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BackgroundStudies have confirmed that osteoporosis has been considered as one of the complications of diabetes, and the health hazards to patients are more obvious. This study is mainly based on the Taiwan National Health Insurance Database (TNHID). Through the analysis of TNHID, it is shown that the combined treatment of traditional Chinese medicine (TCM) medicine in patients of diabetes with osteoporosis (T2DOP) with lower related risks.MethodsAccording to the study design, 3131 patients selected from TNHID who received TCM treatment were matched by 1-fold propensity score according to gender, age, and inclusion date as the control group. Cox proportional hazards analyzes were performed to compare fracture surgery, hospitalization, and all-cause mortality during a mean follow-up from 2000 to 2015.ResultsA total of 1055/1469/715 subjects (16.85%/23.46%/11.42%) had fracture surgery/inpatient/all-cause mortality of which 433/624/318 (13.83%/19.93%/10.16%) were in the TCM group) and 622/845/397 (19.87%/26.99%/12.68%) in the control group. Cox proportional hazards regression analysis showed that subjects in the TCM group had lower rates of fracture surgery, inpatient and all-cause mortality (adjusted HR = 0.467; 95% CI = 0.225-0.680, PConclusionThis study provides longitudinal evidence through a cohort study of the value of integrated TCM for T2DOP. More research is needed to fully understand the clinical significance of these results.

Abstract Background Unhealthy lifestyle has been associated with obesity and type 2 diabetes. Whereas its association with vascular complications in patients with long-duration of type 2 diabetes is still uncertain. Methods A total of 1188 patients with long-duration of type 2 diabetes from the Taiwan Diabetes Registry (TDR) data were analyzed. We stratified the severity of unhealthy lifestyle via scoring three factors (sleep duration 9 h, sit duration ≥ 8h, and meal numbers ≥ with night snack) and analyzed their associations with the development of vascular complications using logistic regression analysis. Besides, we also included 3285 patients with newly diagnosed type 2 diabetes as the comparison. Results Increased numbers of factors that stand for unhealthy lifestyle were significantly associated with the development of cardiovascular disease, peripheral arterial occlusion disease (PAOD) and nephropathy in patients with long-duration of type 2 diabetes. After adjusting multiple covariables, having ≥ 2 factors of unhealthy lifestyle remained significant associations with cardiovascular disease and PAOD, with an odds ratio (OR) of 2.09 (95% confidence interval [CI] 1.18–3.69) and 2.68 (95% CI 1.21–5.90), respectively. Among individual factor for unhealthy lifestyle behaviors, we revealed that eating ≥ 4 meals per day with night snack increased the risk of cardiovascular disease and nephropathy after multivariable adjustment (OR of 2.60, 95% CI 1.28–5.30; OR of 2.54, 95% CI 1.52–4.26, respectively). Whereas sit duration for ≥ 8 h per day increased the risk of PAOD (OR of 4.32, 95% CI 2.38–7.84). Conclusion Unhealthy lifestyle is associated with increased prevalence of macro- and micro-vascular comorbidities in Taiwanese patients with long-duration type 2 diabetes.

Introduction We investigated the prevalence of undiagnosed diabetes and impaired fasting glucose (IFG) in individuals without known diabetes in Taiwan and developed a risk prediction model for identifying undiagnosed diabetes and IFG.Research design and methods Using data from a large population-based Taiwan Biobank study linked with the National Health Insurance Research Database, we estimated the standardized prevalence of undiagnosed diabetes and IFG between 2012 and 2020. We used the forward continuation ratio model with the Lasso penalty, modeling undiagnosed diabetes, IFG, and healthy reference group (individuals without diabetes or IFG) as three ordinal outcomes, to identify the risk factors and construct the prediction model. Two models were created: Model 1 predicts undiagnosed diabetes, IFG_110 (ie, fasting glucose between 110 mg/dL and 125 mg/dL), and the healthy reference group, while Model 2 predicts undiagnosed diabetes, IFG_100 (ie, fasting glucose between 100 mg/dL and 125 mg/dL), and the healthy reference group.Results The standardized prevalence of undiagnosed diabetes for 2012–2014, 2015–2016, 2017–2018, and 2019–2020 was 1.11%, 0.99%, 1.16%, and 0.99%, respectively. For these periods, the standardized prevalence of IFG_110 and IFG_100 was 4.49%, 3.73%, 4.30%, and 4.66% and 21.0%, 18.26%, 20.16%, and 21.08%, respectively. Significant risk prediction factors were age, body mass index, waist to hip ratio, education level, personal monthly income, betel nut chewing, self-reported hypertension, and family history of diabetes. The area under the curve (AUC) for predicting undiagnosed diabetes in Models 1 and 2 was 80.39% and 77.87%, respectively. The AUC for predicting undiagnosed diabetes or IFG in Models 1 and 2 was 78.25% and 74.39%, respectively.Conclusions Our results showed the changes in the prevalence of undiagnosed diabetes and IFG. The identified risk factors and the prediction models could be helpful in identifying individuals with undiagnosed diabetes or individuals with a high risk of developing diabetes in Taiwan.

Abstract The glucokinase regulator gene (GCKR) is located on chromosome 2p23. It plays a crucial role in maintaining plasma glucose homeostasis and metabolic traits. Recently, genome-wide association studies have revealed a positive association between hyperuricemia and GCKR variants in adults. This study investigated this genetic association in Taiwanese adolescents. Data were collected from our previous cross-sectional study (Taipei Children Heart Study). The frequencies of various genotypes (CC, CT, and TT) or alleles (C and T) of the GCKR intronic single-nucleotide polymorphism (SNP) rs780094 and the coding SNP rs1260326 (Pro446Leu, a common 1403C-T transition) were compared between a total of 968 Taiwanese adolescents (473 boys, 495 girls) with hyperuricemia or normal uric acid levels on the basis of gender differences. Logistic and linear regression analyses explored the role of GCKR in abnormal uric acid (UA) levels. Boys had higher UA levels than girls (6.68 ± 1.29 and 5.23 ± 0.95 mg/dl, respectively, p

