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Self-poisoning with pesticides accounts for approximately one-third of all suicides worldwide. To expedite rescue in the emergency department, it is essential to develop a point-of-care analytical method for rapid identification of ingested pesticides. In this study, five of the most common pesticides ingested by self-poisoning patients in Taiwan were analyzed from oral fluid samples. Pesticide-oral fluid mixtures were applied on a cotton swab and then transferred into methanol. A metallic probe was used to sample the methanol solution for subsequent thermal desorption-electrospray ionization mass spectrometry analysis. Altogether, pesticide sampling, transfer, desorption, ionization, and detection took less than 1 min. The reproducibility of this method (n = 6) was shown in the observed low-relative standard deviation (

Although hypersensitivity reaction to insulin was supposed to be less-frequent with current insulin analogue, case reports with different types of allergic reactions to insulin analogue were still reported. The most common form is type I hypersensitivity reaction with IgE-mediated. Besides, type III (IgG and IgM-mediated) and type IV (T-cell mediated delayed reaction) hypersensitivity reactions were also reported. Here we presented a long-standing type 2 diabetes with insulin requirements with hypersensitivity reactions to insulin actrapid, insulin aspart, insulin glargine, insulin detemir, and biphasic insulin aspart 30. Insulin desensitization was performed as initial management but failed as skin biopsy with immunohistochemical staining proved type IV hypersensitivity reaction. We continued with the next treatment approach using subcutaneous injection with the mixture of biphasic insulin aspart 30 and dexamethasone to alleviate allergy, and the result was successful with steroid-free biphasic insulin aspart 30 injection eight months later. Besides, the treatment effect had lasted after ten years even with switched type of insulin analogue from biphasic insulin aspart 30 to insulin glargine and insulin aspart. The case report demonstrated a good example of how clinicians deal with the rare but important questions of hypersensitivity reactions to insulin analogue. Keywords: Insulin, Hypersensitivity, Glucocorticoids

Background O-GlcNAcylation is an important mechanism of diabetic complication. Retinoid homeostasis regulates cell-physiological functions through STRA6-retinol signaling. Therefore, we investigated whether O-GlcNAcylation disrupted STRA6-retinol signals in diabetes. Methods Immunoprecipitation and proximity ligation assay were used to investigate O-GlcNAcylation of STRA6-retinol signals in kidneys of db/db and ob/ob mice. Western blot and immunohistochemistry were done for STRA6/CRBP1/LRAT/RALDH1/RARs pathway, GFAT, OGT, TGFβ1 and collagen 1 level. HPLC and ELISA for retinol, retinal, and retinoic acid concentrations were performed in vivo and vitro. RBP4 binding with STRA6 was measured in vitro. To verify whether O-GlcNAcylation disrupted STRA6-retinol signals, treatment of TMG and OSMI-1, transfection of OGA and OGT, and OGT siRNA were performed in HK-2 cells. Results STRA6 and RALDH1 were highly O-GlcNAc-modified in glomeruli and tubules of db/db and ob/ob mice. RBP4, p-Try, p-JAK2, and p-STAT5 on STRA6 immunoprecipitate were reduced. Cellular retinol signals (CRBP1, LRAT, ADH, retinol, retinal, RA, RARα, RARγ and RXRα) remarkably decreased in kidneys of db/db, ob/ob mice and HG-cultured cells. TMG and OGT transfection induced O-GlcNAcylation of STRA6 and RALDH1, repressed RBP4-bound STRA6, and retinol signals in NG-cultured cells. OSMI-1, OGA transfection, and OGT silence reversed O-GlcNAc-modification of STRA6 and RALDH1, and rescued the decrease of retinol signals, and reversed the increase of TGFβ1 and collagen 1 in HG-treated cells. Conclusions O-GlcNAcylation significantly modified STRA6 and RALDH1, suppressed RBP4 binding activity, and disrupted retinol signals in the kidney of diabetes. General significance This study first indicates that STRA6-retinol signals were directly disrupted by O-GlcNAcylation in diabetic kidney.

The triglyceride (TG) to high-density lipoprotein cholesterol (HDL-C) ratio has been reported to be a marker of insulin resistance. The aim of this study was to investigate associations between the TG/HDL-C ratio and micro- and macroangiopathies in patients with type 2 diabetes mellitus (DM).A total of 1,981 (851 male and 1,130 female) patients with type 2 DM were enrolled from our outpatient clinic. These patients were stratified into 4 groups according to TG/HDL-C ratio quartiles.There were significant trends for stepwise increases in albuminuria ≥30 mg/g ( P.001), coronary artery disease (CAD, P = .040), cerebrovascular disease (CVA, P = .002) and ankle-brachial index (ABI)0.9 ( P = .001) corresponding to TG/HDL-C ratio quartiles, but not diabetic retinopathy ( P = .105). Furthermore, quartile 4 of the TG/HDL-C ratio was significantly associated with albuminuria, CAD, CVA, and ABI0.9 after multivariate analysis compared to quartile 1.A high TG/HDL-C ratio was significantly associated with albuminuria, CAD, CVA, and peripheral artery occlusive disease (PAOD) in patients with DM, which translated into an increased risk of cardiovascular disease.ABI = ankle-brachial index; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin II receptor blocker; BMI = body mass index; CAD = coronary artery disease; CI = confidence interval; CVA = cerebrovascular disease; DM = diabetes mellitus, DR = diabetic retinopathy; eGFR = estimated glomerular filtration rate; HbA1c = glycated hemoglobin A1c; HDL-C = high-density lipoprotein cholesterol; OR = odds ratio; PAOD = peripheral artery occlusive disease; TGs = triglycerides.

Western dietary patterns have been linked with kidney disease. This study investigated the association between Chinese dietary patterns and kidney disease in a Taiwanese population with type 2 diabetes and evaluated dietary fatty acid patterns, a kidney-related dietary biomarker.We recruited 838 patients with type 2 diabetes and used their dietary and renal data obtained from three repeated measures in 2008, 2009 and 2010. Diet was assessed using food-frequency questionnaires, and factor analysis was performed to identify dietary patterns. Albuminuria was defined by having an albumin-to-creatinine ratio=30 mg/g and kidney dysfunction by estimated glomerular filtration rate60 mL/min/1.73m2. Generalized estimating equation models were used to estimate ORs (95% CIs) of kidney disease adjusted for covariates. Erythrocyte fatty acids were only measured in blood samples collected in 2008.Three dietary patterns were identified: high fat-meat, traditional Chinese food-snack, and fish-vegetable. In the adjusted model, the high fat-meat and traditional Chinese food-snack diets were not associated with any kidney outcomes. The fishvegetable diet was inversely associated with kidney dysfunction (quartile 4 vs 1, OR: 0.75, 0.58-0.97), but not associated with albuminuria. A higher fish-vegetable diet factor score was associated with higher n-3 fatty acid levels.In patients with diabetes, we found greater adherence to a fish-vegetable diet to be associated with better kidney function and greater n-3 fatty acid profiles. The inclusion of repeated dietary assessments and dietary biomarker measurements in future diet-disease research, especially in patient populations, may provide more definitive risk evaluation.

The global incidence and prevalence of type 2 diabetes have been escalating in recent decades. Patients with type 2 diabetes have an increased risk of atherosclerotic cardiovascular disease (ASCVD). About two-thirds of death in type 2 diabetes are due to ASCVD, including 40% from coronary heart disease (CHD), 15% from heart failure (HF), and 10% from stroke. The association between hyperglycemia and elevated CV risk has been demonstrated in multiple cohort studies. However, clinical trials of intensive glucose reduction did not significantly reduce macrovascular outcomes. It remains unclear whether the absence of demonstrable benefits is attributed to the inclusion of patients with far advanced ASCVD in whom a short treatment period is barely enough for CV protective effects to be shown, or complications associated with the treatment such as hypoglycemia hamper the beneficial effects to manifest, or simply glucose-lowering per se is ineffective. Since the US FDA issued a mandate in December 2008 that every new anti-diabetic agent requires rigorous assessments of its CV safety, there have been more than 200,000 patients enrolled in a number of randomized controlled trials (RCTs), and around half of them have been completed and published. The results of these CV outcome trials are important for clinicians in their clinical practice, and also provide an opportunity for academic society to formulate treatment guidelines or consensus to provide specific recommendations for glucose control in various CV diseases. The Taiwan Society of Cardiology (TSOC) and the Diabetes Association of Republic of China (DAROC), aiming to formulate a treatment consensus in type 2 diabetic patients with CVD, have appointed a jointed consensus group for the 2018 Consensus of TSOC/DAROC (Taiwan) on the Pharmacological Management of Patients with Type 2 Diabetes and CV Diseases. The consensus is comprised of 5 major parts: 1) Treatment of diabetes in patients with hypertension, 2) Treatment of diabetes in patients with CHD, 3) Treatment of diabetes in patients with stage 3 chronic kidney disease, 4) Treatment of diabetes in patients with a history of stroke, and 5) Treatment of diabetes in patients with HF. The members of the consensus group comprehensively reviewed all the evidence, mainly RCTs, and also included meta-analyses, cohort studies, and studies using claim data. The treatment targets of HbA1c were provided. The anti-diabetic agents were ranked according to their clinical evidence. The consensus is not mandatory. The final decision may need to be individualized and based on clinicians' discretion.

