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Aims Patients with diabetes are predisposed to develop a variety of complications, including lower urinary tract (LUT) dysfunction. We aimed to examine the associations between glycemic control and LUT dysfunction in women with type 2 diabetes (T2D). Methods We included 400 women with T2D (age range, 48–75 years) in this cross-sectional analysis. The participants were divided into tertiles according to glycosylated hemoglobin (Hb A1c ) measurements. The mean Hb A1c levels for tertiles 1, 2, and 3 were 6.2% (N=132), 7.1% (N=132), and 8.4% (N=136), respectively. We evaluated LUT dysfunction with the American Urological Association Symptom Index (AUA-SI) questionnaire, uroflowmetry (UFM), and post-void residual (PVR). Results No significant differences were found among Hb A1c tertiles regarding storage, voiding and total AUA-SI scores, and prevalence of LUT symptoms. However, women in tertile 3 had higher prevalences of severe LUT symptoms (AUA-SI≥20) and clinically significant PVR (≥100mL) compared to women in the other tertiles. Multivariate analysis revealed that diabetic neuropathy, but not Hb A1c , significantly predicted LUT symptoms in women with T2D after adjustment for age, body mass index (BMI) and hypertension. However, Hb A1c was associated with an increased risk of developing clinically significant PVR. Conclusions Our findings do not support significant associations between glycemic control and LUT symptoms in women with T2D. However, women with poor glycemic control are more likely to develop urinary retention than women with proper glycemic control. Clinicians should, therefore, be aware of and educate patients about the association between urinary retention and glycemic control.

Background/Purpose Estrogen in hormone replacement therapy causes homeostatic changes. However, little is known regarding the safety of high-dose phytoestrogen on coagulation and hematological parameters in healthy postmenopausal women. This study evaluated the effects of high-dose soy isoflavone (300 mg/day) on blood pressure, hematological parameters, and coagulation functions including circulating microparticles in healthy postmenopausal women. Methods The original study is a 2-year prospective, double-blind, placebo-controlled study. In total, 431 postmenopausal women (from 3 medical centers) were randomly assigned to receive either high-dose isoflavone or placebo for 2 years. At baseline, 6 months, 1 year, and 2 years after treatment, blood pressure, body weight, liver function tests, hematological parameters, and lipid profiles were measured. The 1 st year blood specimens of 85 cases of 144 eligible participants (from one of the three centers) were analyzed as D-dimer, von Willebrand factor antigen, factor VII, plasminogen activator inhibitor type 1, and circulating cellular microparticles, including the measurement of monocyte, platelet, and endothelial microparticles. Results In the isoflavone group, after 1 year, the changes in liver function tests, hematological parameters, and coagulation tests were not different from those of the control. Triglyceride levels were significantly lower after 6 months of isoflavone treatment than the placebo group, but the difference did not persist after 1 year. Endothelial microparticles increased steadily in both groups during the 1-year period but the trend was not affected by treatment. Conclusion The results of the present study indicate that high-dose isoflavone treatment (300 mg/day) does not cause hematological abnormalities or activate coagulation factors.

Type 2 diabetes mellitus (T2DM) is a global health-care and national policy issue. As fluctuating glycemic control in diabetes often results in serious complications, we must encourage the diabetes educators' efforts at long-term follow-up among patients with T2DM. Therefore, certified diabetes educators (CDEs) play the most pivotal roles as life-long protectors for patients with T2DM. In the past 15 years, more than 4,000 CDEs have been trained and qualified, including health professionals such as physicians, nurses, dieticians, and pharmacists. The most important initiation of diabetes share care in Taiwan was originated in I-Lan County. Initiated to provide regional diabetes care, the name of this program is the Lan-Yang Diabetes Shared Care System. In 2006, the Taiwanese Association of Diabetes Educators (TADE) carried out a nationwide survey to evaluate the status of diabetes control in Taiwan, focusing on the "ABC" goal (A: HbA1c7.0%, B: blood pressure130/80 mmHg, C: LDL-cholesterol100 mg/dl/total cholesterol160 mg/dl). The results revealed that the percentage of patients with diabetes who fulfilled all ABC goals was only 4.1%. Five years later, in 2011, TADE compared two nationwide surveys and found total ABC attainment rates of 4.1% and 8.6%, respectively. The team-care approach to T2DM has been underway for over 20 years in Taiwan. Future interventions and treatment algorithms with team-based education should aim at preventing acute and chronic complications, which remains a long-term challenge in Taiwan.

Background/Purpose Formerly, Taiwan's diabetic population has been estimated by surveys conducted at irregular intervals and using different sampling methods. To obtain nationwide data on the incidence and prevalence of diabetes mellitus (DM) in Taiwan, we performed an analysis of the 2000–2009 claim data from the National Health Insurance (NHI) database. Methods One-third of the claims in the NHI database from 2000 to 2009 were randomly sampled. DM was defined by three or more outpatient visits with diagnostic codes (ICD-9-CM: 250 or A code: A181) within 1 year or by one inpatient discharge diagnosis of DM. Confirmation of type 1 diabetes mellitus was based on the issue of a catastrophic illness certificate with the same diagnostic codes. Age and/or gender distribution for DM were determined. Results In accordance with the global trend for DM, with a near constant standardized incidence rate, there was a more than 70% increase in the total diabetic population, or a 35% increase in the standardized prevalence rate, in Taiwan from 2000 to 2009. The incidence of diabetes was higher in men, especially in the 20–59-year-old age group, and the total number of men with diabetes exceeded the number of women with diabetes in 2005. However, the prevalence and incidence rates in women over the age of 60 years were higher than those in men. Type 1 DM was present in less than 1% of the diabetic population in Taiwan. Conclusion The incidence of diabetes, including type 1, remained stable over this 10-year period in Taiwan. However, the incidence rate in men aged 20–59 years was higher than that in age-matched women. With our nationwide database, subgroup analysis of DM incidence can be performed to refine our health policies for the prevention, screening, and treatment of diabetes mellitus.