IntroductionEndoplasmic reticulum (ER) stress has emerged as a key player in insulin resistance (IR) progression in skeletal muscle. Recent reports revealed that ER stress-induced the expression of protein disulfide isomerase family a member 4 (PDIA4), which may be involved in IR-related diseases. A previous study showed that metformin modulated ER stress-induced IR. However, it remained unclear whether metformin alleviated IR by regulating PDIA4 expression in skeletal muscle.MethodsHerein, we used palmitate-induced IR in C2C12 cells and a high-fat diet-induced IR mouse model to document the relations between metformin, IR, and PDIA4.ResultsIn C2C12 cells, palmitate-induced IR increased inflammatory cytokines and PDIA4 expression. Besides, knocking down PDIA4 decreased palmitate-induced IR and inflammation in C2C12 cells. Furthermore, metformin modulated PDIA4 expression and alleviated IR both in vitro and in vivo. In addition, serum PDIA4 concentrations are associated with IR and inflammatory cytokines levels in human subjects.DiscussionThus, this study is the first to demonstrate that PDIA4 participates in the metformin-induced effects on skeletal muscle IR and indicates that PDIA4 is a potential novel therapeutic target for directly alleviating IR.

Background: Numerous studies have shown that dipeptidyl peptidase-4 inhibitors (DPP-4i) may regulate immunological pathways implicated in asthma. The association between DPP-4i use and risk of asthma development is limited, however. Aim: We aimed to evaluate if DPP-4i treatment in individuals with type 2 diabetes mellitus (T2DM) is associated with a lower risk and severity of asthma. Methods: We performed a population-based retrospective cohort study using the Longitudinal National Health Insurance Research database between 2008 and 2015. After one-to-four propensity score matching from 1,914,201 patients with defined criteria, we enrolled 3001 patients who were on DPP-4i (DPP-4i group) for a diagnosis of T2DM but without a diagnosis of asthma for further analysis. Cox proportional hazards regression analysis was performed to estimate and compare the risk of developing and severity of asthma, including no acute exacerbations event (No-AE), acute exacerbations (AEs), status asthmaticus (Status), and required endotracheal intubation (ET-tube intubated), between the two groups. Results: The participants had a mean age of 66.05 ± 17.23 years and the mean follow-up time was 4.96 ± 4.39 years. The risk of asthma development was significantly lower in the DPP-4i group than in the non-DPP-4i group [adjusted hazard ratio (HR) = 0.65; 95% confidence interval (CI) = 0.29–0.83; p

Background: Diabetic patients are at high risk of developing cancer. Traditional Chinese medicine (TCM) has become increasingly popular as an adjuvant treatment for patients with chronic diseases, and some studies have identified its beneficial effect in diabetic patients with cancer. The purpoes of this study was to outline the potential of TCM to attenuate hospitalization and mortality rates in diabetic patients with carcinoma in situ (CIS). Methods: A total of 6,987 diabetic subjects with CIS under TCM therapy were selected from the National Health Insurance Research Database of Taiwan, along with 38,800 of 1:1 sex-, age-, and index year-matched controls without TCM therapy. Cox proportional hazard analysis was conducted to compare hospitalization and mortality rates during an average of 15 years of follow-up. Results: A total of 3,999/1,393 enrolled-subjects (28.62%/9.97%) had hospitalization/mortality, including 1,777/661 in the TCM group (25.43%/9.46%) and 2,222/732 in the control group (31.80%/10.48%). Cox proportional hazard regression analysis showed a lower rate of hospitalization and mortality for subjects in the TCM group (adjusted HR=0.536; 95% CI=0.367–0.780, P

A 35-year-old woman with unintentional weight gain, hyperpigmentation of bilateral palms, and general fatigue was initially suspected of Cushing’s syndrome or adrenal insufficiency based on the isolated elevation of the plasma adrenocorticotropic hormone (ACTH) level (113.0 pg/mL) in the Siemens ACTH Immulite assay (ACTH [Immulite]). However, both of the diagnoses were excluded by screening tests including the overnight dexamethasone suppression test, the 24-hour urinary free cortisol excretion, and the ACTH stimulation test in spite of the consistent elevation of the plasma ACTH levels. We speculated that the existence of the immunoassay interference may be the underlying cause because the plasma ACTH level analyzed by the CIS Bio International ELSA-ACTH immunoassay (ELSA-ACTH) was within the normal range. After reviewing our case and several reported cases of falsely elevated plasma ACTH levels, we conclude that when discrepancy between clinical symptoms and laboratory measurements exists, medical practitioners ought to rely on formal diagnostic criteria rather than misleading laboratory results to avoid misdiagnosis or even unnecessary invasive testing and procedures. In addition, current methods for investigation and elimination of immunoassay interferences should be applied with caution due to variable efficacy and inevitable deviations.

Abstract Aims/Introduction Obesity is characterized by disturbed adipocytokine expression and insulin resistance in adipocytes. Growth arrest‐specific 6 (GAS6) is a gene encoding the Gas6 protein, which is expressed in fibroblasts, and its related signaling might be associated with adipose tissue inflammation, glucose intolerance and insulin resistance. The aim of this study was to investigate the associations among Gas6, adipocytokines and insulin resistance in adipocytes. Materials and Methods Mature Simpson Golabi Behmel Syndrome adipocytes were treated with high levels of insulin to mimic insulin resistance, and were examined for the expressions of Gas6, cytokines and adipocytokines from preadipocytes in differentiation. In an animal study, high‐fat diet‐induced obese mice were used to verify the Gas6 expression in vitro. Results During the differentiation of adipocytes, the expression of Gas6 gradually decreased, and was obviously downregulated with adipocyte inflammation and insulin resistance. Gas6 levels were found to be in proportion to the expression of adiponectin, which has been regarded as closely relevant to improved insulin sensitivity after metformin treatment. Similar results were also confirmed in the animal study. Conclusions Our results suggest that Gas6 might modulate the expression of adiponectin, and might therefore be associated with insulin resistance in adipose tissues.