The n-3 polyunsaturated fatty acids (PUFAs) and the inflammatory indicator, interleukin-6 (IL-6), have been implied in the development of renal dysfunction. This longitudinal study examined the effect of n-3 PUFAs and IL-6 on the risk of renal function decline and explored whether n-3 PUFAs modify the effect of inflammatory indicators on renal dysfunction risk in type 2 diabetes.Studying 676 type 2 diabetic patients, we analyzed erythrocyte fatty acids and inflammatory markers in 2008 and estimated glomerular filtration rate (eGFR) in 2008 and 2012. Renal function decline was defined as an eGFR decline of ≥25% over a 4-year period.Multivariable logistic regression revealed erythrocyte total PUFAs, n-3 PUFAs, and n-3/n-6 PUFA ratio correlated negatively with risk of renal function decline (OR = 0.75, 0.78, and 0.61, respectively, all p0.01), while n-6 PUFAs did not. IL-6 independently predicted risk of renal dysfunction (OR = 1.18, p = 0.015). Stratifying erythrocyte PUFAs into low (50(th) percentile) or high group (≥50(th) percentile), we found a positive association between IL-6 and risk of renal dysfunction only in the low n-3 PUFA (OR = 1.27, p = 0.035), low n-3/n-6 PUFA (OR = 1.27, p = 0.034), and low total PUFA groups (OR = 1.36, p = 0.005), but not in the high groups.High PUFA concentrations, especially n-3 or higher n-3/n-6 PUFA ratio, may exert protective effects against renal function impairment in type 2 diabetic patients. Whether the effect is mediated via modification of inflammatory biomarker such as IL-6 by high n-3 PUFA status warrants further investigation.

BACKGROUND Little is known about how a universal National Health Insurance program with cost-containment strategies affect costs and quality of diabetes care. OBJECTIVES To examine the trends of healthcare use and costs for patients with type 2 diabetes mellitus (T2DM) in Taiwan over the last decade, and to identify factors associated with high healthcare cost and poor diabetes care. RESEARCH DESIGN We delineated the pattern of healthcare use and costs for T2DM in 2000-2010. Generalized linear and logistic regression models were used to identify factors associated with medical costs and diabetes care. SUBJECTS Representative adult T2DM patients and age-matched and sex-matched nondiabetes individuals were selected from the 2000, 2005, and 2010 National Health Insurance Research Databases. MEASURES Healthcare use included physician visits, hospital admissions, and antidiabetic drug prescriptions. Indicators of diabetes management included completeness of recommended diabetes tests and medication adherence, assessed using medication possession ratio. RESULTS The total healthcare cost per diabetes patient was approximately 2.8-fold higher than that for nondiabetes individual. The growth of healthcare cost per diabetes patient was significantly contained by about 3694 New Taiwan dollars (3.6%) between 2005 and 2010, but diabetes care improved over the decade. Diabetes duration, income, place of residence, continuity of care, and enrollment to a pay-for-performance program were associated with healthcare costs and diabetes management. Some public health measures implemented to support diabetes care were also discussed. CONCLUSIONS Healthcare costs could be controlled without sacrificing the quality of diabetes care by implementing pay-for-performance programs and effective health policies favorable for diabetes care.

Emerging evidence suggests that glycemic variability may be a more reliable measure of glycemic control than mean HbA1c in type 2 diabetes mellitus. This study aimed to determine if HbA1c variability is associated with cardiovascular events in type 2 diabetic patients and if different renal functions affect such association. This longitudinal study enrolled 8259 diabetic patients from the Kaohsiung Medical University Research Database in 2009 and were followed-up until 2015. Intra-individual HbA1C variability was defined as the standard deviation (SD) of HbA1c and cardiovascular events were defined as hospitalization for coronary artery disease, unstable angina, myocardial infarction, stroke, peripheral artery disease, and cardiovascular death. The patients were grouped into two based on their estimated glomerular filtration rate (eGFR) ≥ 60 or < 60 min/ml/1.73m2. In a mean follow-up period of 6.3 years, cardiovascular events were recorded in 8.9% of the patients. In an adjusted Cox model, high HbA1c SD (hazard ratio, 1.290; 95% confidence interval, 1.008-1.650; p = 0.043), but not mean HbA1c, was associated with significantly increased risk of cardiovascular events in patients with eGFR ≥ 60 min/ml/1.73m2. This association was not seen in patients with eGFR < 60 min/ml/1.73m2. In this study, greater HbA1c variability is associated with increased risk of cardiovascular among patients with preserved renal function, but not in those with moderate to advanced chronic kidney disease.

Glomerulosclerosis and tubulointerstitial fibrosis are associated with lower renal parenchymal elasticity. This study was designed to evaluate the predictive ability of renal elasticity in patients with chronic kidney disease (CKD). 148 non-CKD patients and 227 patients with CKD were recruited. 145 (38.7%) were female, 166 (73.1%) had diabetes, the mean estimated glomerular filtration rate (eGFR) was 33.9 ± 15.8 ml/min/1.73 m2 and the median urinary protein-to-creatinine ratio (UPCR) 502 (122–1491) mg/g. Patients with later stages of CKD had lower renal elasticity values, indicating stiffer kidneys (p P P P P = 0.001), body mass index (β = 0.390, P = 0.009) and eGFR (β = 0.146, P P = 0.042). The OR per 1 mm change in renal length for rapid renal deterioration was 1.022 (95% CI, 0.994–1.050; P = 0.125). Renal elasticity is associated with proteinuria and rapid renal deterioration in patients with CKD.

Background: The most electronegative subfraction of low-density lipoprotein (LDL), L5, is atherogenic in vitro and in vivo, and its plasma levels are elevated in patients with high cardiovascular disease risk and ischemic stroke (Blood 2016;127:1336-45). Because L5 LDL may be a useful biomarker for predicting cardiovascular disease, we defined a reference range for L5 plasma levels in healthy adults and examined the power of L5 levels to differentiate patients with hyperlipidemia (HLP) or coronary artery disease (CAD) from healthy individuals. Methods: We enrolled 35 healthy individuals, 40 patients with stable CAD, and 35 patients with HLP without evidence of CAD. Plasma LDL was isolated from each individual, and the percentage of L5 in total LDL (L5%) was quantified by using fast-protein liquid chromatography with an anion-exchange column. Results: Plasma L5% and L5 concentration (ie, [L5]) were significantly higher in patients with HLP or CAD than in healthy controls (P Conclusions: The power of L5% and [L5] in predicting cardiovascular risk is superior to that of other markers currently in use. Therefore, the reference ranges of L5% and [L5] identified in this study may be clinically useful in the prevention and treatment of cardiovascular disease. As previously reported, elevated plasma L5 levels may promote or aggravate ischemic stroke by enhancing platelet aggregation and platelet-endothelium interactions.