HbA(1c) variability has been shown to be an independent risk factor for nephropathy in patients with type 1 diabetes. In this study, we aimed to explore the association between HbA(1c) variability and microalbuminuria development in patients with type 2 diabetes. We also intended to test the applicability of serially measured HbA(1c) over 2 years for this risk assessment.Between 2003 and 2005, we recruited 821 middle-aged normoalbuminuric individuals with type 2 diabetes and followed them through to the end of 2010. The average follow-up time was 6.2 years. We defined microalbuminuria as a urine albumin to creatinine ratio of 30 mg/g (3.4 mg/mmol) or higher. HbA(1c) variability was calculated by the SD of serially measured HbA(1c). The Cox proportional hazards model was used to evaluate the association between HbA(1c) SD quartile and development of microalbuminuria.The incidence of microalbuminuria for the overall population was 58.4, 58.6, 60.8 and 91.9 per 1,000 person-years for Q1- to Q4-adjusted HbA(1c) SD, respectively (p for trend = 0.042). Compared with patients in Q1, those in Q4 were about 37% more likely to develop microalbuminuria. The HR derived from a series of 2 year HbA(1c) measurements was similar to that from data collection for longer than 4 years.In addition to mean HbA(1c) values, HbA(1c) variability, even measured as early as 2 years, is independently associated with the development of microalbuminuria in patients with type 2 diabetes.

SummaryAcetylation of histone and nonhistone proteins is an important posttranslational modification affecting many cellular processes. Here, we report that NuA4 acetylation of Sip2, a regulatory β subunit of the Snf1 complex (yeast AMP-activated protein kinase), decreases as cells age. Sip2 acetylation, controlled by antagonizing NuA4 acetyltransferase and Rpd3 deacetylase, enhances interaction with Snf1, the catalytic subunit of Snf1 complex. Sip2-Snf1 interaction inhibits Snf1 activity, thus decreasing phosphorylation of a downstream target, Sch9 (homolog of Akt/S6K), and ultimately leading to slower growth but extended replicative life span. Sip2 acetylation mimetics are more resistant to oxidative stress. We further demonstrate that the anti-aging effect of Sip2 acetylation is independent of extrinsic nutrient availability and TORC1 activity. We propose a protein acetylation-phosphorylation cascade that regulates Sch9 activity, controls intrinsic aging, and extends replicative life span in yeast.

OBJECTIVE An association between insulin resistance and microalbuminuria in type 2 diabetes has often been found in cross-sectional studies. We aimed to reassess this relationship in a prospective Taiwanese cohort of type 2 diabetic subjects. RESEARCH DESIGN AND METHODS We enrolled 738 normoalbuminuric type 2 diabetic subjects, aged 56.6 ± 9.0 years, between 2003 and 2005 and followed them through the end of 2009. Average follow-up time was 5.2 ± 0.8 years. We used urine albumin-to-creatinine ratio to define microalbuminuria and the homeostasis model assessment of insulin resistance (HOMA-IR) to assess insulin resistance. The incidence rate ratio and Cox proportional hazards model were used to evaluate the association between HOMA-IR and development of microalbuminuria. RESULTS We found incidences of microalbuminuria of 64.8, 83.5, 93.3, and 99.0 per 1,000 person-years for the lowest to highest quartiles of HOMA-IR. Compared with those in the lowest quartile of HOMA-IR, the incidence rate ratios for those in the 2nd, 3rd, and highest quartiles were 1.28 (95% CI 0.88–1.87), 1.44 (0.99–2.08), and 1.52 (1.06–2.20), respectively (trend test: P < 0.001). By comparison with those in the lowest quartile, the adjusted hazard ratios were 1.37 (0.93–2.02), 1.66 (1.12–2.47), and 1.76 (1.20–2.59) for those in the 2nd, 3rd, and highest HOMA-IR quartiles, respectively. CONCLUSIONS According to the dose-response effects of HOMA-IR shown in this prospective study, we conclude that insulin resistance could significantly predict development of microalbuminuria in type 2 diabetic patients.

Studies have identified an association between diabetes and breast cancer in postmenopausal women in Western countries. Such an association needs to be confirmed in an Asian population. The aim of this study was to evaluate the secular trend for breast cancer mortality in Taiwanese women in the general population and the mortality rate ratios between diabetic patients and the general population.Age-specific mortality rates for the general population, categorised into groups aged 25-54, 55-64, 65-74 andor =75 years, were calculated for the years between 1995 and 2006 (inclusive) from vital statistics published by the Taiwanese government. Linear regression was used to test the trends. A total of 131,573 diabetic women agedor =25 years from a national cohort recruited between 1995 and 1998 (inclusive) were followed prospectively for vital status, determined from the National Register of Deaths. Mortality rates and mortality rate ratios (mortality rate in diabetic women vs the average and highest mortality rates for the general population) were calculated.A total of 14,230 women agedor =25 years in the general population died of breast cancer between 1995 and 2006. A trend for an increase in the annual rate was observed for all age groups. A total of 482 diabetic women died of breast cancer, with a crude mortality rate of 45.7 per 100,000 person-years. Compared with the general population the relative risk of mortality for those with diabetes ranged from 1.37 (for the group aged 55-64 years) to 2.43 (for the group aged 25-54 years).We identified a secular trend of an increase in the rate of breast cancer mortality in the Taiwanese general population. Our data suggest a higher risk of breast cancer mortality in diabetic patients in all age groups.

There are two main blood-ocular barriers, the blood-aqueous barrier and the blood-retinal barrier. The blood-aqueous barrier is formed by the nonpigmented ciliary epithelium of the ciliary body and the vascular endothelium of the iris vessels. The blood-retinal barrier is formed by the vascular endothelium of the retinal vessels and the retinal pigment epithelium. Four methods of examination are currently used to study the function of blood-ocular barriers. Among these, laser flare-cell photometry is a noninvasive, quantitative method to evaluate the permeability of the blood-aqueous barrier. Vitreous fluorophotometry is an excellent technique to quantitate blood-retinal barrier function. Fluorescein angiography and optical coherence tomography are excellent qualitative imaging techniques to evaluate blood-retinal barrier function. Current basic research shows prostaglandin E2 and other mediators may produce breakdown of the blood-aqueous barrier, and vascular endothelial growth factor plays an important role in the breakdown of the blood-retinal barrier. Retinal laser photocoagulation can induce breakdown of both the blood-aqueous and blood-retinal barriers in pigmented rabbits. The four methods of examination described herein are excellent measures for clinical application to evaluate blood-ocular barrier function in various ocular diseases, many of which are discussed here. [Tzu Chi Med J 2008;20(1):25–34]

