates the need to use more than one test in screening for diabetic neuropathy.

Prevalence of hypertension and dyslipidemia and their associations with micro- and macrovascular diseases in patients with diabetes in Taiwan: an analysis of nationwide data for 2000-2009.

BACKGROUND/PURPOSE Cardiovascular complication is the leading cause of mortality in patients with diabetes. Dyslipidemia and hypertension are the major risk factors contributing to cardiovascular disease (CVD). This study was carried out to investigate the prevalence of dyslipidemia and hypertension and their associations with microvascular and macrovascular complications in patients with type 2 diabetes in Taiwan. METHODS Health-care data and diagnostic codes were retrieved from the Taiwan Bureau of National Health Insurance claims files for the years 2000-2009. Based on these data the annual prevalences of dyslipidemia and hypertension were calculated and patients were stratified by age, gender, and diabetic complications. RESULTS In patients with diabetes, the prevalence of dyslipidemia increased with age, with the highest rate recorded in adults (inclusive of both genders) between 40 and 65 years of age (p for trend <0.001). The prevalence of hypertension also increased with age with the highest rate seen in adults (inclusive of both genders) >65 years of age (p for trend <0.001). The prevalence of stroke and CVD decreased gradually (p for trend 0.025 and <0.001, respectively), while the prevalence of peripheral vascular disease (PVD) increased in patients with diabetes during the study period (p for trend <0.001). The prevalence of dyslipidemia increased in diabetic patients with eye diseases and in men with nephropathies, but decreased in women with nephropathies during the study period. In contrast, the prevalence of dyslipidemia decreased in patients with macrovascular complications, including CVD and cerebrovascular disease (cerebrovascular accident), but increased in those patients with PVD (p for all trends <0.05). In diabetic patients with various macrovascular complications, except PVD, there was a decrease in the prevalence of hypertension in the past 10 years. The prevalence of hypertension increased in patients with microvascular complications including retinopathy, patients on dialysis (inclusive of both genders), and in men with nephropathy. The prevalence of hypertension along with dyslipidemia increased in patients with microvascular complications including retinopathy, patients on dialysis (inclusive of both genders), and in men with nephropathy; however, the rate decreased in all macrovascular complications except in PVD. CONCLUSION Although progressively increased prevalence of dyslipidemia and hypertension was observed in patients with diabetes in Taiwan, there was a decrease in the prevalence of stroke and CVD in the past 10 years. Among those with macrovascular diseases, except PVD, there was a trend of decreased prevalence of hypertension and dyslipidemia during the study period. In patients with microvascular diseases, prevalence of hypertension and dyslipidemia in patients with eye diseases increased in the past 10 years. More aggressive management of different risk factors is warranted in diabetic patients with various vascular diseases.

Mortality trends in patients with diabetes in Taiwan: A nationwide survey in 2000–2009

BACKGROUND/PURPOSE Medical systems and care for diabetes have changed greatly in Taiwan in recent years. This study investigated mortality trends in patients with diabetes in Taiwan from 2000 to 2009. METHODS We linked the National Health Insurance (NHI) claims database, which contains data on 99% of the population of Taiwan, to the National Death Registry and Cancer Registry. Patients were classified as having diabetes if they had at least one hospital admission or three or more outpatient visits with a diabetes diagnostic code in each calendar year. Mortality data from the Collaboration Center of Health Information Application were used to estimate age- and sex-specific mortality rates, all-cause mortality, and life expectancy (LE). RESULTS The mortality of patients with diabetes in Taiwan decreased continuously from 2000 to 2009 for both sexes and all age groups; the mortality rate was generally higher for men than for women (3.92% vs. 3.29% in 2000; 3.64% vs. 3.11% in 2005, and 3.12% vs. 2.71% in 2009, all p < 0.05). Diabetic patients had a shorter LE than the entire population, although this difference decreased over time. The estimated loss of life due to diabetes was 6.1 years in women and 5.3 years in men in 2009, when diabetes was diagnosed at the age of 40. The four major causes of death were diabetes, malignancies, heart diseases, and cerebrovascular diseases. CONCLUSION The mortality of diabetic patients in Taiwan decreased from 2000 to 2009. Although patients with diabetes had a shorter LE than the entire population, the difference decreased over time.