Background: High-density lipoprotein (HDL), the only lipoprotein class that can cross the blood brain barrier bidirectionally, is positively associated with cognitive functions. To delineate HDL’s role in Alzhenimer’s disease (AD), we analyzed the chemical properties of plasma HDL from AD and healthy normal adult (control) subjects. Methods and results: By using anion-exchange chromatography, we divided HDL into 5 increasingly electronegative subfractions, H1-H5. Compared to the control cohort (4.24±3.22%; n=20), HDL from AD patients (23.48±17.83%; n=30) had a 5.5-fold increase of H5 ( P Figure ), accompanied by a decreased protein/lipid ratio attributed to a significant reduction of albumin essential for prevention of amyloid beta (Aβ) aggregation. As determined by LC/MS E and ProteinLynx Global SERVER (PLGS), AD-HDL was had a rich content of apolipoprotein (apo)CIII, but diminished amounts of sphingosine-1-phosphate (S1P)-associated apoM and antioxidative paraoxonase 1 (PON1). Exposure of murine RAW 264.7 macrophages to H5 induced vibrant expression of ganglioside GM1 in colocalization with apoCIII on lipid rafts, alongside a concomitant increase of TNF-α detectable in the cultured medium ( Figure ). LC/MS E examination localized posttranslational oxidation exclusively in ApoA1 residues of H5 in AD-HDL, which exhibited a compromised cholesterol efflux capacity. Conclusions: Plasma HDL from AD patients has a high proportion of H5, an apoCIII-rich electronegative HDL subfraction. The associated reduction in functional (albumin, S1P, apoM) and increase in proinflammatory (apoCIII, PON1, TNF-α) components may favor Aβ assembly and neuroinflammation. Additionally, a compromised cholesterol-efflux capacity of AD-HDL may also contribute to vascular cognitive impairment.

Oxidative stress (OS) is related to vascular inflammation possibly, contributing to the development of coronary ectasia (CE). Base excision repair (BER) and nucleotide excision repair are the main DNA repair pathways that can help to remove 8-hydroxydeoxyguanine (8-OHdG), a marker of OS. Human 8-oxoguanine DNA glycosylase 1 (hOGG1) is a key enzyme of the BER pathway and catalyzes the removal of 8-OHdG. The aim of our study was to investigate the association between hOGG1 Ser326Cys gene polymorphism and CE in a Chinese population. Five-hundred forty-seven patients who underwent diagnostic coronary angiography in a tertiary medical center were recruited. The angiographic definition of CE is the diameter of the ectatic segment being more than 1.5 times larger compared with an adjacent healthy reference segment. The gene polymorphisms were analyzed by polymerase chain reaction. The urine 8OHdG concentration was measured using a commercial ELISA kit. The distribution of hOGG1 Ser326Cys genotypes was significantly different between CE and non-CE groups (p = 0.033). The odds ratio of CE development for the Ser to the Cys variant was 1.55 (95% confidence interval (CI), 1.04–2.31, p = 0.033). Both univariate and logistic regression analysis showed a significant association of hOGG1 Ser326Cys polymorphism in the dominant model with CE development (p = 0.009 and 0.011, respectively). Urine 8-OHdG levels were significantly higher in subjects carrying the hOGG1 Ser variant than in those with the Cys/Cys genotype (p < 0.03). In conclusion, our study suggests that the hOGG1 Ser326Cys gene variant might play a role in susceptibility to the development of CE.

Aim To assess the associations of changes in self-management behaviours, diabetes self-efficacy, resilience, social support, patient empowerment and their interactions with changes in diabetes distress in patients with type 2 diabetes mellitus. Background Many patients with type 2 diabetes mellitus experience diabetes distress. Few longitudinal studies have investigated the associations of changes in various psychosocial factors with changes in diabetes distress in patients with type 2 diabetes mellitus. Design This study adopted a longitudinal design. Data were collected at baseline and 12 months later. Methods Overall, 304 patients with type 2 diabetes were recruited from four hospitals in southern Taiwan by convenience sampling. A self-report questionnaire and medical record were used to collect demographic data, clinical indicators, self-management behaviours, diabetes self-efficacy, resilience, social support, patient empowerment, and diabetes distress. Data were collected from February 2014–March 2015. Results/Findings An increase in resilience or diabetes self-efficacy significantly associated with a decrease in diabetes distress, whereas an increase in patient empowerment significantly associated with an increase in diabetes distress. The interactions between increase in patient empowerment and increase in self-management behaviours significantly associated with decrease in diabetes distress. Conclusion Nurses could endeavour to improve the diabetes self-efficacy and resilience to reducing diabetes distress. Arbitrarily empowering patients may increase diabetes distress. Increasing self-care management behaviours and patient empowerment might need to be simultaneously addressed to reduce the diabetes distress in patients with type 2 diabetes.

Liraglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effect on pulmonary arterial hypertension (PAH) is unknown. In this study, we investigated its effects on rats with monocrotaline (MCT)-induced PAH and mechanisms on rat pulmonary artery smooth muscle cells (PASMCs). Liraglutide was investigated for both prevention and treatment of MCT-induced PAH. The hemodynamic and body weight changes, right heart hypertrophy, lung morphology, immune-reactivity of endothelial nitric oxide synthase (eNOS), endothelin-1 and cyclic guanosine monophosphate (cGMP) levels, protein expressions of eNOS, soluble guanylyl cyclase (sGCα), protein kinase G (PKG) and Rho kinase (ROCK) II pathway were measured in both in vivo and in vitro. Cell migration and cell cycle were also determined. Liraglutide both prevented and reversed MCT-induced PAH, right ventricle hypertrophy and pulmonary vascular wall remodeling. Protein expression of ROCK II was increased while eNOS, sGC and PKG were decreased. Pretreatment with liraglutide inhibited platelet-derived growth factor (PDGF)-BB stimulated PASMCs migration, which were associated with cell-cycle arrest at G0/G1 phase. Liraglutide may have both preventive and therapeutic effects on MCT-induced PAH, through the eNOS/sGC/PKG and Rho kinase pathways. Thus, liraglutide may have a therapeutic role in pulmonary vascular remodelling.

Objective To examine associations between a diabetes pay-for-performance (P4P) program in Taiwan and all-cause of mortality and competing causes of death in cancer survivors with type 2 diabetes. Design A longitudinal observational intervention and comparison group study design. Setting and participants Cancer survivors with type 2 diabetes who enrolled in the P4P program compared with survivors who did not participate (non-P4P) under the Taiwan National Health Insurance program. Intervention(s) A nationwide diabetes P4P program. Main outcome measures The main outcome was a comparison of all-cause, diabetes-related and cancer mortality in P4P and non-P4P patients during a 5-year follow-up period. Total person-years and mortality rates per 1000 person-years for causes of death were calculated. Multivariate Cox proportional hazard models and competing risk regression were used in the analysis. Results Overall, our results indicate that P4P cancer survivors had lower risk of all-cause mortality and diabetes-related mortality than non-P4P survivors. Specifically, the hazard ratio (95% confidence interval) was 0.581 (0.447-0.756) for all-cause mortality; SHRs were 0.451 (0.266-0.765) for diabetes-related mortality and 0.791 (0.558-1.121) for cancer mortality. Conclusions Our empirical findings provide evidence of potential benefits of diabetes P4P programs in reducing risks of deaths due to diabetes or cardiovascular diseases among cancer survivors, compared with survivors who did not enroll in the P4P program. In consideration of recommended care for long-term survival, the diabetes P4P program can serve as a care model for cancer survivors for reducing mortality due to diabetes or cardiovascular diseases.

Taiwan's National Health Insurance program implemented a pay-for-performance (P4P) program based on process measures in 2001. In late 2006, the P4P was revised to also include achievement of outcome measures.This study examined whether a change in P4P incentive design structure affected diabetes outcomes.We used a longitudinal cohort study design using 2 population-based databases. Newly enrolled P4P patients with diabetes in 2002-2003 (phase 1) and 2007-2008 (phase 2) made up the study cohorts. Propensity score matching was used to match comparable cohorts in each phase. In total, 46,286 matched cohorts in phase 1 and 2 were analyzed. Process measures were defined as the provision of tests of glycosylated hemoglobin A1c (HbA1c), low-density lipoprotein cholesterol, and blood pressure, and outcome measures as changes in those values between baseline and last follow-up within 3 years. Patient-level generalized linear regression models were used and patient characteristics, physician characteristics, and health care facility characteristics were adjusted for.Our results indicated that the process measures of HbA1c and low-density lipoprotein cholesterol tests did not differ significantly between the 2 phases. In addition, better improvements were noted in outcome measures for the phase 2 patients (ie, HbA1c level and lipid profiles), whereas nonincentivized intermediate measures (eg, blood pressure) showed no negative unintended consequences.Quality of care tended to be better when both process and targeted outcome measures were combined as quality metrics in the P4P program in Taiwan.