Elevated homocysteine, causing tissue injury by such mechanisms as oxidative stress, endothelial damage, and protein homocysteinylation, is associated with multiple age-related problems including cardiovascular diseases, dementia, and osteoporotic fracture. Disability is one of the most common features in older adults. However, little is known about the role of homocysteine in physical disability among older adults.Participants (60 years, N = 1677) were from the National Health and Nutrition Examination Survey (NHANES) 1999-2002. Nineteen questionnaires in five major domains were administered to assess the level of difficulty in performing various tasks: activities of daily living (ADL), instrumental ADL (IADL), leisure and social activities (LSA), lower extremity mobility (LEM), and general physical activities (GPA). Peak quadriceps strength was obtained by using an isokinetic dynamometer. Habitual gait speed was obtained from a 20-foot timed walk. Homocysteine levels were measured by the Abbott homocysteine assay, an automated fluorescence polarization immunoassay (FPIA).Elevated homocysteine was associated with disability in ADL, IADL, LSA, and GPA after multivariate adjustment. The odds ratios (ORs) for disability in these domains comparing participants in the highest quartile of homocysteine to those in the lowest were 2.18 (95% confidence interval [CI], 1.32-3.59) for ADL; 1.62 (95% CI, 1.02-2.57) for IADL; 2.00 (95% CI, 1.14-3.51) for LSA; and 1.52 (95% CI, 1.05-2.21) for GPA. The strength of associations weakened somewhat after additional adjustment of quadriceps strength and/or gait speed, suggesting a mediating role of quadriceps strength and gait speed in the association between homocysteine and disability. Homocysteine had an inverse relationship to quadriceps strength and gait speed. Likewise, quadriceps strength seemed to mediate the inverse association between homocysteine and gait speed.Elevated homocysteine is associated with multiple domains of disability mediated in part by muscle strength and gait speed. The results suggest that homocysteine levels may be important indicators of performance status in older adults.

Compared with the well-documented association with betel-related cancer, little is known about the long-term effect of areca nut chewing on other fatal diseases. The authors' analyses were based on a population-based cohort study in Taiwan, including 4,049 participants aged 60 years or older enrolled in 1989 and 2,462 participants aged 50-66 years enrolled in 1996. Information regarding betel quid chewing and covariates was collected at baseline and was updated at subsequent interviews. Proportional hazards analysis was performed to determine the effect of chewing on all-cause and cause-specific deaths. During a mean follow-up of 9.5 years, 2,309 deaths occurred. Ever chewers were at higher risk of only total (hazard ratio = 1.19, 95% confidence interval: 1.05, 1.35) and cerebrovascular (hazard ratio = 1.66, 95% confidence interval: 1.19, 2.30) deaths. Furthermore, increased chewing-years or quid-years appeared to be associated with increased mortality risk (linear trend: p = 0.02 for total mortality and p = 0.001 for cerebrovascular mortality). The authors found that, although betel quid chewing resulted in a statistically significant increase in the risk of total and cerebrovascular deaths in the elderly population, the associations were weak and should be interpreted with caution. Further studies are needed to confirm these findings and to better understand the possible mechanisms of death.

Background Small-fibre sensory neuropathy of diabetes presenting as impaired thermal sensations is associated with ominous consequences, such as foot ulcer and amputation, but there is a lack of systematic studies on its occurrence in large cohorts. We investigated (1) the impact of glycemic control on thermal thresholds, (2) the frequencies and patterns of sensory deficits, and (3) the contribution of sensory nerve abnormalities to neuropathic symptoms. Methods Quantitative sensory testing and nerve conduction studies were performed to measure warm and cold thresholds of extremities, and amplitudes of nerve action potentials on 498 type 2 diabetic patients and 434 control subjects with similar age and gender distributions, enrolled during the same period. Results The diabetic patients had higher thermal thresholds than control subjects (p < 0.0001). Thermal thresholds of the lower and upper extremities were linearly correlated with HbA1C on multiple linear regression analysis (p < 0.01). By the multivariate logistic regression analysis, HbA1C and age were the most important risk factors independently associated with elevated thermal thresholds (p < 0.01). Elevated warm threshold in the big toe was the most frequent abnormality (60.2%) compared to abnormal cold threshold in the big toe (39.6%) and abnormal sural nerves on nerve conduction studies (12.9%). Elevated thermal thresholds were risk factors for neuropathic symptoms independent of HbA1C. Conclusion Small-fibre neuropathy with the impairment of thermal sensations is the most frequent sensory deficit in diabetes, and HbA1C is significantly associated with the elevated thermal thresholds. Copyright © 2007 John Wiley & Sons, Ltd.

Aims This study aimed to evaluate the long-term effects on glycemic control of a diabetes care program focusing on case management and to discuss challenges in the quality of diabetes care in Taiwan. Methods We randomized 1,060 study subjects recruited from the Diabetes Management through an Integrated Delivery System project in 2003–2005 into intervention (n = 789 from 27 clinics) and control (n = 271 from 7 clinics) groups. The quarterly self-care and nutrition-education program in the intervention group was delivered by case managers, and standard care was provided to the control group. The intervention program was conducted during 2003–2007. A multivariate mixed model analysis was used to assess the 3.5-year intervention effects on glycemic control. Results Glycated hemoglobin (HbA 1c ) level in the intervention group (especially for those with a baseline HbA 1c level of 7–9% and >9%) was significantly lower than that in the control group 6 months after recruitment and remained lower through the subsequent three intervention years. Conclusions The current findings provide evidence that case management provided in the pay-for-performance (P4P) diabetes care program in Taiwan was effective at improving glycemic control for at least 3 years. However, previous research indicated poverty is associated with not only higher diabetes incidence but also inequality of diabetes care in Taiwan despite universal health coverage. Those with a more severe condition were less likely to be enrolled in the P4P diabetes care program. Additional cost-effectiveness studies and more health policy reforms are needed to optimize diabetes care in Taiwan.

Background This study evaluated the association between triglycerides (TG) and coronary artery disease (CAD) in Taiwanese adults with type 2 diabetes mellitus (T2DM). Methods A total of 1150 patients (542 men and 608 women) aged 62.5±11.6 years were studied. CAD was diagnosed by history or an abnormal electrocardiogram (coronary probable or possible by Minnesota codes). Age, body mass index (BMI), smoking, use of insulin, anti-hypertensive agents and lipid-lowering agents, fasting plasma glucose (FPG), hemoglobin A 1c (HbA 1c ), systolic blood pressure (SBP), diastolic blood pressure (DBP), serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c) and low-density lipoprotein cholesterol (LDL-c) were considered as potential confounders. Results Patients with CAD were older, had higher prevalences of use of anti-hypertensive and lipid-lowering agents, and had higher BMI, SBP, DBP and TG. CAD increased significantly with increasing quartiles of TG ( P -trend 1c , DBP, TC, HDL-c (inversely) and LDL-c. Ln(TG) was associated with CAD with an unadjusted odds ratio of 1.411 (1.145–1.740). The odds ratio after adjustment for all confounders was slightly attenuated but still statistically significant: 1.380 (1.043–1.826). None of the other lipid parameters of TC, HDL-c and LDL-c were significantly associated with CAD in logistic models when they were entered for adjustment either separately or simultaneously. Sensitivity analyses by using history alone or history and coronary probable as diagnostic criteria for CAD did not change the association between TG and CAD. Conclusions TG is an independent risk factor for CAD in Taiwanese T2DM, independent of TC, HDL-c, LDL-c or other confounders.