Transcomplementation of HLA DQA1-DQB1 in DR3/DR4 and DR3/DR9 Heterozygotes and IDDM in Taiwanese Families

OBJECTIVE To study the human leukocyte antigen (HLA)-DQ heterodimers in the susceptible DR haplotypes for patients with insulin-dependent diabetes mellitus (IDDM) in Taiwan. RESEARCH DESIGN AND METHODS Extended class II HLA haplotypes were studied in 57 unrelated IDDM patients, 31 simplex IDDM families, and 105 unrelated control subjects recruited from the same area in Taiwan. Class II HLA genotyping was based on PCR-SSO DNA typing techniques. Extended class II HLA haplotypes were deduced unequivocally by the Taiwanese pedigree studies. RESULTS DR3/DR3, DR3/DR4, and DR3/DR9 genotypes were strongly associated with IDDM susceptibility in this population. In addition to the reported DR3/DR4 in Caucasians, the heterozygotic effect of DR3/DR9 for IDDM was remarkable in the Taiwanese population. Extended HLA haplotypes studies revealed that DRB1*0301/DQA1*0501/DQB1*0201, DRB1*0405/DQA1*0301/DQB1*0302, and DRB1*0405/DQA1*0301/DQB1*0401 were the susceptible haplotypes in this population. There were several hypothetical ways to produce susceptible HLA-DQ heterodimers to explain the susceptibility carried by DR3/DR4 and DR3/DR9 genotypes. Among all DR4 subtypes, only DRB1*0405 was associated with the increased risk of IDDM. CONCLUSIONS These data strongly suggest that the HLA-DR-associated IDDM susceptibility is most likely explained by the formation of the susceptible DQ heterodimers encoded by the DQA1/DQB1 either in cis or in trans.

Link Between Hypertension and Diabetes Mellitus Epidemiological Study of Chinese Adults in Taiwan

Objective To elucidate the relationship between hypertension and non-insulin-dependent diabetes. Research Design and Methods The study consisted of a random sample of adults aged ≥ 40 yr from the Ta-An district of Taipei City and 5 of 12 villages of Taiwan province, which had established primary health-care centers since 1984. A total of 11,478 subjects were recruited into the survey with a response rate of 65.3 and 72%, respectively. Blood glucose and blood pressure levels were measured, and a structured questionnaire was given to each participant. Those identified as having diabetes received further blood tests for lipids and creatinine and were evaluated for vascular complications. Results The age- and sex-adjusted prevalence of hypertension among diabetic subjects was twice that of nondiabetic subjects (30.6 vs. 16.4%, P < 0.0005). Hypertensive subjects had a higher prevalence of diabetes than normotensive subjects (10.2 vs. 4.9%, P < 0.0005). Among hypertensive subjects, the prevalence of diabetes was 12.7% for those taking antihypertensive drugs and 9.1% for those not taking any drug (P < 0.05). The prevalence of diabetes significantly increased as mean arterial pressure rose, whether the subjects were stratified by various factors. Multiple regression analysis, including sex, age, body mass index, and other risk factors as independent variables, also showed a significant association between diabetes and hypertension. Conclusions The univariate and multivariate analyses revealed that there seemed to be a tight link between hypertension and non-insulin-dependent diabetes. Family history of diabetes, diabetes duration, diabetes regimen, control of blood glucose, and the presence of nephropathy, as attested by proteinuria, did not contribute to the risk of hypertension. Further studies are necessary to determine whether these two conditions are causally related.

No association between the Gly971Arg variant of the insulin receptor substrate 1 gene and NIDDM in the Taiwanese population.

OBJECTIVE To study the role of the Gly971 Arg variant of the insulin receptor substrate 1 (IRS-1) gene in the development of NIDDM in the Chinese population living in Taiwan. RESEARCH DESIGN AND METHODS A total of 82 unrelated normal control subjects, 89 subjects with NIDDM, and 23 multiplex families were recruited in Taiwan. All of them were Han Chinese. Pedigree members without a history of diabetes were studies by the standard 75-g oral glucose tolerance test. Detection of the Gly971 Arg variant of the IRS-1 gene was performed by polymerase chain reaction and restriction fragment-length polymorphism analysis. RESULTS The frequency of Gly971 Arg variant of the IRS-1 gene in the normal population was 1.2% which was lower than frequencies reported in white populations. The prevalence of the Gly971 Arg variant was not significantly increased in both the nonselected NIDDM population (1.1%) and the probands of the multiplex families (4.3%). More importantly, the Gly971 Arg variant of the IRS-1 gene did not cosegregate with BMI and NIDDM in these families, CONCLUSIONS The Gly971 Arg variant of the IRS-1 gene is an infrequent normal allele among Taiwanese. This variant is neither associated nor cosegregated with NIDDM in the Taiwanese population and families. Gly971 Arg of IRS-1 gene does not play an important role in the development of NIDDM in this population.