Aims Interleukin-6 (IL-6), an inflammatory cytokine, is considered a candidate gene possibly involved in susceptibility to nephropathy in diabetes. This study aimed to examine whether IL-6 polymorphisms predict the progression of nephropathy in a prospective Chinese cohort of patients with type 2 diabetes. Methods A total of 568 type 2 diabetic patients with normoalbuminuria at baseline were followed up for a mean of 5.3 ± 1.5 years. Urinary albumin-to-creatinine ratio (ACR) ⩾30 mg/g in two consecutive urine tests were defined as progression to diabetic nephropathy (n = 143). Five polymorphisms of IL-6 gene, rs1800795, rs1800796, rs1524107, rs2069837, and rs2069840, were genotyped. Cox proportional hazard models were used to estimate hazard ratio (HR) and 95% CI of progression to diabetic nephropathy under different genetic models. Results Almost all patients (99.6%) carried the rs1800795 GG homozygous genotypes. In the Cox proportional models adjusted for multiple covariates, the HR under recessive model was 2.02 for rs1800796 GG (vs. CC + CG, 95% CI: 1.08–3.75, p = 0.027), 2.37 for rs2069837 GG (vs. AA + AG, 95% CI: 1.15–4.87, p = 0.019), and 2.08 for rs1524107 CC (vs. TT + TC, 95% CI: 1.12–3.89, p = 0.021). These associations remained significant for rs1800796 and rs1524107 after correction for multiple testing (α = 0.017). Overall, our results suggest that rs1800796 GG and rs1524107 CC homozygous genotypes may confer a greater risk for development of nephropathy in type 2 diabetes. Conclusions IL-6 gene polymorphisms rs1800796 and rs1524107 may serve as predictors of progression of nephropathy in Chinese patients with type 2 diabetes.

The aim of the present study was to investigate relationships between the risk of chronic kidney disease (CKD) and obesity and weight changes in Asian patients with type 2 diabetes.At baseline (2003-05), 1187 diabetic patients aged 30-70 years were recruited to the study, with follow-up surveys completed in 2008, 2009, and 2010. Chronic kidney disease was defined as an estimated glomerular filtration rate (eGFR)60 mL/min per 1.73 mOver 7 years of follow-up, obesity (RR 1.48; 95% CI 1.08-2.04; P = 0.015) and high WC (RR 1.23; 95% CI 1.00-1.52; P = 0.049) were associated with CKD after adjusting for covariates. Among participants without CKD at baseline, those who gained10% weight (RR 1.43; 95% CI 1.07-1.90; P = 0.015) and in whom WC increased15% (RR 1.37; 95% CI 1.01-1.85; P = 0.045) had a higher risk of incident CKD than those who remained stable (±5% changes in weight or WC).Diabetic patients who are obese and those with excessive central fat were more likely to have CKD. Large weight gain (10%) and increases in WC (15%) independently predicted incident CKD.

Metabolic syndrome (MetS) represents a cluster of metabolic derangements. Dyslipidemia is an important factor in MetS and is related to atrial fibrillation (AF). We hypothesized that very low density lipoproteins (VLDL) in MetS (MetS-VLDL) may induce atrial dilatation and vulnerability to AF. VLDL was therefore separated from normal (normal-VLDL) and MetS individuals. Wild type C57BL/6 male mice were divided into control, normal-VLDL (nVLDL), and MetS-VLDL (msVLDL) groups. VLDL (15 µg/g) and equivalent volumes of saline were injected via tail vein three times a week for six consecutive weeks. Cardiac chamber size and function were measured by echocardiography. MetS-VLDL significantly caused left atrial dilation (control, n = 10, 1.64 ± 0.23 mm; nVLDL, n = 7, 1.84 ± 0.13 mm; msVLDL, n = 10, 2.18 ± 0.24 mm; p < 0.0001) at week 6, associated with decreased ejection fraction (control, n = 10, 62.5% ± 7.7%, vs. msVLDL, n = 10, 52.9% ± 9.6%; p < 0.05). Isoproterenol-challenge experiment resulted in AF in young msVLDL mice. Unprovoked AF occurred only in elderly msVLDL mice. Immunohistochemistry showed excess lipid accumulation and apoptosis in msVLDL mice atria. These findings suggest a pivotal role of VLDL in AF pathogenesis for MetS individuals.

OBJECTIVE The discrepancy of diabetes incidence and care between socioeconomic statuses has seldom been studied concurrently in nations with universal health coverage. We aimed to delineate whether income disparity is associated with diabetes incidence and inequality of care under a national health insurance (NHI) program in Asia. RESEARCH DESIGN AND METHODS From the Taiwan NHI database in 2000, a representative cohort aged ≥20 years and free of diabetes (n = 600,662) were followed up until 2005. We regarded individuals exempt from paying the NHI premium as being poor. Adjusted hazard ratios (HRs) were used to discover any excess risk of diabetes in the poor population. The indicators used to evaluate quality of diabetes care included the proportion of diabetic patients identified through hospitalization, visits to diabetes clinics, and completion of recommended diabetes tests. RESULTS The incidence of type 2 diabetes in the poor population was 20.4 per 1,000 person-years (HR, 1.5; 95% CI, 1.3–1.7). Compared with their middle-income counterparts, the adjusted odds ratio (OR) for the poor population incidentally identified as having diabetes through hospitalization was 2.2 (P < 0.001). Poor persons with diabetes were less likely to visit any diabetes clinic (OR, 0.4; P < 0.001). The ORs for the poor population with diabetes to receive tests for glycated hemoglobin, low-density lipoprotein cholesterol, triglycerides, and retinopathy were 0.6 (0.4–0.9), 0.4 (0.2–0.7), 0.5 (0.4–0.8), and 0.4 (0.2–0.9), respectively. CONCLUSIONS Poverty is associated not only with higher diabetes incidence but also with inequality of diabetes care in a northeast Asian population, despite universal health coverage.

The increase of apo-/holo-retinol-binding protein 4 (RBP4) concentrations has been found in subjects with renal dysfunction and even in diabetic patients with microalbuminuria. Holo-RBP4 is recognized to possess cytoprotective function. Therefore, we supposed that the relative increase in apo-RBP4 might induce cell damage. In this study, we investigated the signal transduction that activated apoptosis in response to the increase of apo-/holo-RBP4 concentration. We found that increase of apo-/holo-RBP4 concentration ratio delayed the displacement of RBP4 with "stimulated by retinoic acid 6" (STRA6), enhanced Janus kinase 2 (JAK2)/STAT5 cascade, up-regulated adenylate cyclase 6 (AC6), increased cAMP, enhanced JNK1/p38 cascade, suppressed CRBP-I/RARα (cellular retinol-binding protein/retinoic acid receptor α) expression, and led to apoptosis in HK-2 and human umbilical vein endothelial cells. Furthermore, STRA6, JAK2, STAT5, JNK1, or p38 siRNA and cAMP-PKA inhibitor reversed the repression of CRBP-I/RARα and apoptosis in apo-RBP4 stimulation. In conclusion, this study indicates that the increase of apo-/holo-RBP4 concentration may influence STRA6 signaling, finally causing apoptosis.

O-linked N-acetylglucosamine (O-GlcNAc) protein modification has been implicated in the regulation of signaling pathways, cell function, and gene expression. Glutamine:fructose-6-phosphate amidotransferase-1 (GFAT-1) is the rate-limiting enzyme in the hexosamine biosynthetic pathway (HBP), which generates the sugar nucleotide UDP-GlcNAc, where this nucleotide acts as the donor for O-GlcNAc modification. In this study, we determined whether GFAT-1 regulates adipogenesis in adipocytes. 3T3-L1 preadipocytes were differentiated using medium containing high glucose, insulin, dexamethasone, and isobutylmethylxanthine. Cells were harvested 4, 8, and 12 h and 1, 2, 3, 4, 6, and 8 days after the initiation of differentiation. Global level of O-GlcNAc modification increased 4 h after induction and persisted for 8 days of observation. GFAT-1 mRNA and protein expression was also upregulated beginning 4 h after induction. Pharmacological inhibition of GFAT-1 or GFAT-1 siRNA treatment blocked the increase in O-GlcNAcylation and the formation of lipid droplets in adipocytes. GFAT-1 may regulate the expression of C/EBPβ, PPARγ, SREBP-1, fatty acid synthase, S3-12, perilipin, or adipophilin during adipogenesis. Our results suggest that GFAT-1 plays a critical role in modulating adipogenesis via the regulation of protein O-GlcNAcylation in adipocytes. J. Cell. Physiol. 227: 108–115, 2012. © 2011 Wiley Periodicals, Inc.