The research aimed at examining betel nut chewing and other risk factors associated with obesity among Taiwanese male adults. The research analyzed the data obtained by the 2001 National Health Interview Survey in Taiwan that covered all the administrative divisions in Taiwan. Multistage stratified systematic sampling design was adopted for survey. All members of a sampled household received the interview. The research analyzed questionnaires answered by nonaboriginal male respondents aged between 20 and 59 years old, and the total number of samples analyzed read 6126. Since very few female subjects chewed betel nut, they were excluded from the analysis. Criteria of obesity was defined as body mass index⩾27 kg/m2. The variables incorporated for analysis included the respondents' status of betel nut chewing, age, educational background, presence of hypertension and diabetes mellitus, drinking and smoking status, exercise status, and demand for physical strength at job. Generalized estimating equations model was employed to estimate the odd ratios (with 95% CI) of obesity of each independent variable. Approximately 16.2% of respondents were obese. The distribution of betel nut chewing was current chewers 15.9%, ex-chewers 4.3%, and nonchewers 79.8%. After controlling above-mentioned independent variables, hypertension, diabetes mellitus, betel nut chewing, never exercising, and sedentary jobs were closely associated with obesity. The research found that betel nut chewing closely associated with obesity. The increased appetite of betel nut chewers is speculated as the underlying cause. The prospective study is needed to clarify this issue. In addition to increasing the risk of developing oral cancer, betel nut chewing seemed to be related with another health hazard: obesity.

Aims The study was designed to survey the change of adiponectin levels before and after interferon-alpha (IFN-alpha) therapy in patients with chronic hepatitis B and C infections. Methods Twenty-one biopsy-proved patients with chronic hepatitis B (10 cases) and hepatitis C (11 cases) were given IFN-alpha for a total of 24 weeks. Fasting plasma glucose, insulin and adiponectin levels were obtained before and 12 weeks after completion of IFN-alpha therapy. Insulin suppression test was conducted before and within 1 week after IFN-alpha therapy. Results The change of adiponectin levels differed significantly between responders (eight cases) and non-responders (13 cases) to IFN-alpha treatment (-4.8+/-2.2 vs. 0.5+/-1.0 microg/ml, P=0.03). After adjusting for age, gender and change in body mass index, the study found the change of adiponectin levels still significantly related to the response to IFN-alpha (P=0.04). When hepatitis B virus (HBV) and hepatitis C virus (HCV)-infected patients were separately analyzed, the adiponectin levels reported a trend to decrease in HCV responders (11.9+/-3.2 vs. 10.8+/-3.0 microg/ml, P=0.02, n=4) and HBV responders (17.7+/-4.1 vs. 9.2+/-1.0 microg/ml, P=0.10, n=4). In addition, a significant decrease of steady-state plasma glucose in insulin suppression test was noted in responders (13.6+/-1.8-11.7+/-1.2 mmol/l, P=0.03), but not in non-responders (12.3+/-1.1-11.0+/-1.0 mmol/l, P=0.20), after IFN-alpha therapy. Conclusions IFN-alpha resulted in a decrease of serum adiponectin levels but an improvement of insulin resistance in responders to the treatment. The result contradicts previous concept of the relationship between insulin resistance and adiponectin levels. Whether and how the augmented immune response, which was supposed to result from the disappearance or the profound down-regulation of the virus or viral antigens in responders to IFN-alpha treatment, contributes to the lowering of adiponectin levels needs to be further investigated.

The development of osteoarthritis (OA) has recently been implicated as a result of immune-mediated damage of chondrocytes and their supporting matrixes. Pro-inflammatory cytokines like interleukin (IL)-1 and tumor necrosis factor alpha (TNF-alpha) play pivotal roles in immunopathogenesis of OA. Because vitamins preserving anti-oxidative effects are suggested to provide protection in OA patients from joint damage, in the present study, we examined the effects and mechanisms of all-trans retinoic acid (t-RA) in suppressing pro-inflammatory cytokine-induced matrix metalloproteinases (MMPs) production in human chondrocytes. Chondrocytes were prepared from cartilage specimens of OA patients receiving total hip or total knee replacement. The protein concentration was measured by ELISA, the mRNA expression by reverse transcriptase-polymerase chain reaction, the protein expression by Western blotting, the transcription factor DNA-binding activity by electrophoretic mobility shift assay and the protein kinase activity by kinase assay. We showed that both MMP-1 and MMP-13 mRNA expression, protein production and enzyme activity induced by either IL-1 or TNF-alpha were suppressed by t-RA or different retinoid derivatives. The molecular investigation revealed that the t-RA-mediated suppression was likely through blocking p38 kinase and c-Jun N-terminal kinase-activator protein-1 signaling pathways. In contrast, t-RA had no effect on extracellular signal-regulated kinase activity, nuclear factor (kappa)B (NF-(kappa)B) DNA-binding activity and I(kappa)B(alpha) degradation. Furthermore, we showed that t-RA could reduce IL-1-induced TNF-alpha production in chondrocytes. Our results suggest that vitamin A may protect OA patients from pro-inflammatory cytokine-mediated damage of chondrocytes and their supporting matrixes.