In articular cartilage-repair, grafts usually fuse unsatisfactorily with surrounding host cartilage. Enzymatic dissociation of cartilaginous matrix to free chondrocytes may benefit fusion. We tested such a hypothesis with human cartilage in vitro, and with porcine cartilage in vivo. Human articular cartilage was collected from knee surgeries, cut into disc-and-ring sets, and randomly distributed into three groups: disc-and-ring sets in Group 1 were left untreated; in Group 2 only discs, and in Group 3 both discs and rings were treated with enzyme. Each disc-and-ring reassembly was cultured in a perfusion system for 14 days; expression of cartilage marker proteins and genes was evaluated by immunohistochemistry and PCR. Porcine articular cartilage from knees was similarly fashioned into disc-and-ring combinations. Specimens were randomly distributed into a control group without further treatment, and an experimental group with both disc and ring treated with enzyme. Each disc-and-ring reassembly was transplanted into subcutaneous space of a nude mouse for 30 days, and retrieved to examine disc-ring interface. In in vitro study with human cartilage, a visible gap remained at disc-ring interfaces in Group 1, yet became indiscernible in Group 2 and 3. Marker genes, including type II collagen, aggrecan and Sox 9, were well expressed by chondrocytes in all specimens, indicating that chondrocytes’ phenotype retained regardless of enzymatic treatment. Similar results were found inin vivo study with porcine cartilage. Enzymatic dissociation of cartilaginous matrix promotes fusion of adjacent cartilage. The clinical relevance may be a novel method to facilitate integration of repaired cartilage in joints.

Background: In the past decade, Tri-Service General Hospital has trained many actors-background standardized patients (SPs). However, we also have recruited some nonactor SPs since 2010. Reviewing the literature, the reliability of SPs with or without actor background would be the impact factor on high-stakes OSCE has not been well studied. Aim: The purpose of this retrospective observation is to clarify whether a SP with or without a professional actor background will affect the performances of the examination when participating in the Taiwan high-stakes objective structured clinical examination (OSCE). The result will be the policy for selecting which kind of SPs to participate in the high-stack OSCE in our hospital. Methods: In this retrospective observation, we analyzed 74 actor background SPs (A-SPs), and 70 no actor background SPs (NA-SPs) who have participated in each spring test of 2015–2017 Taiwan high-stakes OSCE. The data of SPs performance have come from two parts: one is from the examinee with the global rating of the SPs performance and the other is from the examiner with eight-item checklist for the SPs performance. The scoring of both examinee and examiner is a five-point Likert scale. Results: The results show that there is no significant difference in SPs performance from the examinee scoring in the subsequent 3 years, stable and satisfactory, and let examinees feel like real patients. The scores from examiners also showed that two groups of SPs performed equally well without significant differences. Their performance is reliable and consistent, simulating to be a real patient in both groups. However, only one interest finding, when compared to the different age subdivision of SPs, showed the aged subgroup of A-SPs and NA-SPs with the significant difference in the item of reliability and consistent (4.67 ± 0.53 vs. 4.41 ± 0.50, P < 0.05), the possible reason is related to the less-experienced associate with mild memory decline in aged NA-SPs.Conclusions: Our observation gives the essential information, that the well-trained and experienced SP are necessary for participating in the high-stakes OSCE examination, even without the background of the actor. What we need is a professional SP who not only has excellent professionalism but also has a good personality literacy to engage in his/her work.

Abstract Background Increasing evidence suggests that high glucose (HG) causes abnormalities in endothelial and vascular smooth muscle cell function (VSMC) and contributes to atherosclerosis. Receptor for advanced glycation end-products (RAGE) has been linked to the pathogenesis of both the macrovascular and microvascular complications of diabetes. Cilostazol is used to treat diabetic vasculopathy by ameliorating HG-induced vascular dysfunction. Objectives In this study, we investigated whether the cilostazol suppression of HG-induced VSMC dysfunction is through RAGE signaling and its possible regulation mechanism. Method We investigated the effect of HG and cilostazol on RAGE signaling in A7r5 rat VSMCs. Aortic tissues of streptozotocin (STZ) diabetic mice were also collected. Results Aortic tissue samples from the diabetic mice exhibited a significantly decreased RAGE expression after cilostazol treatment. HG increased RAGE, focal adhesion kinase (FAK), matrix metalloproteinase-2 (MMP-2), intercellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) expressions, and was accompanied with increased reactive oxygen species (ROS), cell proliferation, adhesion and migration. Cilostazol significantly reversed HG-induced RAGE, ROS, downstream gene expressions and cell functions. RAGE knockdown significantly reversed the expressions of HG-induced vasculopathy related gene expressions and cell functions. Cilostazol with RAGE knockdown had additive effects on downstream ERK/NF-κB signaling pathways, gene expressions and cell functions of A7r5 rat VSMCs in HG culture. Conclusions Both in vitro and in vivo experimental diabetes models showed novel signal transduction of cilostazol-mediated protection against HG-related VSMC dysfunction, and highlighted the involvement of RAGE signaling and downstream pathways.

Background: Diabetic kidney disease is a major cause of uremia worldwide; recently, controversial roles for growth arrest-specific protein 6 (GAS 6) have been revealed in the pathogenesis of diabetic nephropathy. A better understanding of the association between GAS6 and diabetic nephropathy may lead to the development of novel therapeutic approaches for the prevention and treatment of diabetic uremia. Objectives: The aim of this study was to investigate the levels of GAS6 and its role in uremic patients with Type 2 diabetes. Materials and Methods: A total of 109 adults were recruited, of whom 23 had Type 2 diabetes and uremia and 56 had newly diagnosed Type 2 diabetes without remarkable nephropathy; thirty individuals with normal glucose tolerance without significant clinical comorbidities served as controls. Plasma GAS6 concentration and common anthropometric and biochemical variables were analyzed. Results: Plasma GAS6 levels were significantly lower in patients with Type 2 diabetes than in controls regardless of nephropathy (P < 0.001). A trend in declined level of GAS6 among the three groups was also observed. In addition, GAS6 levels were significantly inversely correlated with plasma creatinine, blood urea nitrogen, and uric acid levels in all patients (P < 0.01 for all comparisons). In multivariate logistic regression analysis, higher plasma GAS6 concentration was significantly associated with decreased risk of diabetic uremia, even after adjusting for age, sex, and fasting glucose (C-statistic, 0.72; 95% confidence interval 0.57–0.92; P < 0.01). Conclusions: Our results suggest that plasma GAS6 levels are associated with Type 2 diabetes and may play a role in development of diabetic uremia.