There are controversies regarding the association of visfatin with overweight/obesity, type 2 diabetes mellitus, insulin resistance (IR), metabolic syndrome and cardiovascular disease in published articles. A meta-analysis was performed to identify the significance of visfatin in these diseases. We searched for relevant articles in Pubmed, Scopus and SCIE. A total of 1035 articles were surveyed and 46 articles were identified, with 14 reports reporting more than one of our investigated diseases. A total of 13 (n = 644), 19 (n = 2405), 20 (n = 2249), 5 (n = 527) and 5 (n = 851) articles/(participants) were included in each meta-analysis regarding the association of visfatin and overweight/obesity, type 2 diabetes mellitus, insulin resistance, metabolic syndrome and cardiovascular diseases, respectively. Plasma visfatin concentrations were increased in participants diagnosed with overweight/obesity, type 2 diabetes mellitus, metabolic syndrome and cardiovascular diseases, with pooled log odds ratios of 1.164 [95% confidence interval (CI): 0.348 to 1.981, p = 0.005], 1.981 (95% CI: 1.377 to 2.584, p < 0.001), 1.094 (95% CI: 0.678 to 1.511, p < 0.001), and 2.902 (95% CI: 0.924 to 4.879, p < 0.005), respectively. The circulating visfatin level was positively associated with insulin resistance, with a Fisher's z of 0.089 (95% CI: 0.013 to 0.165, p = 0.022). No single study was found to affect the overall result of each analysis by sensitivity testing. No publication bias was found by the Egger test. Our study suggests that the use of visfatin may be promising for predicting obesity, diabetes status, insulin resistance, metabolic syndrome and cardiovascular disease.

Osteoprotegerin (OPG) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) have recently been reported to be associated with diabetic nephropathy in an in vitro study. However, the literature regarding serum OPG and TRAIL in type 2 diabetes mellitus patients is scarce. To investigate the role of OPG/TRAIL in diabetic nephropathy, we measured the serum concentrations of OPG and TRAIL in type 2 diabetes mellitus patients with different stages of nephropathy by enzyme-linked immunosorbent assay. One hundred seventy-nine subjects with type 2 diabetes mellitus were studied and stratified according to urinary microalbumin and serum creatinine measurements. The serum concentrations of OPG and TRAIL were significantly elevated in patients with microalbuminuria (OPG, 2154.2 ± 922.1 pg/mL; TRAIL, 80.2 ± 24.1 pg/mL) and macroalbuminuria (OPG, 2251.5 ± 925.7 pg/mL; TRAIL, 88.1 ± 23.8 pg/mL) as compared with patients with normoalbuminuria (OPG, 1690.1 ± 627.2 pg/mL; TRAIL, 70.7 ± 23.3 pg/mL). Serum OPG and TRAIL levels were increased in parallel and were significantly associated with each other. Using multivariate stepwise regression analysis, serum OPG was found to be an independent factor associated with the severity of diabetic nephropathy. Our results suggested that serum OPG may be a marker for the severity of diabetic nephropathy. Further studies are necessary to investigate the role of elevated serum OPG in the pathogenesis of diabetic nephropathy.

Background and Aims: The adiponutrin/patatin-like phospholipase-3 (PNPLA3) I148M polymorphism has recently been found to contribute to differences in hepatic lipid content. Nonalcoholic fatty liver disease (NAFLD) has recently been considered a hepatic component of insulin resistance and a risk factor in the emergence of type 2 diabetes. However, whether there is an association between PNPLA3 I148M and insulin resistance and NAFLD in a normoglycaemic population is still unknown. Methods: This study enrolled 156 normoglycaemic individuals with NAFLD and 723 controls. All participants received complete biochemical and clinical workups including liver ultrasonography. They were then genotyped for the PNPLA3 I148M polymorphism. Results: We found significant differences in the genotype and the dominant model of the PNPLA3 I148M polymorphism between the NAFLD groups and the controls (P=0.018 and P=0.01 respectively). Furthermore, there was a dose effect of the PNPLA3 I148M genotype, in that CG heterozygotes had a risk of NAFLD between CC and GG homozygotes [adjusted odds ratio (OR)=2.03, 95% confidence interval (CI)=1.23–3.375 for the GG genotype and adjusted OR=1.55, 95% CI=1.02–2.35 for the CG genotype]. The dominant model of the PNPLA3 I148M polymorphism showed higher waist circumference, fasting insulin, Homeostasis Model Assessment (HOMA-IR), alanine aminotransferase concentrations and ferritin level. Multivariate analysis showed the PNPLA3 I148M polymorphism to be independently and significantly associated with NAFLD in our normoglycaemic participants. Conclusion: This study reports an association between the PNPLA3-I148M polymorphism and insulin resistance and NAFLD in a normoglycaemic population.

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.

We describe a case of diabetic ketoacidosis that lead to fetal loss during week 33 of gestation in a woman who had normal glucose tolerance 11 days previously. We believe this represents a case of fulminant type 1 diabetes.

Aim: Thedevelopment of Type2 diabetes mellitus (T2DM) has been recognized to beassociated with a combination of pancreatic β-cell dysfunction and insulin resistance. Nuclear factor-κB (NF-κB) has been recognized as one central mediator in the reaction of inflammation and proapoptotic event in β-cells. A functional polymorphism at the codon 55 (methionine to valine; A163G) of the small ubiquitin-like modifier-4 (SUMO4) gene may result in higher NF-κB activity. This study investigates whether this SUMO4 Met55Val polymorphism also contributes to the development of T2DM. Materials and methods: The study was peformed using genomic DNA samples from 574 Type 2 diabetic patients and 323 healthy controls. The SUMO4 Met55Val polymorphism was genotyped using allele-specific real-time PCR. Results: The frequency of the G allele (encoding Val55) was-significantly higher in Type 2 diabetic patients and Type 2 diabetic patients with the GG genotype had higherhemoglobin A1c level. Multivariate logistic regression analysis revealed the genotype of GG and GA was an independent risk factor contributing to the development of T2DM. Conclusion: This study suggests that in Taiwan the SUMO4 Met 55Val polymorphism is associated with susceptibility to T2DM and Type 2 diabetic patients with GG genotype have worse glycemic control

A diagnosis of sporadic medullary thyroid carcinoma (MTC) is complicated. On first diagnosis it may present with distant metastasis. There has been inconsistency regarding metastatic MTC tissue expression of calcitonin, its tumor marker. Adding to the difficulty is the fact that the radiographic pattern of pulmonary metastasis from MTC may vary substantially among patients. Herein is reported the case of a 73-year-old man who presented with two ill-defined pulmonary opacities, clinically resembling primary lung carcinoma. MTC was diagnosed on histopathology of tissue obtained from a total thyroidectomy. The pulmonary biopsy specimens were confirmed to be MTC metastasis on positive immunohistochemical staining of chromogranin-A and synaptophysin, even though only a few cells were stained for calcitonin. To the authors' knowledge this is the first reported case of MTC presenting initially as complex pulmonary metastasis with weakened expression of calcitonin in the metastatic lesion.