Accepted 28 April 2005Background We established the association between arsenic ingestion and increased risk ofvascular diseases associated with diabetes. However, the specific microvasculardiseases in relation to arsenic exposure level have not been well reported.Methods The study population was obtained through national health database linkage.A total of 28 499 subjects living in the study area were successfully linked withtheir medical records from the National Health Insurance database in 1999–2000.The arsenic concentrations of artesian well water in the villages of the study areawere utilized as indices of previous ingestion level. Both stratified analysis andunconditional logistic regression were used to examine mainly neurologicaland renal disease in relation to the arsenic exposure taking into accountdiabetes status.Results The age-adjusted and gender-adjusted prevalence of microvascular diseases was7.51% [95% confidence interval (CI) 7.50–7.51] for arsenic level of 0.1 mg/litre,and then increased from 6.59% (6.59–6.60) for the arsenic concentrations of0.1–0.29 mg/litre to 8.02% (8.02–8.03) and 11.82% (11.81–11.83) for those of0.3–0.59 mg/litre and 0.6 mg/litre in non-diabetic subjects. For diabeticpatients, the prevalence was 16.41% (95% CI 16.37–16.45), 15.85%(15.8–15.9), 21.69% (21.6–21.8), and 28.31% (28.2–28.4) for arsenic levels0.1, 0.1–0.29, 0.3–0.59, and 0.6 mg/litre, respectively. The prevalence ofmicrovascular diseases increased significantly with arsenic exposure, especially athigher levels, and the relationship is stronger in diabetics than in non-diabeticsubjects. The results for neurological disease are very similar, and the patterns arethe same for renal disease.Conclusions The increased prevalence of microvascular diseases, including neurological andrenal disorders, is associated with arsenic ingestion. This excess risk was furtherelevated in diabetic subjects. Further studies are necessary to verify thehypotheses of threshold or dose–response relationships.Keywords Arsenic, health insurance, neurological disease, renal disease, environmentalhealth, microvascular disease, non-insulin-dependent diabetes mellitus, waterpollutants1of8

Background . Diabetes has been the fifth leading cause of death in Taiwan since 1987, and the complications are a burden to the patients, their families, and society. Purpose . The purpose of this study was to examine the self-control behaviors of diabetics and associated factors. Methods . Data for this study came from the 2001 National Health Interview Survey in Taiwan. Subjects with diabetes confirmed by medical professionals, aged 40 years or older, were included. Self-care behaviors included any of the following: taking medicine regularly, reducing weight, avoiding cigarettes or alcohol, exercising, practicing diet control, and maintaining a regular life style and avoiding late hours. The factors considered were demographic factors including age, sex, education, income, and health behavior factors including smoking, drinking alcohol, chewing betel nuts, and health conditions such as existence of other chronic diseases, limitation of activity of daily living (ADL), and self-perceived health. Results . There were 764 subjects aged 40 years or older who were diagnosed with diabetes. Logistic regression showed that females, those with older age or chronic disease such as hypertension or dyslipidemia, and those with long duration of diabetes took medicine regularly. Old age group, middle school educated, and longer duration of the disease had a higher chance of using any self-care method than their counterparts. Conclusion . Attention should be given to the younger age group, shorter duration of the disease in practicing self-care of diabetes.

Background The aim of the present study was to examine the impact of the clinical use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) on the association between the urinary albumin/creatinine ratio (ACR) and ankle-brachial index (ABI) or peripheral arterial disease (PAD) in elderly Taiwanese patients with type 2 diabetes mellitus. Methods and Results Two-hundred and ninety patients (108 men, 182 women) aged ≥65 years (mean ± SD, 71.6 ±4.9) were cross-sectionally studied. ACR was expressed as the natural logarithm [ln(ACR)] and divided into normoalbuminuria (

OBJECTIVE—To study the effect of body composition and adiponectin on insulin resistance and β-cell function in schoolchildren during puberty. RESEARCH DESIGN AND METHODS—Plasma adiponectin level and its relationships with insulin sensitivity and β-cell function were analyzed in 500 randomly recruited nondiabetic Taiwanese schoolchildren (245 boys and 255 girls) aged 6–18 years in a national survey program for diabetes in 1999. Insulin resistance and β-cell function were evaluated by homeostasis model assessment (HOMA). Plasma adiponectin concentrations were determined with radioimmunoassay. RESULTS—Plasma glucose levels remained stable, whereas insulin resistance increased with a compensatory rise in β-cell function during this period. A transient drop of adiponectin level with a trough at 10–12 years was found in boys but not in girls. This pubertal drop of adiponectin levels in boys coincides with the sharp rise in testosterone concentration. A negative correlation between testosterone levels and adiponectin concentration was also noted in boys (r = −0.142, P = 0.032). Plasma adiponectin levels correlated inversely with relative body weight, fasting insulin concentrations, and insulin resistance index by HOMA in boys aged 15–18 years and in girls aged 11–14 years. No association was observed between adiponectin levels and β-cell function by HOMA. CONCLUSIONS—There is a transient drop in the level of adiponectin during male puberty, correlated with the increase in testosterone level in boys. Plasma adiponectin levels were inversely correlated with obesity and insulin resistance in boys and girls during the pubertal period.

Adiponectin is an adipose-derived plasma protein. Recently the plasma adiponectin levels have been linked to most variables of metabolic syndrome (MS) and risk factors of coronary artery disease (CAD). However, its relation with blood pressure is yet unclear. Here we report the relationship between the plasma adiponectin levels and blood pressures in 68 female adolescents (age 16.1 +/- 1.8 yr). We found that the plasma adiponectin levels correlated significantly with both the systolic blood pressure (SBP) (gamma = -0.47, P = 0.000) and diastolic blood pressure (gamma = -0.30, P = 0.014). In linear regression models with adjustment for age and the other anthropometric or metabolic factors, only the SBP, but not the diastolic blood pressure, was independently related to the plasma adiponectin levels. The mean plasma adiponectin levels between the subjects in the lowest quartile of SBP (SBPor = 100 mm Hg) and those in the highest quartile (SBPor = 118 mm Hg) were significantly different (P = 0.035). In conclusion, the SBP is inversely related to the plasma adiponectin independent of the other variables of the MS and other risk factors of CAD in healthy adolescent females. This further strengthens the potential roles of adiponectin in the pathophysiology of MS and CAD.

The purpose of the study is to observe the relation between anthropometric measurements, focusing on sagittal abdominal diameter (SAD), and insulin sensitivity indices in Chinese hypertensive patients and their siblings. In total, 907 participants, 537 hypertensive and 370 nonhypertensive, from 311 Taiwanese families were drawn from the Stanford Asia and Pacific Program for Hypertension and Insulin Resistance for the study. The participants received anthropometric measurements and 75-g oral glucose tolerance tests after an overnight fast. Fasting insulin, homeostasis model assessment for insulin resistance (HOMA-IR), and the insulin sensitivity index ISI(0,120) were chosen as surrogate measures of insulin sensitivity. In addition to Pearson and partial correlations, we used generalized estimating equations (GEEs) to examine the association between anthropometric measurements and insulin sensitivity indices. A small deviance in the GEEs indicates the goodness of model fit, irrespective of the independence among variables. The hypertensive patients were older in age, wider in waist circumference (WC), larger in body mass index (BMI) and SAD, and more insulin resistant than the nonhypertensive counterparts. The logarithmic transformation of fasting insulin, HOMA-IR, and ISI(0,120) significantly correlated with SAD, WC, and BMI before and after adjustments for age and sex. The deviances of SAD in the GEEs were similar to those of WC in all subjects, while BMI had smaller deviances than SAD and WC in the hypertensive patients. Our results suggest that the performance of SAD in predicting insulin sensitivity is comparable with WC in Chinese hypertensive patients and their siblings. BMI, however, seems to have better association with insulin sensitivity than SAD and WC in the patients with hypertension.