Summary: Background: Diabetes is characterized by increased insulin resistance (IR) and decreased insulin secretion. The roles of glucose effectiveness (GE), first- and second-phase insulin secretion (FPIS, SPIS) are often overlooked. We denote these factors as diabetic factors (DF). Hemoglobin (Hb) has been shown to be related to IR and FPIS, but not to SPIS and GE. The aims of this study are to investigate the relationships between Hb and DFs and to compare which one has the tightest correlation with Hb in old Chinese. Methods: We randomly enrolled 5109 men and 5851 women, whose age were over 65 years old. Subjects, who were obese or on medications, were excluded. Simple correlation was applied to evaluate the relationships between Hb and 4 DFs. To compare the relative tightness between each correlation lines, all the units of the DFs were transformed into percentage. Results: All the biochemistry data were higher in subjects with metabolic syndrome (MetS) in both genders, except for GE and HDL. Similar trends were also noted when dividing subjects into quartiles of Hb. The results of simple correlation showed that all the DFs are significantly related to Hb except for FPIS in women. The association between Hb and GE is negative. After transforming the different units into percentage, the relationships with Hb, from the highest to lowest, were IR, SPIS, GE and FPIS in both genders. Conclusion: Our data show that all DFs are almost related to Hb. IR has the tightest correlation with Hb in old Chinese. Keywords: hemoglobin, insulin resistance, glucose effectiveness, first-phase insulin secretion and second-phase insulin secretion

Background: Meniscus tissue engineering has yet to achieve clinical application because it requires chondrogenic induction and in vitro cell expansion. Contrarily, cartilage engineering from autologous chondrocytes has been successfully applied in one-stage surgery. If the natural chondrogenic potential of meniscus cells can be demonstrated, meniscus tissue engineering would have more value in clinical settings. Materials and Methods: In total, 10 menisci and pieces of cartilage were obtained during total knee replacements. The tissues were collected for cell isolation and expansion. Their chondrogenic properties were examined by immunohistofluorescence and gene expression analyses. Results: In native cartilage, immunofluorescence demonstrated the presence of collagen I, aggrecan, and traces of collagen I, whereas comparable staining was seen in the inner and middle meniscus. The presence of collagen I but the absence of collagen II and aggrecan were observed in the outer meniscus. In passage 2, chondrocytes showed the presence of collagen II and aggrecan, and the absence of vimentin. The vimentin and aggrecan staining were comparable in the inner and middle meniscus cells, whereas the outer cells showed only vimentin staining. In the gene expression analyses, the expressions of collagen II and aggrecan in the native chondrocyte and the inner and middle meniscus were higher than those of the cells from the outer meniscus, but they were not different in collagen I. In the passage 2 culture, chondrocytes had a higher expression of collagen II and aggrecan than the meniscus cells. Cells from the inner and middle areas had higher collagen II and aggrecan expression than those from the outer meniscus. Conclusion: Without chondrogenic induction, inner and middle meniscus cells possess a chondrogenic phenotype. Specifically, native meniscus cells exhibited more robust chondrogenic potential compared with those of the passage 2 monolayer culture.

Obesity and regional adiposity are important risk factors for cardiometabolic disorders. The aim of this study is to compare 7-site skinfold (SF) measurement to dual-energy x-ray absorptiometry (DXA) as the reference method for estimating body fat percentage (BF%) and regional adiposity in diabetic outpatients. A total of 59 diabetic patients (36 females and 23 males) aged 28.5-78 years (median 67.7 years) with BMI 18.8-40.6 kg/m2 (median: 25.5 kg/m2) were enrolled. 7-site skinfold measurement and DXA were performed at the same visit day and biochemistry data were collected. Our results demonstrate the BF% calculated via Jackson & Pollock 7-site skinfold equation presents a strong correlation (r = 0.672, p < 0.001 in females; r = 0.885, p < 0.001 in males) with that measured by DXA, but the means of BF% between these two methods are significantly different in both sexes (paired t-test, p < 0.001). The Bland-Altman analysis showed the mean differences (DXA-SF) of BF% were positive for female (8.74%) and male (7.22%), suggesting Jackson & Pollock 7-site skinfold equation tends to underestimate the BF%. Besides, regional SF thicknesses of 7-site skinfold measurement were significantly correlated with the matched regional adiposity quantified by DXA. Furthermore, truncal and android SF thicknesses were notably positively correlated with several cardiometabolic risk factors in gender-specific manner. Our data indicate the 7-site skinfold measurement is not an interchangeable method for precisely measuring BF%, but might be practical for evaluating the cardiometabolic risks in Taiwanese diabetic outpatients.