Abnormal response of ankle pressure after exercise in seemingly normal subjects living in blackfoot disease-hyperendemic villages in Taiwan

Arsenic-related peripheral vascular disease has been reported in many countries, including Taiwan, where the disease was called blackfoot disease (BFD) after the dry gangrene at its terminal stages. Because the induction period of BFD is twenty to thirty years, the authors speculated that subclinical arterial insufficiency might be present. The purpose of this study was to detect possible minor arterial insufficiency in the seemingly normal subjects who had consumed the high-arsenic well water for more than thirty years. Twenty-three seemingly normal men living in BFD-hyperendemic villages and 28 age-sex-BMI-matched men from a nearby nonendemic area were recruited. All of them were not obese, had neither diabetes mellitus nor hypertension, did not smoke, and had normal Doppler ultrasound examination findings at rest. Brachial pressures on both arms and ankle pressures on both right and left dorsal pedal and posterior tibial arteries were measured before and after treadmill exercise (1.2 mph, 10% grade, ten minutes). Before exercise, brachial pressures, ankle pressures, ankle-brachial index, and ankle- brachial gradients were similar in BFD area and nonBFD area groups. After exercise, ankle pressure increased in correspondence to increased brachial pressure in the nonBFD area group, maintaining ankle-brachial index and ankle-brachial gradient within normal limits. However, in the BFD area group, a paradoxical drop of ankle pressures led to a significant fall of ankle-brachial index and ankle-brachial gradient. Only 3 (10.7%) cases (continued on next page) (Abstract continued) with 4 (7.1%) limbs from the nonBFD area showed negative values of ankle-brachial gradients (-3 mmHg to -10 mmHg). However, there were 13 (56.5%) cases with 20 (43.5%) limbs showing negative gradients (-1 mmHg to -33 mmHg) in the BFD area group. The odds ratios of having minor arterial occlusive disease was about 10 times higher in the seemingly normal subjects living in BFD-hyperendemic villages with ankle- brachial gradients after exercise either < 0 mmHg or < -9 mmHg as a cutoff point. The authors conclude that subclinical arterial insufficiency could be demonstrated in a high percentage of the seemingly normal subjects who had been chronically exposed to arsenic. For early detection of arterial disease and early intervention to prevent future amputation, they advocate the exercise test as a screening and monitoring method.

Anti‐GAD65 autoantibody in Taiwanese patients with insulin‐dependent diabetes mellitus: effect of HLA on anti‐GAD65 positivity and clinical characteristics

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.

A rapid method to study heat shock protein 70-2 gene polymorphism in insulin-dependent diabetes mellitus

To examine the role of DNA loci within the human leukocyte antigen (HLA) region and insulin-dependent diabetes mellitus (IDDM), we studied fine mapping of HSP70-2 gene. Polymerase chain reaction (PCR)-based genotyping was then developed and applied to type HSP70-2 in 59 patients with IDDM and 83 unrelated controls recruited from the inhabitants of northern Taiwan. Southern blot analysis revealed a diallelic PstI polymorphism of the HSP 70-2 gene, i.e., 9.6- and 8.5-kb alleles. The polymorphic site was mapped in the intragenic PstI sequences (nucleotides 1051-1056) of the HSP70-2 gene. PCR-based restriction fragment length polymorphism studies revealed that the frequency of the 8.5-kb allele was increased in IDDM (56.8%, vs. 40.4% in controls; p < 0.009), with a relative risk of 1.93 (95% confidence interval = 1.20-3.11). The genotypic frequencies of 9.6/9.6, 9.6/8.5, and 8.5/8.5 were 17.0, 52.5, and 30.5% for IDDM were different from those of controls (36.1, 47.0, and 16.9%, respectively; the homozygous 9.6/ 9.6 genotype was significantly decreased in the IDDM group, p < 0.02). In conclusion, we provide a simple, rapid, and nonradioactive method for HSP70-2 genotyping. Our data confirmed that the 8.5-kb allele of HSP70-2 was associated with IDDM susceptibility in the Taiwanese population.