The purpose of this study was to examine the effects of a nurse-designed discharge-planning project in a teaching hospital in Taiwan. A before-and-after quasi-experimental design was used. Craniotomy (n = 112) and stroke (n = 171) patients were recruited and divided into control and intervention groups. Outcome indicators included length of hospital stay, change in activities of daily living (ADL), rate of nursing home placement, rate of unplanned readmission, and level of satisfaction. In the stroke sample length of hospital stay was shorter in the intervention group than in the control group. In the craniotomy sample unplanned readmission was less frequent in the intervention group than in the control group. No differences were found between the control and intervention groups in other outcome indicators. © 2003 Wiley Periodicals, Inc. Res Nurs Health 26:53–63, 2003

YANG, WEI-SHIUNG, WEI-JEI LEE, TOHRU FUNAHASHI, SACHIYO TANAKA, YUJI MATSUZAWA, CHIA-LING CHAO, CHI-LING CHEN, TONG-YUAN TAI, AND LEE-MING CHUANG. Plasma adiponectin levels in overweight and obese Asians. Obes Res. 2002;10:1104 –1110. Objective: Hypoadiponectin has been documented in subjects with obesity, diabetes mellitus, or coronary heart disease, suggesting a potential use of plasma adiponectin in following the clinical progress in subjects with metabolic syndrome (MS). In this study, we investigated the plasma adiponectin levels in relation to the variables of MS among overweight/obese Asian subjects. Research Methods and Procedures: The plasma adiponectin, anthropometric and biochemical measurements, oral glucose tolerance tests (OGTT), and modified insulin suppression tests were performed on 180 overweight/obese Asian subjects [body mass index (BMI) 23 kg/m 2 ], including 47 subjects with morbid obesity (BMI 40 kg/m 2 ). Results: The plasma adiponectin levels negatively correlated with BMI, waist-to-hip ratio, fasting plasma glucose, insulin, triglyceride, uric acid levels, hyperinsulinemia, and glucose intolerance in OGTT, but positively with highdensity lipoprotein-cholesterol. In contrast, they were not related to blood pressure and total cholesterol. Moreover, insulin sensitivity, measured by quantitative insulin sensitivity check index (QUICKI) or in insulin suppression tests, significantly correlated with the plasma adiponectin levels. Among morbidly obese subjects, only the waist-to-hip ratio correlated with the plasma adiponectin levels. Using multivariate linear regression models, the area under curve of plasma glucose in OGTT and high-density lipoprotein-cholesterol among the overweight/obese subjects and WHR among the morbidly obese subjects were significantly related to the plasma adiponectin levels after adjustment for other variables. Discussion: In overweight/obese Asians, the plasma adiponectin levels significantly correlated with various indices of MS except hypertension. Whether the plasma adiponectin level could be a suitable biomarker for following the clinical progress of MS warrants further investigation.

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.

To elucidate the direct effect of rosiglitazone (RSG), a new thiazolidinedione antihyperglycemic agent, on pancreatic insulin secretion, an in situ investigation by rat pancreatic perfusion was performed. At a basal glucose concentration of 6 mmol/l, RSG (0.045–4.5 μmol/l) stimulated insulin release in a dose-dependent manner. In addition, 4.5 μmol/l RSG potentiated the glucose (10 mmol/l)-induced insulin secretion. Both the first and second phases of glucose-induced insulin secretion were significantly enhanced by RSG, by 80.7 and 52.4%, respectively. The effects of RSG on insulin secretion were inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. In contrast, the glucose-stimulated insulin secretion was not affected by LY294002. The potentiation effect of RSG on glucose-stimulated insulin secretion, in both the first and second phases, was significantly blocked by LY294002. These results suggest that RSG has a direct potentiation effect on insulin secretion in the presence of 10 mmol/l glucose, mediated through PI3K activity. The inability of LY294002 to inhibit glucose-induced insulin secretion suggests that different pathways are responsible for glucose and RSG signaling.

The purpose of the present study was to examine the characteristics of healthcare costs for diabetic patients in Taiwan. The study analyzed claim data from the Bureau of National Health Insurance for the period from July 1997 to June 1998. There were 536159 documented diabetic patients who were treated within the universal healthcare system in Taiwan during this study period. The annual number of visits of these diabetic patients was 6.2% of the total outpatient visits of all patients due to all causes during the one-year study period. Diabetes-related problems were the causes of 25.2% of outpatient visits among diabetic patients, while 74.8% of visits were for causes unrelated to diabetes. The distribution of treatment for the diabetic patients was by oral hypoglycemic agents 88.3%, insulin only 6.9%, and a combination of insulin and oral agents 4.8%. Diabetic patients accounted for 4,724,711 hospital inpatient days during the study period, which was 22.1% of the total inpatient days in Taiwan. Of the inpatient admissions, 13.9% were for diabetes as the principal cause, 23.4% were for diabetes-related disease, and 62.7% were for causes unrelated to diabetes. The direct costs of healthcare for the documented diabetic patients was 11.5% of the total costs of healthcare in Taiwan, and was 4.3 times higher than the average costs of care for non-diabetic individuals.