Aims: The first aim of the present study is to evaluate the current glycemic control and characteristics of overall and newly diagnosed diabetes mellitus (DM) population from two cohorts population (2011–2012 and 2014–2015). Furthermore, the hemoglobin A1C (HbA1C) levels of newly diagnosed in these two cohorts population will be also compared to HbA1C levels on 2013 in subjects of previous diagnosed DM ongoing therapy. Settings and Design: This is a retrospective observational cohort study. Subjects and Methods: All of the data come from the Nauru Diabetes Registry database from Nauru Public Health Center from 2011 to 2015. All patients with their HbA1C will be analyzed and compared between year of 2011–2012 and 2014–2015. Statistical Analysis Used: Descriptive results of continuous variables will be expressed as means ± standard deviation. We use unpaired t-test for comparisons of quantitative variables. A two-tailed P < 0.05 was considered statistically significant. The statistical analyses will be performed using the program SPSS (Chicago, Illinois, USA; version 18.0). Results: A total of 614 patients were enrolled for the analysis with mean age of 49.8 year old and mean diabetic duration of 10.1 years. The mean age of onset of DM is 40.4 year old. The female population had long duration of DM than male population. The overall HbA1C levels are slightly greater in 2014–2015 than 2011–2012 without statistical significance (10.9% ± 2.7% and 10.6% ± 2.2%, respectively). The HbA1C levels also do not differ among DM patients with regular outpatient visits. The mean HbA1C of newly diagnosed DM is significant higher in 2014-15 than that in 2011-2012 (11.5% ± 2.4 and 10.6% ± 2.1%, respectively, P = 0.039), but not different from HbA1C levels in 2013 in DM patients who received ongoing treatment (10.9% ± 2.3%). Furthermore, HbA1C worsened significantly in 2 of the 15 districts between 2011–2012 and 2014–2015. Conclusions: Nauru has a high prevalence rate with early onset and inadequately controlled diabetes. It needs to propose strategy to early detect and improve glycemic control early to prevent future diabetic complications.

Recent evidence has suggested that synovial inflammation and macrophage polarization were involved in the pathogenesis of osteoarthritis (OA). Additionally, high-molecular-weight hyaluronic acid (HMW-HA) was often used clinically to treat OA. GRP78, an endoplasmic reticulum (ER) stress chaperone, was suggested to contribute to the hyperplasia of synovial cells in OA. However, it was still unclear whether HMW-HA affected macrophage polarization through GRP78. Therefore, we aimed to identify the effect of HMW-HA in primary synovial cells and macrophage polarization and to investigate the role of GRP78 signaling. We used IL-1β to treat primary synoviocytes to mimic OA, and then treated them with HMW-HA. We also collected conditioned medium (CM) to culture THP-1 macrophages and examine the changes in the phenotype. IL-1β increased the expression of GRP78, NF-κB (p65 phosphorylation), IL-6, and PGE2 in primary synoviocytes, accompanied by an increased macrophage M1/M2 polarization. GRP78 knockdown significantly reversed the expression of IL-1β-induced GRP78-related downstream molecules and macrophage polarization. HMW-HA with GRP78 knockdown had additive effects in an IL-1β culture. Finally, the synovial fluid from OA patients revealed significantly decreased IL-6 and PGE2 levels after the HMW-HA treatment. Our study elucidated a new form of signal transduction for HMW-HA-mediated protection against synovial inflammation and macrophage polarization and highlighted the involvement of the GRP78-NF-κB signaling pathway.

OBJECTIVES:Traits of metabolic syndrome (MetS) and biomarkers of inflammation and endothelial dysfunction were examined. We investigated the differences of various biomarkers among individuals with or without Mets in a gender-specific manner. The gender-specific associations between E-selectin and MetS were further evaluated. METHODS:A total of 205 patients were recruited from the outpatient clinics of Tri-Service General Hospital, Taipei, Taiwan. Inclusion criteria were age between 20-75 years and BMI < 35 kg/m2. Demographic, anthropometric and MetS index data were compared between genders. Markers of inflammation and endothelial dysfunction were compared between individuals with or without MetS by gender. RESULTS:Age-adjusted E-selectin values showed significant positive correlations with BMI, waist-hip ratio, fasting plasma glucose, systolic and diastolic blood pressure, triglycerides, TNF-α, hsCRP and ICAM-1, and inverse correlation with HDL cholesterol. E-selectin levels were positively correlated with numbers of MetS components in females (P < 0.001) but not in males (P = 0.125). CONCLUSIONS:Increased E-selectin levels are significantly associated with increased MetS risk in females, but not in males.

Objective: Hematological parameters play a significant role in metabolic syndrome (MetS) and its development in the elderly, but the association and different ability of each parameter to predict MetS have not been investigated in the very old populations. Subjects and Methods: This cross-sectional and longitudinal study included 18,907 participants aged over 65 years and followed up until MetS development with a mean duration of 4 years from the entry date. MetS was diagnosed according to the latest harmonized criteria with modification for waist circumference. Correlations between hematological parameters and MetS were analyzed and operating characteristic curves were compared among each parameter. Stratification was conducted by gender and age as follows: young-old (65-74 years), old-old (75-84 years), and oldest-old (85-94 years). Results: White blood cell count (WBC) and hemoglobin (Hb) levels in both genders of young-old (65-74 years) and old-old (75-84 years) and platelet (PLT) in young-old (65-74 years) males were independent factors for risk of MetS. However, only WBC (P < 0.001) and Hb level (P < 0.001) in young-old (65-74 years) males and Hb level (P = 0.03) in old-old (75-84 years) females were independent factors of future MetS development. For predicting MetS, WBC and Hb levels were better markers than PLT in the old-old (75-84 years) and young-old (65-74 years) males group. In young-old (65-74 years) females, WBC was the most sensitive marker. Conclusions: Hematological parameters were associated with MetS, showing gender and age effects. These findings can be used for risk estimation of MetS development in the older population.