Deprivation of neurotrophic factors contributes to the pathogenesis of diabetic neuropathy. However, the role of glial cell-derived neurotrophic factor (GDNF) in the pathogenesis of diabetic neuropathy remains unclear. The present study evaluated the pathogenic role of GDNF deficiency and the therapeutic potential of GDNF gene transfer for diabetic neuropathy. After injection of streptozotocin (STZ) for 2 weeks, diabetic rats displayed significant alteration in electrophysiological parameters, which was associated with structural changes and defective myelination in the sciatic nerves. The early diabetic neuropathy was accompanied by attenuation of the GDNF/GFRalpha1/Akt signaling cascade and depletion of sensory neuropeptides in the peripheral nerves. After detection of neuropathy, intramuscular GDNF gene transfer reversed the deficiency of GDNF/Akt signaling in the sciatic nerve and improved the neurological functions of diabetic rats. Moreover, GDNF gene delivery alleviated the axonal demyelination and restored the sensory neuropeptide levels in the sciatic nerve of diabetic rats. In summary, peripheral GDNF gene delivery ameliorates the diabetes-induced downregulation of the GDNF signaling complex in the peripheral nervous system and holds promises for treatment of diabetic neuropathy.

Summary Objective Epicardial adipose tissue (EAT) is a part of visceral fat deposited around the heart between the pericardium and myocardium along the distribution of coronary arteries. EAT thickness is reported to be associated with coronary atherosclerosis; however, no study has measured EAT volume in patients with type 2 diabetes or investigate its association with coronary artery disease. Design A hospital-based case control study. Patients A total of 49 patients with type 2 diabetes mellitus (T2DM) and 78 nondiabetic controls were studied. Measurements Cardiac multislice computed tomography was used to measure EAT volume, Gensini score, coronary artery calcium score and, coronary lesions. The relationships between EAT volume, markers of coronary atherosclerosis and anthropometric and biochemical parameters of metabolic syndrome (MetS) were investigated. Results EAT volume was significantly higher in patients with T2DM than in nondiabetic subjects (166·1 ± 60·6 cm3 vs. 123·4 ± 41·8 cm3, P

Background While some studies have reported that retinol-binding protein 4 (RBP4) might induce insulin resistance, other studies have demonstrated that the presence of albuminuria in diabetic patients and increased uric acid are related to insulin resistance. Therefore, this study attempted to further investigate the relationship among serum RBP4, serum uric acid, and the severity of albuminuria in diabetic patients. Methods A total of 95 type 2 diabetic patients and 16 healthy subjects participated in this study. Diabetic patients were classified into normoalbuminuria, microalbuminuria and macroalbuminuria groups according to their urine albumin-to-creatinine ratio (ACR). Serum RBP4 was measured by an enzyme-linked immunosorbent assay (ELISA). Results Serum RBP4 was significantly elevated in type 2 diabetic patients with normoalbuminuria (43.4 ± 14.9 µg/mL), microalbuminuria (57.3 ± 24.2 µg/mL) and macroalbuminuria (64.7 ± 27.6 µg/mL) as compared with control patients (32.6 ± 10.0 µg/mL). Serum RBP4 was also significantly elevated in type 2 diabetic patients with microalbuminuria or macroalbuminuria as compared with the normoalbuminuric group. Serum RBP4 in diabetic subjects was positively correlated with triglycerides, uric acid and ACR, and negatively correlated with low-density lipoprotein cholesterol and estimated glomerular filtration rate (eGFR; with age and gender adjustment in each parameter). Multiple stepwise linear regression analysis showed that uric acid and eGFR remained significantly associated with serum RBP4. Conclusions Both eGFR and uric acid are significant determinants of serum RBP4, suggesting that the impaired renal clearance of early diabetic nephropathy affects RBP4 and indirectly supporting the hypothesized link among metabolic syndrome, uric acid and insulin resistance. Copyright © 2008 John Wiley & Sons, Ltd.

There is growing evidence suggesting the mutual link between type 2 diabetes mellitus (T2DM) and hepatitis C virus (HCV) infection. However, the impact of HCV infection on the suite of glucose abnormalities has rarely been investigated. The study aimed to determine the difference regarding the prevalence and the characteristics of glucose abnormalities between chronic hepatitis C (CHC) patients and community-based controls. It also aimed to investigate the related clinical, virological, and histological features of glucose abnormalities in HCV infection.Six hundred eighty-three CHC patients and 515 sex-/age-matched controls were included. Oral glucose tolerance test (OGTT) was performed in 522 CHC patients and 447 controls without known T2DM. Clinical data were assessed upon the different stages of glucose abnormalities based on OGTT results.The prevalence of normoglycemia, IGT, and T2DM in 683 CHC patients was 27.7%, 34.6%, and 37.8%, respectively. There was a significant linear trend from normoglycemia to T2DM in terms of age, family history of T2DM, and advanced liver fibrosis in CHC patients. For those CHC patients without fibrosis, the prevalence of glucose abnormalities reached 67.9% high. All CHC patients carried a significantly higher prevalence than controls regarding those aged65 yr. For those without known DM, there was a 3.5-fold increase in the prevalence of glucose abnormalities in CHC (65.8%) patients in comparison with controls (35.3%) (OR 3.51, 95% CI 2.70-4.56, P0.001).CHC patients carried a high prevalence of glucose abnormalities. Determination of glucose abnormalities by OGTT may be suggested.

The absorption efficiency of cholesterol is closely correlated to dietary phytosterol content and determined by genetic factors. The ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 act as a sterol efflux pump to regulate the absorption of cholesterol and phytosterol. The levels of cholesterol and phytosterol associated with a Chinese diet are very different from those associated with a Western diet. This study aims to explore the association between serum total cholesterol/LDL-C levels and ABCG5/ABCG8 polymorphisms in a Taiwanese population consuming an ordinary Chinese diet. A total of 1,046 subjects (894 men and 152 women) were recruited in a hospital-based health check-up center in Kaohsiung Medical University Hospital. Five nonsynonymous polymorphisms of Q604E (ABCG5), D19H, C54Y, T400 K and A632 V (ABCG8) were analyzed by TaqMan genotyping assay. Analysis showed that the D19H polymorphism of the ABCG8 gene was significantly associated with serum total cholesterol, LDL-C levels and HOMA-IR index. Adjusting for sex and age, subjects with the D19H (GC) genotype were significantly associated with a threefold higher risk of high cholesterol and LDL-C levels than subjects with D19 (GG). These results suggest that the D19H polymorphism of ABCG8 could be considered a susceptible gene marker indicating an increased likelihood of developing high cholesterol and LDL-C levels in Taiwanese consuming an ordinary Chinese diet. It is supposed that the coexistence of higher insulin resistance and hypercholesterolemia for carriers of the D19H polymorphism may result in a greater risk of cardiovascular disease.

Retinol-binding protein 4 (RBP4) has been found to induce insulin resistance and to be increased in type 2 diabetes. Thiazolidinediones (TZDs) can improve insulin sensitivity through the activation of peroxisome proliferators-activated receptor-gamma (PPAR-gamma) and have been suggested as an adjunct to metformin (MF) and sulfonylurea (SU) in type 2 diabetes in a consensus statement from the ADA and EASD. Therefore, we investigated whether TZD could affect serum RBP4 level in type 2 diabetes already treated with MF and/or SU. Eighty-one type 2 diabetic patients were divided into 2 groups: (1) TZD group (n = 55): Pioglitazone 30 mg/day was given as an add-on medication; (2) SU group (n = 26): Gliclazide MR 30-120 mg or glimepiride 2-8 mg/day was prescribed. The average period of study was 97.1 days. Serum RBP4 and adiponectin were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. The addition of pioglitazone (TZD group) markedly decreased homeostasis model assessment of insulin resistance (HOMA-IR) (P = 0.021) compared with the SU group (P = 0.688). The change of RBP4 in the TZD group (-3.87 +/- 11.27 microg/mL) significantly differed from that in the SU group (2.52 +/- 8.24 microg/mL, P0.012). The increase of adiponectin in the TZD group (11.49 +/- 7.85 microg/mL) was apparently higher than that in the SU group (1.54 +/- 5.62 microg/mL, P0.001). Despite the change of glycosylated hemoglobin (HbA1c) did not differ (-0.77 +/- 1.3 vs -0.50 +/- 1.7, P = 0.446), the addition of pioglitazone could significantly lower serum RBP4 and HOMA-IR values, whereas an increased dosage of sulfonylurea agents did not alter HOMA-IR, RBP4, or adiponectin in type 2 diabetic patients who had been treated with metformin and/or sulfonylurea.