The peroxisome proliferator activated receptor (PPAR) γ2 is a transcription factor that has been shown to be involved in adipocyte differentiation, adipogenesis, and insulin sensitivity. To address the role of PPARγ2 in glucose homeostasis and insulin sensitivity, among many other objectives, we conducted a sibling-controlled association study in a multicenter program – the Stanford Asian-Pacific Program in Hypertension and Insulin Resistance (SAPPHIRe). Approximately 2525 subjects in 734 Chinese and Japanese families have been recruited from six field centers for SAPPHIRe. In total, 1702 subjects including parents and siblings from 449 families have been genotyped for PPARγ2, of which 328 families were Chinese and 121 Japanese. Only 88 subjects of the 1525 siblings screened for the P12A polymorphism were found to be carriers of the A variant, the most common variant of the PPARγ2 gene. A variant frequencies of the siblings were 4.27% in Chinese and 2.72% in Japanese. A sibling-controlled association study was performed through genetically discordant sibships (i.e., P/P genotype vs. P/A + A/A genotypes). Specifically, we examined whether there were differences in metabolic variables between the discordant siblings within families. In total, 88 subjects carrying either 1 or 2 A alleles had at least one sibling who was discordant for the P12A polymorphism, yielding a total of 180 individuals from 47 families for analyses, among which 92 siblings were homozygous for wild-type P allele. Siblings with the A variant tended to have lower levels of fasting plasma glucose (OG-10), and lower glucose levels at 60 min following oral glucose loading after adjusting for age, gender, and body mass index. Using a mixed model treating family as a random effect, we found that P12A polymorphism of the PPARγ2 gene contributes significantly to the variance in fasting plasma glucose, glucose level at 60 min, and insulin-resistance homeostasis model assessment. Our results suggest that within families siblings with the A variant in the PPARγ2 gene may be more likely to have better glucose tolerance and insulin sensitivity independent of obesity in Chinese and Japanese populations.

In the mouse, the SH3P12 or the c-Cbl-associated protein (CAP) has been shown as an important signaling molecule in insulin-stimulated glucose uptake. The human homolog for the sorbin and SH3-domain-containing-1 gene, termed SORBS1, might play a role in human disorders with insulin resistance. To explore the genetic role of SORBS1 in human obesity and type 2 diabetes, we investigated the nucleotide polymorphisms in the SORBS1 gene with molecular scanning. After scanning for a total of 13,136 bp in each of 40 chromosomes, we have identified 14 single nucleotide polymorphisms (SNPs) in the human SORBS1 gene. Among them, two SNPs affected amino acid coding (R74W and T228A), four occurred within exons but did not affect amino acid coding, and the remaining eight occurred within introns, which were located outside of the consensus region of the splicing mechanism. Further studies in 202 non-obese, 113 obese and 455 subjects with type 2 diabetes revealed that the A-allele of the T228A polymorphism in exon 7 exerted a protective role for both obesity [relative risk 0.466; 95% confidence interval (95% CI) 0.265-0.821] and diabetes (relative risk 0.668; 95% CI 0.472-0.945). Neither allele of the R74W polymorphism was associated with either obesity or diabetes. In conclusion, our results suggest that the A228 allele of the T228A polymorphism of the SORBS1 gene is a protective factor for both obesity and diabetes, and also imply that the SORBS1 gene plays an important role in the pathogenesis of human disorders with insulin resistance.

SH3P12/CAP/ponsin, a gene product with a sorbin homology domain and three consecutive SH3 domains in the carboxy-terminus, has been isolated from murine adipocytes and identified as an important adaptor during insulin signaling. Here we describe the cloning, mapping, and expression of the human homologue, termed SORBS1 (sorbin and SH3 domain containing 1). Multiple transcripts of this gene with different mRNA isoforms were observed among different tissues. Here we report 13 alternatively spliced exons, which were ascertained from the full-length cDNA cloned in adipose, liver, and skeletal muscle tissues. Among the major isoforms, the shortest, 2223-bp, open reading frame (ORF) encodes a protein with a predicted molecular weight of 81.5 kDa, while the longest, 3879-bp, ORF encodes a protein of about 142.2 kDa. This gene was mapped to human chromosome 10q23.3-q24.1, which is a candidate region for insulin resistance found in Pima Indians. In human hepatoma Hep3B cells, SORBS1 was partly dissociated from the insulin receptor complex and bound to c-Abl protein upon insulin stimulation. This interaction with c-Abl was through the third SH3 domain and a possible conformational change of SORBS1 induced by insulin. Our data suggest that c-Abl oncoprotein via SORBS1 might play a role in the insulin signaling pathway.

Currently, diabetes mellitus is the fifth leading cause of death in Taiwan. The trends of diabetes mortality is increasing steadily. Epidemiologic studies also showed increasing prevalence of diabetes mellitus over the past few decades. The incidence of diabetes mellitus in Taiwan has only been studied in recent 10 years. The areas that have been included as study areas for diabetes incidence are Kin-Chen (Kinmen), Chu-Dung, Pu-Tzu, Pu-Li and Pu-Tai. The reported incidence rates ranged from 1.0 to 4.0% per year for people with varying degrees of baseline plasma glucose levels not reaching the diagnosis of diabetes mellitus according to the criteria of the World Health Organization. Age, baseline glucose level, and obesity are important predictors for the development of diabetes mellitus. In the Pu-Tai study, which was aimed at following a group of people who had been living in the hyperendemic villages of blackfoot disease and had been exposed to arsenic from drinking artesian well water, the incidence of diabetes mellitus was calculated to be 27.4 per 1000 person years. The incidence of diabetes mellitus in these arseniasis-hyperendemic villages correlated with age, body mass index and cumulative arsenic exposure.

Diabetes mellitus (DM) in adults is a global health problem, although its prevalence varies widely between different populations and the rate has generally increased worldwide. In Taiwan, the mortality rate from DM has almost doubled over the past 10 years. The prevalence of DM in Taiwan was established between 1985 and 1996 and the rates were between 4.9 and 9.2%. The prevalence of impaired glucose tolerance (IGT) was 15.5% (men 15% and women 15.9%). The prevalence of DM and IGT increased significantly with age for both genders. The significant factors associated with newly diagnosed DM were age, BMI, family history of DM, systolic blood pressure (hypertension), physical activity and serum triglyceride levels. The prevalence of large vessel disease (LVD) in DM and non-diabetic subjects were 20.0 and 12.9%, respectively. Among diabetics, 15.8% had ischemic heart disease (IHD), 1.7% leg vessel disease (leg VD), and 2.5% stroke. In non-diabetics, the prevalence of the aforementioned macroangiopathies were 11.5, 0.2 and 1.2%, respectively. The diabetics had a significantly higher prevalence of macrovascular disease than non-diabetic subjects. The most significantly associated with the LVD was serum cholesterol levels. Serum cholesterol and HbA1(c) were significantly associated with the development of IHD. Cigarette smoking and female gender were significantly associated with the leg VD. The prevalence of diabetic retinopathy (DR) was 35.0%. (background DR 30%, preproliferative DR 2.8% and proliferative DR 2.2%, respectively.) The prevalence of DR for previously and newly diagnosed diabetics were 45.2 and 28.3% (men 42.8 vs. 33.3% and women 47.5 vs. 24.8%), respectively. From multiple logistic regression analysis, duration of DM was the most important risk factor related to DR. Diabetic subjects treated with insulin had a higher risk of developing retinopathy than those treated with dietary control. The prevalence of nephropathy and neuropathy were 12.9 and 23.5%, respectively. For those patients with and those without nephropathy and neuropathy, the duration of DM, percentage of insulin treatment, percentage of hypertension, and fasting plasma glucose were significantly different. Diabetic duration, hypertension, insulin treatment and glycemic control consistently correlated with nephropathy and neuropathy. In conclusion, the prevalence of DM in Taiwan was between 4.9 and 9.2%, and the prevalence of IGT was 15.5%. The possible risk factors of newly diagnosed diabetes were age, family history of DM, BMI, SBP (hypertension), physical activity and triglyceride levels. Diabetes in Chinese subjects share many characteristics similar to other Asian populations. The burden imposed by the chronic complications of diabetes is massive. In Taiwan, the mortality rates from DM have increased greatly over the past 10 years. Reduction of the modificable risk factors such as BMI, hypertenion and dyslipidemia, and increase of physical activity and good glycemic control through public health efforts may help to reduce the risk of DM and its chronic complications.