Osteoarthritis (OA) is the most common form of arthritis associated with an increased prevalence of type 2 diabetes mellitus (T2DM), however their impact on decreasing joint replacement surgery has yet to be elucidated. This study aimed to investigate if the combination of COX-2 inhibitor and metformin therapy in OA with T2DM were associated with lower the rate of joint replacement surgery than COX-2 inhibitor alone.In total, 968 subjects with OA and T2DM under COX-2 inhibitor and metformin therapy (case group) between 1 January to 31 December 2000 were selected from the National Health Insurance Research Database of Taiwan, along with 1936 patients were the 1:2 gender-, age-, and index year-controls matched without metformin therapy (control group) in this study. Cox proportional hazards analysis was used to compare the rate of receiving joint replacement surgery during 10 years of follow-up.At the end of follow-up, 438 of all enrolled subjects (15.08%) had received the joint replacement surgery, including 124 in the case group (12.81%) and 314 in the control group (16.22%). The case group tended to be associated with lower rate of receiving the joint replacement surgery at the end of follow-up than the control group (p = 0.003). Cox proportional hazards regression (HR) analysis revealed that study subjects under combination therapy with metformin had lower rate of joint replacement surgery (adjusted HR 0.742 (95% CI = 0.601-0.915, p = 0.005)). In the subgroups, study subjects in the combination metformin therapy who were female, good adherence (>80%), lived in the highest urbanization levels of residence, treatment in the hospital center and lower monthly insurance premiums were associated with a lower risk of joint replacement surgery than those without.Patients who have OA and T2DM receiving combination COX-2 inhibitors and metformin therapy associated with lower joint replacement surgery rates than those without and this may be attributable to combination therapy much more decrease pro-inflammatory factors associated than those without metformin therapy.

The present study evaluated the relative influence of body mass index (BMI) on insulin resistance (IR), first-phase insulin secretion (FPIS), second-phase insulin secretion (SPIS), and glucose effectiveness (GE) at a fixed fasting plasma glucose level in an older ethnic Chinese population.In total, 265 individuals aged 60 years with a fasting plasma glucose level of 5.56 mmol/L were enrolled. Participants had BMIs of 20.0-34.2 kg/m2. IR, FPIS, SPIS, and GE were estimated using our previously developed equations. Pearson correlation analysis was conducted to assess the correlations between the four diabetogenesis factors and BMI. A general linear model was used to determine the differences in the percentage of change among the four factor slopes against BMI.Significant correlations were observed between BMI and FPIS, SPIS, IR, and GE in both women and men, which were higher than those reported previously. In men, BMI had the most profound effect on SPIS, followed by IR, FPIS, and GE, whereas in women, the order was slightly different: IR, followed by FPIS, SPIS, and GE. Significant differences were observed among all these slopes, except for the slopes between FPIS and SPIS in women (p = 0.856) and IR and FPIS in men (p = 0.258).The contribution of obesity to all diabetes factors, except GE, was higher than that reported previously. BMI had the most profound effect on insulin secretion in men and on IR in women in this 60-year-old cohort, suggesting that lifestyle modifications for obesity reduction in women remain the most important method for improving glucose metabolism and preventing future type 2 diabetes mellitus.

[This corrects the article DOI: 10.1371/journal.pone.0189115.].

Background/Aims: Nonalchoholic fatty liver disease (NAFLD) has been reported as a hepatic manifestation of metabolic syndrome (MetS); it is common and accounts for 80% of the cases with abnormal liver function tests (LFTs). In addition, several studies have proved that there is a correlation between abnormal LFTs and MetS. Therefore, LFTs may represent the abnormal metabolic status of livers in the patients with MetS. To identify the early state of metabolic dysfunction, we investigate the value of LFTs for the future MetS development in the relatively healthy (non-NAFLD) elderly. Patients and Methods: A total of 16,912 subjects met the criteria for analysis. In the first stage of this study, subjects were enrolled in the cross-sectional study in order to find out the optimal cutoff value in different LFTs with higher chances to have MetS. In the second stage of the present study, subjects with MetS at baseline were excluded from the same study group, and a median 5.6-year longitudinal study was conducted on the rest of the group. Results: Among all LFTs, only aspartate aminotransferase in both genders and the α-fetal protein in women failed to show the significance in distinguishing subjects with MetS by the receiver operating characteristic curve. In the Kaplan-Meier plot, only γ-glutamyl transpeptidase (γ-GT) in men and the alanine aminotransferase (ALT) in women could be used to successfully separate subjects with higher risk of developing the MetS from those with lower risk. Finally, in the multivariant Cox regression model, similar results were identified. Still, the hazard ratio (HR) to have future MetS, γ-GT in men, and ALT in women showed significance (HR = 1.511 in men and 1.504 in women). Conclusion: Among all the different LFTs, γ-GT (>16 U/L) in male and ALT (>21 U/L) in female were the best predictors for the development of MetS in healthy elderly. These two liver markers could be an ancillary test in predicting future MetS development/diagnosis. Elevation of the LFTs without underlying liver diseases should be treated as a warning sign of the possible MetS development in the elderly.

Protein disulfide isomerase (PDI) family members are specific endoplasmic reticulum proteins that are involved in the pathogenesis of numerous diseases including neurodegenerative diseases, cancer and obesity. However, the metabolic effects of PDIA4 remain unclear in humans. The aims of this study were to investigate the associations of serum PDIA4 with the metabolic syndrome (MetS) and its components in Chinese adults.A total of 669 adults (399 men and 270 women) were recruited. Serum PDIA4 concentrations and biochemical variables were recorded. Insulin sensitivity and β-cell function were examined by homeostasis model assessment. MetS was defined based on the modified National Cholesterol Education Program Adult Treatment Panel III criteria for Asia Pacific.The participants with MetS had significantly higher serum PDIA4 levels than those without MetS (P

Chang-Hsun Hsieh1, Yi-Jen Hung1, Dee Pei2, Shi-Wen Kuo3, Eugene Lin41Division of Endocrinology and Metabolism, Tri-Service General Hospital, Taipei; 2Division of Endocrinology and Metabolism, Cardinal Tien Hospital, Taipei County; 3Division of Endocrinology, Buddhist Xindian Tzu Chi General Hospital, Taipei; 4Vita Genomics Inc., Wugu Shiang, Taipei, TaiwanAbstract: Nowadays diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). Recent studies have demonstrated that the myosin, heavy chain 9, non-muscle (MYH9) gene is associated with ESRD in African Americans. In this study, we tested the hypothesis that a common single nucleotide polymorphism rs16996677 in the MYH9 gene may contribute to the etiology of DN in type 2 diabetes (T2D) in a Taiwanese population with T2D. There were 180 T2D patients diagnosed with DN and 178 age- and sex-similar T2D without DN controls. Single locus analyses showed no significant main effects of MYH9 rs16996677 on the risk of DN in T2D. The results suggest that the rs16996677 SNP in MYH9 may not contribute to the risk of DN in T2D in Taiwanese T2D patients.Keywords: diabetic nephropathy, end-stage renal disease, single nucleotide polymorphisms, type 2 diabetes