To assess continuing diabetic education in Taiwan, we evaluated the impact of comprehensive diabetes care program for Taiwanese people with type 2 diabetes.211 diabetic patients were enrolled and followed up for 1 year at Kaohsiung Medical University Hospital. Patients were provided comprehensive care and their medications were not changed. Clinical and biophysical variables were collected and assessed at 0, 3, 6, 9, 12 months.Metabolic control had improved significantly by 1 year: fasting plasma glucose (164.6+/-60.4 vs. 137+/-37.5mg/dl, p0.001); total serum cholesterol (198.7+/-38.8 vs. 187.2+/-43.1mg/dl, p0.001); high-density lipoproteins cholesterol (43.2+/-10.2 vs. 46.2+/-11.7 mg/dl, p0.001); low-density lipoproteins cholesterol (121.1+/-32.9 vs. 113.1+/-29.6 mg/dl, p0.005). In the male group, HbA1c level fell from 8.16+/-1.99% to 7.61+/-1.31% and 7.72+/-1.40% after 9 months and 1 year, respectively, p0.05. There were also significant improvements in female group after 6 months and 9 months (7.89+/-1.62% after 6 months; 7.94+/-1.66% after 9 months vs. 8.22+/-1.70% at baseline). The change of HbA1c level was significant in male patients, patients whose duration of disease was shorter and in those with higher baseline HbA1c levels after multi-variable and age-adjusted analysis.The comprehensive diabetes care program effectively improved glycemic and cholesterol control. The patients who were more likely to achieve better glycemic control were male, had diabetes for shorter periods of time and had high baseline HbA1c levels. Therefore, diabetic education should be offered to patients as close to the time of diagnosis as possible.

Atrial natriuretic peptide, besides its role in the regulation of volume homeostasis, has been noted to exert cytoprotective effects in several cell types from hypoxia. The present study was performed to explore the effect of ANP on high glucose-activated transforming growth factor-beta1 (TGF-beta1), Smad and collagen synthesis in renal proximal epithelial cells. Cultured NRK-52E cells were divided into five groups: (1) normal glucose (5.5 mM), (2) high glucose (35 mM), (3) D-mannitol (29.5 mM), (4) high glucose plus ANP (10(-6)-10(-9) M), and (5) high glucose plus ANP (10(-6) M) and guanylate cyclase inhibitor LY83583 (10(-7) M) groups. Messenger RNA levels of TGF-beta1, Smad2, and collagens were measured by RT-PCR. ELISA, immunocytochemistry and Western blotting were used to detect protein levels of TGF-beta1, Smad2, phospho-Smad 2/3 and collagen type 1. We found high glucose to significantly increase mRNA levels of TGF-beta1, Smad 2, collagen types I and III and protein levels of TGF-beta1, phospho-Smad 2/3 and collagen type 1, but mannitol did not affect their expression. The addition of ANP significantly attenuated high glucose-enhanced mRNA and protein levels of TGF-beta1, Smad and collagens. LY83583 blocked the influence of ANP on high glucose-activated TGF-beta1, Smad and collagen synthesis. This is the first study to demonstrate that activation of TGF-beta1, Smad and collagen synthesis stimulated by high glucose can also be inhibited by exogenous ANP in renal tubular epithelial cells.

Background and Aim: It is known that ultrasonography (US) cannot differentiate between non-alcoholic fatty liver disease (NAFLD) and steatohepatitis. However, US can accurately estimate the severity of the steatosis. The clinical significance of severe hepatic fatty change by US has not been explored. The aim of this study was to investigate the relationship between the severity of the fatty liver, classified by US, and the degree of metabolic disorders with insulin resistance. Methods: In 16 486 Taiwanese patients, severity of fatty change on US was classified as follows: group A (n = 6950), absence of fatty change; group B (n = 8694), mild; and group C (n = 842), severe fatty liver change. Biometabolic parameters included body mass index (BMI), blood pressure (BP), fasting plasma glucose, triglycerides, cholesterol, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum creatinine. Nominal logistic regression analysis was used to estimate the odds ratio for different degrees of fatty liver. Results: The frequencies of obesity, hypertension, glucose intolerance and hypertriglyceridemia were all significantly higher in group C than in group A or B (P

Insulinoma is the most common functional tumor among pancreatic islet cell tumors. This type of tumor is difficult to localize prior to surgery and can lead to serious hypoglycemia. This paper presents the case of a young female who suffered from insulinoma associated with transient hypothalamus-pituitary-adrenal axis impairment. To localize her insulinoma, we used two alternative testing methods, somatostatin receptor scintigraphy and selective arterial calcium stimulation with venous sampling, after a failure of conventional imaging methods. We treated her adrenal insufficiency and prevented serious hypoglycemia by giving her prednisolone. The impairment in her hypothalamus-pituitary-adrenal axis and her serious hypoglycemia recovered after excision of the tumor.

Hereditary hemochromatosis (HH) is very rare in Asia. Here, we describe a Taiwanese woman presenting with fully developed characteristics of HH including bronze skin, DM, decreased MRI T2 signal intensity over liver and pituitary gland. Biochemistry of iron profile indicated a severe status of iron overload by serum iron: 194 microg/dL, serum ferritin: 6640 microg/L, transferrin saturation: 92.8%. By measuring the hepatic iron index 8.48 (>1.9) of her liver biopsy tissue, the diagnosis of HH was established. Diagnosis of non-HFE HH was carried out since the whole HFE genome was sequenced but failed to localize any genetic alterations. The whole genome of transferrin receptor 2 (TfR2) was sequenced and a novel mutation of 13528 G-->A (Arg 481 His) in exon 11 was detected. Therefore, type 3 hemochromatosis was confirmed. The distinct clinical features, extremely high iron index and impressive iron staining in her liver biopsy tissue may represent an aggravated iron deposition in the liver caused by this novel mutation. Our finding implicates functional importance of histidine in exchange of arginine at amino acid 481 of transferrin receptor 2 in iron homeostasis. This case reminds physicians in Asia to keep in mind that hemochromatosis could be a rare cause of DM.

Context: Graves’ disease (GD) is an autoimmune disorder with genetic predisposition. The thyroglobulin (Tg) is a major autoantigen for GD. The human Tg gene polymorphism has specific features that make it important in GD. Objective: This study investigated whether Tg single nucleotide polymorphisms (SNPs) relate to GD development in a Taiwanese population. Design and Setting: This was a case-control association study. Patients and Main Outcome Measures: We enrolled 215 Taiwanese patients with GD and 141 controls from the Endocrine Clinic of Kaohsiung Medical University Chung-Ho Memorial Hospital. This study investigated the association between gene polymorphism and relapse of hyperthyroidism after medication was discontinued in three GD patient groups and a control group. We also compared clinical and laboratory data obtained from patients with the three different genotypes with the three different Tg SNPs (E10SNP158, E12SNP, and E33SNP). Results: We found a significant increase in the T/T genotype of E33SNP compared with the control group (P < 0.001). We also found the E33SNP C/C genotype of the Tg gene was strongly associated with a subgroup of GD patients who were also characterized as having a higher relapse rate, significantly higher levels of persisting TSH-receptor antibody at the end of treatment, a higher frequency in smoking, and a higher incidence of ophthalmopathy (P < 0.05). Conclusions: This study showed that Taiwanese patients with the C/C genotype of E33SNP, smoking, ophthalmopathy, and positive TSH-receptor antibodies at the end of the treatment were more likely to have a relapse of Graves’ hyperthyroidism after antithyroid medication is withdrawn.

To compare the macular retinal thickness and macular volume between subjects with high myopia and non-myopia.This prospective nonrandomized, comparative study recruited healthy subjects with high myopia subjects, defined as a spherical equivalence (SE) over -6 dioptres (D) or AXLor=26.5 mm and the best corrected visual acuity better than 20/25, and subjects with non-myopia, defined as an with SE between 1.5D and -1.5 D and the BCVA better than 20/25. Optical coherence tomography was performed in each eye.Eighty high myopic eyes and 40 non-myopic eyes were included. The mean age of the high myopic group and non-myopia group was 29.6 and 27.5 years old, respectively. The mean refraction was -9.27 D in the high myopia group and -0.22 D in the non-myopia group. The high myopia group had significantly greater mean retinal thickness in the foveola and fovea 1 mm area than the non-myopia group (166 vs149 microm, P0.0001, 199 vs188 microm, P=0.0063, respectively). However, the mean retinal thickness in the inner and outer macular area (superior, nasal, inferior, or temporal) of the high myopia group was significantly less than in the non-myopia group. In addition, the high myopia group had significantly smaller macular volume than the non-myopia group (P0.0001).This study demonstrated that the retinal thickness in individuals with high myopia is thicker in the foveola and fovea, but thinner in the inner and the outer macular region. The retina of individuals with high myopia had smaller macular volume than those with non-myopia.