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.

As a major counterregulatory hormone of insulin, glucagon plays an important role in regulating glucose homeostasis through its binding to the glucagon receptor. Recently a missense mutation in the glucagon-receptor gene (Gly40Ser) was found to be associated with type 2 diabetes in France and Sardinia, with a frequency as high as 4.6% and 8.3%, respectively. This mutation was also found to be associated with essential hypertension in the white population with a frequency of 5.4%. To investigate the role of this mutation in the pathogenesis of type 2 diabetes and essential hypertension in Taiwanese population, we screened 121 normal controls, 213 unrelated subjects with type 2 diabetes, and 107 unrelated subjects with essential hypertension by use of polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP). None of the Taiwanese subjects recruited in the study had this receptor mutation. Our results demonstrate a strong genetic heterogeneity among the ethnic group and suggest that the Gly40Ser mutation of the glucagon receptor gene plays little role, if any, in the pathogenesis of type 2 diabetes and essential hypertension in the Taiwanese population.

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.

IRS-1 has been found to relay the signals from the receptors for insulin, insulin-like growth factor-1, growth hormone, and many cytokines for the downstream effects in the various cell types tested. For interleukin 4 signaling, most studies were performed on hematopoietic cells and cell lines transfected with rat liver IRS-1 cDNA. In a liver cell lineage, IRS-1 expression has been found to be increased in hepatoma cells and hepatocytes in regenerating liver. To elucidate the possible function and the signal transduction pathway for interleukin 4, in comparison with insulin, in liver cells, we used the Hep 3B hepatoma cell line as a model system. Following insulin and interleukin 4 stimulation, rapid tyrosyl phosphorylation of IRS-1 occurred. Interleukin 4, but not insulin, stimulated the tyrosine phosphorylation of JAK1 and, to a lesser extent, JAK2. In contrast to the other cell types, the association of IRS-1 and Grb2 through the SH2 of Grb2 was demonstrated after IL-4 and insulin stimulation of the Hep3B hepatoma cells. Both insulin and interleukin 4 stimulated tyrosine phosphorylation and the enzyme activity of Erk1 kinase. Our results indicate that interleukin 4 and insulin might modulate hepatic cell growth and differentiation through many different or common pathways for the activation of JAK kinases and the usage of IRS-1 as a docking protein. The binding of IRS-1 with Grb2 after IL-4 as well as insulin stimulation may lead to MAP kinase activation, probably through the Grb2/sos/p21ras pathway.

The purpose of this study was to examine the correlation between previous arsenic exposure and peripheral vascular disease after stopping consumption of high-arsenic artesian well water for more than two decades in blackfoot disease endemic villages in Taiwan. A total of 582 adults (263 men and 319 women, aged 52.6 +/- 10.6 years) living in these villages underwent Doppler ultrasound measurement of systolic pressures on bilateral ankle (posterior tibial and dorsal pedal) and brachial arteries and estimation for long-term arsenic exposure. The diagnosis of peripheral vascular disease was based on an ankle-brachial index (the ratio between ankle and brachial systolic pressures)0.90 on either side. Three indices of arsenic exposure were estimated: (1) duration of living in blackfoot disease endemic villages; (2) duration of artesian well water consumption; and (3) cumulative arsenic exposure in mg/l-years based on the detailed history of residential addresses and artesian well water consumption and the arsenic concentration in artesian well water. Multiple logistic regression analysis was used to assess the association between peripheral vascular disease and arsenic exposure. A dose-response relation was observed between the prevalence of peripheral vascular disease and the long-term arsenic exposure. The odds ratios (95% confidence intervals) after adjustment for age, sex, body mass index, cigarette smoking, serum cholesterol and triglyceride levels, diabetes mellitus and hypertension were 2.77 (0.84-9.14), and 4.28 (1.26-14.54) for those who had cumulative arsenic exposure of 0.1-19.9 andor = 20.0 mg/l-years, respectively, compared with those who were not exposed. This study suggests a close relation between long-term arsenic exposure and peripheral vascular disease in blackfoot disease endemic villages in Taiwan after stopping consumption of artesian well water.

Abstract To examine the association between long-term exposure to inorganic arsenic and the prevalence of hypertension, we studied a total of 382 men and 516 women residing in villages where arseniasis was hyperendemic. Hypertension was defined as a systolic blood pressure of 160 mm Hg or greater, a diastolic blood pressure of 95 mm Hg or greater, or a history of hypertension treated regularly with antihypertensive drugs. The long-term arsenic exposure was calculated from the history of artesian well water consumption obtained through standardized interviews based on a structured questionnaire and the measured arsenic concentration in well water. Residents in villages where long-term arseniasis was hyperendemic had a 1.5-fold increase in age- and sex-adjusted prevalence of hypertension compared with residents in nonendemic areas. Duration of artesian well water consumption, average arsenic concentration in drinking water, and cumulative arsenic exposure were all significantly associated with hypertension prevalence. The higher the cumulative arsenic exposure, the higher the prevalence of hypertension. This dose-response relation remained significant after adjustment for age, sex, diabetes mellitus, proteinuria, body mass index, and serum triglyceride level. The results suggest that long-term arsenic exposure may induce hypertension in humans.