Aims. There are two phases of insulin secretion, the first (FPIS) and second phase (SPIS). In this study, we built equations to predict FPIS with metabolic syndrome (MetS) components and fasting plasma insulin (FPI). Methods. Totally, 186 participants were enrolled. 75% of participants were randomly selected as the study group to build equations. The remaining 25% of participants were selected as the external validation group. All participants received a frequently sampled intravenous glucose tolerance test, and acute insulin response after the glucose load (AIRg) was obtained. The AIRg was considered as FPIS. Results. When MetS components were only used, the following equation was built: log (FPIS) = 1.477 − 0.119 × fasting plasma glucose (FPG) + 0.079 × body mass index (BMI) − 0.523 × high-density lipoprotein cholesterol (HDL-C). After FPI was added, the second equation was formulated: log (FPIS) = 1.532 − 0.127 × FPG + 0.059 × BMI - 0.511 × HDL-C + 0.375 × log (FPI), which provided a better accuracy than the first one. Conclusions. Using MetS components, the FPIS could be estimated accurately. After adding FPI into the equation, the predictive power increased further. We hope that these equations could be widely used in daily practice.

Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored.Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years.The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development.Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.

The present study was designed to explore the effects of GAS6 and AXL gene polymorphisms on adiposity, systemic inflammation, and insulin resistance in adolescents. After multistage sampling from the data of the Taipei Children Heart Study-III, we collected 358 boys and 369 girls with an average age of 13.3 years. We genotyped the adolescents’ GAS6 rs8191973, GAS6 rs8191974, AXL rs4802113, and AXL rs2304232 polymorphisms. Significantly higher body mass index (BMI), waist circumference (WC), and hsCRP levels were found in boys with the GG genotype of GAS6 rs8191974 than A allele carriers; higher IL-6 and insulin levels and increased HOMA-IR were found in boys with the GG genotype of AXL rs2304232 than the A allele carriers. There was a significant difference in hsCRP levels of boys with the TT, TC, and CC genotypes of AXL rs4802113. Boys with both the GG genotype of GAS6 rs8191973 and the GG genotype of GAS6 rs8191974 exhibited higher BMI, WC, IL-6, and hsCRP levels than the boys carrying both the C allele of the GAS6 rs8191973 and the A allele of the GAS6 rs8191974. In conclusion, GAS6 and AXL polymorphisms are associated with adiposity, systemic inflammation, and insulin resistance in adolescents, especially in boys.

The aim of this cross-sectional study was to investigate the relationship between soluble form of receptor for advanced glycation end products (sRAGE), obesity, and metabolic syndrome (MetS) in adolescents. A total of 522 male and 561 female adolescents were enrolled into the final analyses. Anthropometric parameters, blood pressure, blood biochemistry, fasting insulin, and plasma sRAGE levels were measured. In males, sRAGE was significantly and inversely correlated with waist circumference (WC), body mass index (BMI), systolic blood pressure, triglyceride (TG), low density lipoprotein cholesterol (LDL-C), and homeostasis model assessment-insulin resistance (HOMA-IR). Only WC and BMI were significantly and inversely correlated with sRAGE in females. Using linear regression analysis adjusting for age and gender, significant association was found between sRAGE and WC, BMI, TG, LDL-C, and HOMA-IR in adolescents of either gender (P

Little is known about iodine nutritional status in island countries in the Pacific Ocean. The primary objective of this study was to report for the first time the iodine nutritional status of people in Nauru. In addition, sources of iodine nutrition (i.e., water and salt) were investigated. A school-based cross-sectional survey of children aged 6–12 years was conducted in three primary schools of Nauru. Urinary iodine concentration (UIC) was determined by spot urine samples. Available water and salt samples in Nauru were collected for the measurement of iodine content. A food frequency questionnaire was conducted. The median UIC was 142 μg/L, and 25.2% and 7.4% of the population had median UIC below 100 μg/L and 50 μg/L, respectively. Natural iodine-containing foods such as seaweeds and agar were rare. Iodine was undetectable in Nauruan tank water, filtered tap water, and raindrops. Of the analyzed salt products, five kinds were non-iodized, and three were iodized (iodine content: 15 ppm, 65 ppm, and 68 ppm, respectively). The results indicate that the iodine status in Nauruan school children is adequate. Iodized salt may serve as an important source of iodine nutrition in Nauru.

ABSTRACT Objective We denote the four major factors related to the development of type 2 diabetes (T2D) as “diabetes factor” (DF); increased insulin resistance (IR); decreased glucose effectiveness (GE); and the first-and-second-phase of insulin secretion (FPIS, SPIS). The level of hemoglobin (Hb) was found to be related to IR and FPIS, but no-known studies focused on its role in relation to SPIS and GE. In this study, we aim to evaluate the relationships between Hb and all four DFs in the same individual. Subjects and methods We randomly enrolled 24,407 men and 24,889 women between 30 and 59 years old. IR, FPIS, SPIS and GE were measured according to equations published in our previous studies. To compare the slopes between Hb and the four DFs with different units, we converted their units to percent of change per unit of increased Hb. Results Age, HDL-cholesterol and GE were higher in women; BMI, blood pressure, LDL-cholesterol, TG, Hb, FPIS, SPIS and IR were higher in men. After they were converted into percentage, the closeness of their relationships to Hb, from the highest to the lowest, were GE, IR, FPIS and SPIS for women and IR, GE, FPIS and SPIS for men. GE was the only one negatively related to Hb. Conclusions Our data showed that IR, FPIS and SPIS were both positively and, GE negatively, related to the Hb in adult Chinese. For women, GE had the closest association with Hb; for men, it was IR. Both phases of insulin secretion had relatively weaker relationships than IR and GE.