Antisense oligonucleotide (AON) has been applied to modern molecular pharmacology. We have previously demonstrated that angiotensin-II (Ang-II) is an active stimulator of endothelin-1 (ET-1) production in glomerular mesangial cells. This study was designed to investigate the specific effect of ET-1 AON on inducing proliferation of cultured rat mesangial cells stimulated with Ang-II. ET-1 was measured by radioimmunoassays. The results were: (1) Ang-II enhanced ET-1 production of mesangial cells; (2) ET-1 production of mesangial cells was significantly suppressed by ET-1 AON, and this production was not affected by either ET-1 sense or scramble oligonucleotide in different concentrations; (3) Ang-II increased [ 3 H]-thymidine uptake of mesangial cells, which was suppressed to 25% by ET-1 AON but not by ET-1 sense or scramble oligonucleotide. Our results indicate that ET-1 AON effectively suppresses the ET-1 production and the Ang-II-stimulated proliferation of mesangial cells, and therefore may offer treatment for proliferative glomerulonephritis.

The metabolic syndrome refers to insulin resistance and its associated cluster of related cardiovascular metabolic risk factors including type 2 diabetes, hypertension, dyslipidemia and central obesity. Although many hypotheses and facts have been proposed to explain the interaction between genetic and environmental causes of this syndrome, the primary etiology of the metabolic syndrome is adipose tissue dysregulation. Firstly, the thrifty genotype and phenotype hypothesis may explain the endemic increase in type 2 diabetes and cardiovascular disease in developing countries and may elucidate congenital susceptibility to and environmental triggering of the metabolic syndrome. Secondly, overnutrition leads to fatty acid (FA) accumulation in adipocytes and to an overflow to ectopic fat storage organs. This causes functional changes in adipocytes shifting the intra-cellular metabolic pathway toward insulin resistance. Thirdly, obese subjects exhibit increased fat cell size and over-secretion of biologic adipocytokines. Fourthly, failure to adequately develop adipose tissue mass, as seen in lipodystrophy cases, causes severe insulin resistance and diabetes. Lastly, similarly to human type 2 diabetes, Psammonys obesus, a desert rat which feeds mainly on low-calorie vegetation, develops the metabolic syndrome when given a diet of calorie-rich food. The above evidence indicates that adipocyte dysregulation and secretion of FA as well as certain molecules from overloaded adipocytes-adipokines contribute to the pathogenesis of impaired insulin secretion and insulin resistance, endothelial dysfunction, a pro-inflammatory state and promote progression of atherosclerosis. The metabolic syndrome is a modern disease resulting in adipocyte dysmetabolism which originates from the paradox of slow human evolution combined with rapid environmental changes.

Acute poisoning should be handled with high efficiency in order to minimize morbidity and mortality in the emergency room. Unfortunately, history-taking and physical examination are not always reliable. Mis-swallowing of oral medications is common in the pediatric group. This study aimed at developing a rapid point-of-care ambient mass spectrometric method for the early identification of ingested oral medications in gastric lavage content.Four different types of oral medications that are most commonly mis-swallowed by children were diluted to different concentrations. Each of these chemical solutions was mixed with human gastric lavage content. A direct metallic sampling probe was dipped into the solution. It was then inserted promptly into the thermal desorption electrospray ionization source to carry out ionization and subsequent mass spectrometric analysis of the medications. The corresponding compounds were identified through matching of the obtained mass spectrometric data with those provided by well-established databases.Since no pretreatment of the specimen was required, the sampling step, and the subsequent thermal desorption electrospray ionization and mass spectrometric detection of the medications were completed within 30 s. Mass spectra were obtained for four different kinds of oral medication. The limit-of-detection of the four tested oral medications in gastric lavage content is at sub-ppm level, which is sensitive enough for emergency medicine applications since the quantities of medications ingested by pediatric patients are usually much higher.Thermal desorption electrospray ionization mass spectrometry, with informational support provided by an online mass spectral database, allows for early point-of-care identification of mis-swallowed oral medications in the evacuated gastric lavage contents obtained from gastric lavage of patients in the emergency room, and it is promising in providing important toxicological information to ensure the appropriateness of the subsequent medical management. Copyright © 2016 John WileySons, Ltd.

Objective To examine association of interactions between patient empowerment (PE) and health literacy with 1-year-later self-management behaviors in patients with type 2 diabetes (T2DM). Methods A prospective design was employed in this study. Overall, 395 patients with T2DM completed self-reported questionnaires at baseline and 1 year later. A hierarchical multiple regression was used to identify the association of interactions between PE and health literacy at baseline with the 1-year-later self-management behaviors. Results Interactions between PE and communicative and critical health literacy (CCHL) at baseline significantly associated with the 1-year-later global self-management behaviors in patients with T2DM. Among the participants who exhibited high PE at baseline, the scores of 1-year-later global self-management behaviors of the participants with a high CCHL at baseline were significantly higher than those with a low CCHL at baseline. Nevertheless, among the participants who exhibited low PE at baseline, no significant differences were identified in the 1-year-later global self-management behaviors between the participants with high vs. low CCHL at baseline. Conclusions PE may improve self-management behaviors in patients with high CCHL, but may prove useless in patients with low CCHL. Practice implications Healthcare providers should ensure that patients with T2DM have adequate CCHL prior to empowering them.

Self-poisoning with pesticides accounts for approximately one-third of all suicides worldwide. To expedite rescue in the emergency department, it is essential to develop a point-of-care analytical method for rapid identification of ingested pesticides. In this study, five of the most common pesticides ingested by self-poisoning patients in Taiwan were analyzed from oral fluid samples. Pesticide-oral fluid mixtures were applied on a cotton swab and then transferred into methanol. A metallic probe was used to sample the methanol solution for subsequent thermal desorption-electrospray ionization mass spectrometry analysis. Altogether, pesticide sampling, transfer, desorption, ionization, and detection took less than 1 min. The reproducibility of this method (n = 6) was shown in the observed low-relative standard deviation (7%) in the detection of pesticide in oral fluid. The detection limits of the pesticides in oral fluid obtained from four human subjects by thermal desorption-electrospray ionization mass spectrometry were between 1-10 ppb with relative standard deviation 10.7%. Moreover, in this study, linear responses of five pesticides in oral fluid with concentrations between 1 ppb-1 ppm (R2 between 0.9938 and 0.9988) were observed. As the whole analytical process is extremely short, this technique allows for early non-invasive point-of-care identification of pesticides in the oral fluid of self-poisoning patients in the emergency room, providing important toxicological information for decision-making during critical resuscitation.

Background: It is well known that diabetes mellitus impairs immunity and therefore is an independent risk factor for tuberculosis. However, the influence of associated metabolic factors, such as hypertension, dyslipidemia and gout has yet to be confirmed. This study aimed to investigate whether the strong association between tuberculosis and diabetes mellitus is independent from the influence of hypertension and dyslipidemia, and its treatment in elderly Taiwanese patients. Methods: A total of 27,958 patients aged more than 65 years were identified from the National Health Insurance Research Database (NIHRD) in 1997 and were followed from 1998 to 2009. The demographic characteristics between the patients with and without diabetes were analyzed using the χ2 test. A total of 13,981 patients with type 2 diabetes were included in this study. Cox proportional hazard regression models were used to determine the independent effects of diabetes on the risk of tuberculosis. Results: After adjusting for age, sex, other co-morbidities and medications, calcium channel blocker, beta blocker and statin users had a lower independent association, with risk ratios of 0.76 (95% CI, 0.58–0.98), 0.72 (95% CI, 0.58–0.91) and 0.76 (95% CI, 0.60–0.97), respectively. Conclusion: Calcium channel blocker, beta blocker and statin therapy may decrease the incidence of tuberculosis infection in elderly Taiwanese patients with type 2 diabetes.