Context: There is a medical need for effective insulin-independent antidiabetic drugs that can promote pancreatic β-cell function and have a low risk of hypoglycemia in type 2 diabetes mellitus (T2DM) patients. R-form verapamil (R-Vera), which is able to enhance the survival of β-cells and has higher cardiovascular safety margin compared with racemic verapamil, was developed as a novel approach for T2DM treatment. Objective: This randomized, double-blind, placebo-controlled clinical trial was designed to evaluate the efficacy and safety of 3 dosages of R-Vera added to ongoing metformin therapy in T2DM patients who had inadequate glycemic control on metformin alone. Methods: Participants were randomly assigned in an equal ratio to receive R-Vera 450, 300, or 150 mg per day, or matching placebo, in combination with metformin. The primary endpoint was change in hemoglobin A1c (HbA1c) after 12 weeks of treatment. Results: A total of 184 eligible participants were randomized to receive either R-Vera or placebo plus metformin. At week 12, significant reductions in HbA1c were observed for R-Vera 300 mg/day (-0.36, P = 0.0373) and 450 mg/day (-0.45, P = 0.0098) compared with placebo. The reduction in HbA1c correlated with decreasing fasting plasma glucose levels and improved HOMA2-β score. Treatment with R-Vera was well tolerated with no hypoglycemic episodes occurring during the trial. Conclusion: Addition of R-Vera twice daily to ongoing metformin therapy significantly improved glycemic control in T2DM patients. The favorable efficacy and safety profile of R-Vera 300 mg/day can be considered as the appropriate dose for clinical practice. [ABSTRACT FROM AUTHOR]

Background: Patients with diabetes have a relatively high risk of fracture due to osteoporosis. However, the risk of osteoporosis associated with the use of oral hypoglycemic drugs and dipeptidyl peptidase-4 inhibitor (DPP-4i) by patients with diabetes is unclear. This study aimed to explore the effect of DPP-4i on the risk of osteoporosis in Taiwanese patients with type 2 diabetes mellitus (T2DM). Methods: This study enrolled 6339 patients on DPP-4i (DPP-4i group) and 25 356 patients without DPP-4i (non-DPP-4i group). They were matched by 1:4 propensity score matching, using confounding variables including sex, age, comorbidities, medication, and index year. Cox proportional hazards analysis was used to compare hospitalization and mortality during an average follow-up period of 7 years. Results: The mean age of patients in the two groups was 66 years. Men were slightly higher in number (51.79%) than women. At the end of the follow-up period, 113 (0.36%) patients had osteoporosis, of which 15 (0.24%) were in the case group and 98 (0.39%) in the control group. The risk of all-cause osteoporosis was significantly lower in the DPP-4i group than in the non-DPP-4i group (adjusted hazard ratio [HR] 0.616; 95% confidence interval [CI] 0.358--0.961; p = 0.011). Kaplan--Meier analysis showed that the preventive effect on osteoporosis was positively correlated with the cumulative dose of DPP-4i (log-rank, p = 0.039) with the class effect. Conclusion: Compared with not using DPP-4i, the use of DPP-4i in Taiwanese T2DM patients was associated with a lower risk of osteoporosis due to the class effect, and the preventive effect was dose-dependent. However, larger prospective studies are needed to validate this finding and to explore the possible mechanism of the preventive effect of DPP-4i. [ABSTRACT FROM AUTHOR]

Chronic inflammation, a hallmark of gout, is implicated in the pathogenesis of atherosclerosis. Thus, in theory, gout can be expected to increase the risk of acute myocardial infarction (AMI). Yet, results from several epidemiological studies have been inconclusive. A retrospective cohort study was conducted using the National Health Insurance Research Database of Taiwan dated from 2000 to 2013. The study cohort comprised 3581 patients with gout (the gout cohort) and 14,324 patients without gout (the non-gout cohort). The primary outcome was the incidence of AMI. To estimate the effect of gout on the risk of AMI, the Lunn-McNeil competing risk model was fitted to estimate cause-specific hazard ratios (HRs) and their 95% confidence intervals (CIs). The cumulative incidence of AMI was significantly higher in the gout cohort than in the non-gout cohort, resulting in an adjusted HR of 1.36 (95% CI 1.04 to 2.76). Further, HRs of gout with incident AMI were higher in patients without hypertension, diabetes mellitus, or hyperlipidemia (ranging from 1.63 to 2.09) than in those with each of these comorbidities (ranging from 0.95 to 1.13). The results of this study suggest that patients with gout have an increased risk of AMI. The AMI risk associated with gout was conditional on patients’ cardiovascular risk profile. Future work is needed to confirm these findings. [ABSTRACT FROM AUTHOR]

Background. Type 2 diabetes (T2D) is known to be one of the most prevalent diseases, and its prevalence is significantly associated with age and metabolic syndrome (MetS). Few studies have been conducted on liver function, MetS and insulin secretion among young adults. Objectives. In the present study, we explored the relationship between the liver function enzyme - alanine aminotransferase (ALT) - and first-phase insulin secretion (FPIS) among young adults. Material and methods. There were 22,971 men and 28,740 women, aged 18-27 years, assigned to subgroups according to the presence of MetS and quartiles of ALT values. Simple correlation was applied to evaluate their relationship. The difference between the slopes of these relationships and FPIS were statistically analyzed with Chris's calculator. Results. Most values for metabolic parameters, including ALT and FPIS, were determined to be relatively high in individuals with MetS. By contrast, individuals with MetS had lower high-density-lipoprotein cholesterol (HDL-C) counts and FPIS. Similar results were observed in the quartiles of ALT. Significant positive results were also found in the linear model. Depending on the ALT level, the slope change of FPIS still demonstrated a positive correlation between ALT and FPIS. This correlation was stronger for men than for women. Conclusions. A positive correlation between ALT and FPIS exists among young adults. Moreover, this correlation was stronger for men than for women. Both the cause and the effect require further investigation. [ABSTRACT FROM AUTHOR]